Journal of IiMER June 2024 What’s Next? Journal of IiMER Volume 14 Issue 1 June 2024 Invest in ME Research Invest in ME Research www.investinme.org Page 1 of 32

Journal of IiMER June 2024 CHAIRMAN’S MESSAGE We last published a journal in 2019 for the conference week in London – the last before the pandemic hit. The Journal, and conference week events, were always a good time to reflect on what progress had been made and discover what was happening in research. A great deal has happened since the pandemic began and some things have changed, although Myalgic Encephalomyelitis (ME) still faces the same issues as we have recorded over the last eighteen years since the charity was formed. This is plainly apparent from the findings of the European ME Alliance Pan-European ME Patient Survey, which was published, appropriately, on World Health Day 2024. We have the overview of findings from the report included in the Journal. Since 2005, the charity has maintained an unwavering commitment to driving significant strides in the field of ME research. How else could it be as the charity is run by volunteers - patients or parents of children with ME - no salaries, no government funding, not controlled by outside influences - but with wonderful supporters? As an independent UK charity facilitating and funding a strategy of high-quality biomedical research and promoting better education about ME, our journey has been marked by relentless dedication to using innovation to progress biomedical research. In this period, we have organised and hosted sixteen influential annual conferences, thirteen annual and progressive international biomedical research colloquiums, (a sequence broken only by the pandemic), and facilitated four early career researcher workshops. Notably, we have established the first Fellowship for ME, completed five PhDs, and are on the brink of initiating our second Fellowship. The charity is also funding the only clinical trial for ME in the UK, and is looking to fund more research that is on the way, embodying the urgency that defines our approach in translating research into tangible outcomes, where all of our income is used to fund and facilitate biomedical research into ME. Beyond borders, we have been involved in the recent NIH Roadmap Research programme and fostered and galvanised collaboration through the creation of European groups for patients, researchers, clinicians, and young Invest in ME Research DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME Research. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Page 2 of 32 INVEST IN ME RESEARCH PO Box 561 Eastleigh SO50 0GQ Hampshire, UK Email: info@investinme.org Web site: www.investinme.org UK charity Nr. 1153730 IN THIS ISSUE PAN-EUROPE SURVEY HIGHLIGHTS Journal of IiMER June 2024 researchers, driving international initiatives that support and strengthen our shared mission. Our work has facilitated the foundations of the Centre of Excellence for ME firmly in place in Norwich Research Park,a source of hope for advancing research and developing treatments. The one missing element – adequate funding – would expedite and complete our efforts for the benefit of all patients. In the last parliamentary debate on ME, we laid out a bold vision for research, proposing a substantial allocation to kick-start biomedical research and support the foundations that we have laid. We recently made a document to update all MPs on the opportunities that have been created. Likewise, we have made the case for investment in the centre in Norwich Research Park in the UK DHSC/UKCRC though, unfortunately, our ideas have neither been fully distributed nor discussed, resulting in no tangible progress being achieved in two years of meetings. Our involvement in the recent far more productive NIH Roadmap Research Programme has guided our Colloquium planning, shaping this year's theme - "Acknowledging the acceptance by both clinicians and researchers of 'THE INFECTIOUS AETIOLOGY’ of ME/CFS" focuses on uncovering the complexities of ME, exploring acute infection, chronic infection, and co-infection. And asking What's Next?' The conference and colloquium are ideal timing as they directly follow from the NIH Roadmap report to be published just before our International Conference Week - so much to discuss and plan. The colloquium, especially, has proven to be important in bringing together researchers. Last year was the first time that the charity had organised in person events in conference week since the pandemic began. Invest in ME Research In the 2017 Colloquium, a new approach had been established for structuring the presentations in sessions to focus more effort in determining the information that was relevant to making progress. Session chairs were tasked with asking presenters to consider - • What we know (proven) • What we think we know (unproven) • What we need to know • How (who?) should the gaps be filled? • How does this relate to other strategies/research? We were pleased to see that the recent NIH Roadmap of webinars during 2023-24 had adopted this same approach to use for structuring their webinars. Our colloquiums and conferences provide an international platform for education and collaboration - uniting professionals, patients, researchers, early-career researchers, doctors, nurses, the media, and ME - and bridging the clinical and research divide to focus on benefits for patients - a testament to our commitment to fostering collaboration and knowledge exchange over almost two decades. The name of our charity truly becomes the main calling for all interested in resolving this disease. Whatever the disappointing experiences from the last two years of the DHSC/UKCRC project we still believe there are the building blocks already in place in the UK and Europe which just require a little ambition and courage and one important factor – funding. What better slogan to use at this point in time than the one that this small charity has uniquely been promoting for so long? Time to #InvestinMEresearch. Welcome to our conference week. Kathleen McCall Page 3 of 32

Journal of IiMER June 2024 Philanthropy ….. is about 'giving' - not just in terms of funding. We are eternally grateful to those supporting the charity and to partners The Hendrie Foundation for their consistent and generous support for the RESTORE_ME clinical trial and other research at the centre; and to LunaNova for their funding of the LunaNova fellowship that begins this year. Also appreciated are non-monetary aspects, such as time, ideas, raising awareness of what the charity is trying to do, or being a volunteer. Our supporters have achieved and they deserve recognition for all their incredible support and efforts to bring change to the landscape of ME research and awareness. From WE - A Community and ME https://www.investinme.org/2019booklet.shtml The Irish ME Trust – Sponsor of #IIMEC16 A word of thanks to the Irish ME Trust who, yet again, will be sponsoring one of the speakers to the conference. IMET have been a constant friend and supporter of IiMER, and of ME patients. They have been a leading member in the European ME Alliance. The Irish ME Trust has sponsored every single Invest in ME Research International ME Conference Week and we would like to thank them for their continued support. We received very sad news as we planned the conference this year. Our good friend and valued and respected advocate for people with ME - 𝗠𝗶𝗰𝗵𝗮𝗲𝗹 𝗢’𝗥𝗲𝗶𝗹𝗹𝘆 - had passed away. Michael was in the Irish ME Trust and, with IMET’s Declan Carroll, were one of the founder members of the European ME Alliance (EMEA). Michael regularly came to the Invest in ME Research international Conferences in London. Michael was a wonderful person and a great storyteller. IMET issued this statementIt is with deep sadness that we announce the passing of our founding member and chairman Michael O’Reilly. As well as being a great family man, Michael devoted a great part of his life in helping those with ME in whatever way he could. Due to his foresight and desire to help, our ME Therapy Week was founded in 2003 and took place each year at An Grianán in County Louth until 2016. Following that event, our ME Therapy Retreat still runs to this day, currently in Adare, Co Limerick. Michael was due to attend this year’s event which takes place next month. He will be greatly missed. Ar dheis Dé go raibh a anJournal of IiMER June 2024 What we have been doing Our research strategy is oriented to achieving the best and most rapid outcome with the resources we have – which is only possible via a coordinated, collaborative structure of biomedical research, using the capacity of Europe. Since the charity was formed it has concentrated on prioritising biomedical research as the quickest way to improve and effect better education and to galvanise advocacy. We concentrated, as best as we could, on setting up some of the key building blocks that would create sustainable and permanent change in how ME is researched and treated, by creating solid foundations for a research programme on ME  research based on solving scientific questions to find treatments based on research evidence  raising standards on all levels of patient care  facilitating European and international collaboration  changing attitudes toward ME from within institutes and organisations via funded researchers and medical students The Only Clinical Trial for ME in UK The charity is fully funding the only clinical trial for ME in the UK. This is being carried out at the centre in Norwich Research Park at the Quadram Institute. The Aim of the RESTORE-ME study is to undertake a clinical feasibility study of FMT in ME/CFS and determine if a full clinical trial is justified. This will be achieved by providing evidence for efficacy in this patient group, a mechanistic understanding of FMT in ME/CFS, the acceptability of the treatment for patients, the measurement properties of outcome measures, and to provide bounds for efficacy. A significant proportion of ME/CFS patients date the onset of their symptoms to a GI illness. FMT may be helpful in these patients. A study undertaken in a single centre in Australia reported significant clinical improvement in 70% of ME/CFS patients administered an FMT (Borody et al., 2012). Since gut dysbiosis might be a contributing factor in ME/CFS, particularly in those with IBS, replacing the gut microbiota could be an effective treatment. This is the hypothesis behind the RESTORE-ME clinical trial – a phase 2b, double blind and placebo controlled – which focuses on establishing safety and efficacy. A pilot study, called Light ME Up, is being supported by Invest in ME Research to assess the acceptability, safety and potential benefit of red light exposure in ME patients. It is a remote feasibility study that patients can undertake from their home. People with ME are reported to have reduced function of mitochondria, the powerhouses in our bodies’ cells that generate energy. Mitochondria can absorb red light and use this to boost energy production, so there is interest in using red light therapy to treat ME. This has been used to manage the symptoms of acne, muscle and joint pain, arthritis, blood circulation issues and hair loss; this will be the first study to assess the use of red light therapy on ME. Symptoms will be monitored for a couple of weeks before and after this period, to see whether the red light therapy provides any benefits. The Light ME Up study will trial objective Invest in ME Research Page 5 of 32

Journal of IiMER June 2024 assessments of cognitive function and physical activity levels and an online clinical trial management platform. A Centre of Excellence for ME Already functioning with world class research, facilities, projects and international collaboration, university and university hospital, collaborations with other groups and local clinic for people with ME. The place to invest. Invest in ME Research asked MPs to consider the following document for last year's' APPG for ME November meeting (which Invest in ME Research are not allowed to attend). We felt that MPs should be made aware of developments and status at the centre in Norwich Research Park rather than the sanitised input they receive. We also updated the Executive Summary for MPs regarding our Centre of Excellence for ME. All available on our web site at investinme.org/centre PhD students introduced to research The charity has funded five PhDs to perform research into ME - including the first crowd-funded PhD for ME - another first. The latest PhD project is with Rik Haagmans, whose research project focuses on the relationship between gut viruses and ME. During the project Rik will be working on the RESTORE-ME clinical trial and look at virology and gut viruses, a field that has gained a lot of public attention in the past years with the outbreak of SARS-CoV-2. While one normally is able to recover from most viral infections, recovery from an infection does not always mean a rapid and full return to health. For example, many COVID-19 patients suffer for a long time after the initial infection from what is sometimes called “Long COVID”. This is something that many ME patients are familiar with. Leading up to the development of ME, many patients experience a viral infection. Various viruses are associated with ME and some of these viruses are also associated with gastrointestinal diseases and dysbiosis. Invest in ME Research This suggests that, at least in a subgroup of ME patients, gut viruses could play an important role. To investigate this, Rik has aimed to:  Identify viruses in faecal samples DNA through sequencing technologies  Define the collection of viruses in the gut of ME patients  Determine if ME patients have unique viruses in their gut  Determine whether FMT leads to a change in gut viruses and how this relates to improvement of symptoms  This has involved preparing experiments that allow us to optimise this process and ensure we can obtain high quality data. Underlying this is the aim to gain valuable information about the mechanism underlying ME and the role of gut viruses in human health. Page 6 of 32 Journal of IiMER June 2024 Invest in ME Research Fellowships The first Fellowship for ME was launched in collaboration with Quadram Institute followed soon after by the second fellowship. The charity decided to name the first fellowship as The Ian Gibson Fellowship for ME – in agreement with Dr Ian Gibson’s wife. Dr Gibson passed away in 2021 and was a great supporter of people with ME and of the charity. This first fellowship for ME recognises Dr Gibson's great influence in supporting people with ME and in helping the charity move ahead with facilitating the research programme and centre for research into ME. Dr Gibson was a unique MP in that he understood the science and politics and was always interested in all kinds of views, and was consistently engaged in debates spanning diverse issues. He was a steadfast advocate for the underdog, lending his voice to those often ignored. This profound commitment to fairness and justice manifested not only in his advocacy but also in his resolute support for organisations that echoed his ethos. It is why he aligned himself with a volunteerdriven charity such as Invest in ME Research. In recognising the intrinsic value of every effort, regardless of size or financial backing, he embodied the transformative power of standing alongside those tirelessly Invest in ME Research working for change, emphasising that true impact arises from the heart, not just the spotlight - something that perfectly describes our supporters. The Ian Gibson Fellowship is being performed by Dr Katharine Seton and continues her career in research into ME at Quadram Institute. Recently, Dr Seton completed her PhD that was funded by Invest in ME Research and the University of East Anglia [2]. This is an important step in supporting the continuity of the research strategy for ME that has been well established and is being performed and planned at Quadram Institute and University of East Anglia. Details of some of Dr Seton’s planned research will include determining the contribution of the intestinal microbiome to oxidative stress in ME patients and whether this can cause alterations in immune function, accelerating premature immune ageing in patients. She also plans to determine the impact of microbiota replacement therapy (MRT) on intestinal and systemic oxidative stress in ME patients. This will be the first study to directly assess intestinal microbiome contribution to oxidative stress in ME patients. Identifying the source of oxidative stress and its impact on immune cell function will enable the development of treatment options to break this cycle. Page 7 of 32

Journal of IiMER June 2024 The Invest in ME Research ‘LunaNova’ Fellowship for ME Invest in ME Research also unveiled the launch of the 'The Invest in ME Research ‘LunaNova’ Fellowship for ME, a new research initiative that will be undertaken at the Quadram Institute, with UK and European collaboration. This fellowship, made possible through the remarkable generosity of LunaNova, the brand of a small UK technology company, underscores the commitment to advancing the Centre of Excellence for ME approach and the benefits it provides. This marks the second fellowship championed by Invest in ME Research, focusing on elevating ME research efforts. The 'LunaNova' Fellowship seeks to deepen our understanding of ME and accelerate progress toward effective treatments. The two-year 'LunaNova' Fellowship exemplifies a pivotal investment in ME research, reinforcing commitment to driving progress in the field. The fellowship leverages Quadram Institute's world-class facilities, incorporating collaboration with European ME Research Group (EMERG) member, Professor Elisa Oltra from the Catholic University of Valencia, Spain, and immune ageing specialists at the University of Birmingham. This collaboration extends our dedication to international partnerships in advancing ME research. Invest in ME Research Page 8 of 32 Mike Buckingham, CEO of LunaNova’s parent company, said: “We have seen first-hand the devastating impact ME has on patients’ lives. Even at its mildest, it is a condition that can completely stunt a person’s potential and at its severest is nothing short of a living death that persists for decades.” “Biomedical research is the only path that can credibly solve this, yet it has been spectacularly neglected over the last few decades in favour of now debunked psychological approaches. During this time the global economic impact of this condition has run into trillions of US dollars.” “Whilst we wait for Governments and policymakers to wake up to the gravity of the situation and begin to fund biomedical research at a scale and pace truly commensurate with the condition’s impact, it is largely charities that have been driving progress. Invest In ME Research (IIMER) are one such charity. They have worked tirelessly in the UK to raise awareness and promote funding of biomedical research.” Journal of IiMER June 2024 European Infrastructure for ME The charity has instigated several initiatives to begin to build this presence in the absence of any official European strategy - a European ME Alliance of ME Patient Groups, a European ME Research Group, a European ME Clinicians Group and a European Young ME Researchers Network. Researchers, clinicians and carers – coming together. Young EMERG The European ME Research Group early career researcher network, formed last year, brings together the new wave of researchers to form a European support base that can facilitate collaboration with early career investigators in other continents. This group published a well-received paper last year – Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives - https://www.mdpi.com/2077-0383/13/2/325 Advocacy The charity has not forgotten the need for advocacy and has regularly commented and acted on issues affecting ME - in parliament, CMO, UKRI, NHS, DHSC. NICE, and abroad. In the 2018/2019 UK parliamentary debates on ME, Invest in ME Research produced a document that summarised the status of ME. It also laid out a bold vision for research - proposing that £20 million be allocated every year for five years to kick-start biomedical research and support the foundations that this small charity has laid. More recently, the charity was involved in the DHSC/UKCRC Delivery Plan for ME that was set up by an ex-health minister – some time after he left that position, where he actually could have made a difference. Sadly, our final report from that two-year project is not optimistic for any breakthrough. The charity had submitted proposals at the first meeting that we attended – proposals meant to take rapid action and address existing issues - but these proposals were not even discussed as the working group exhibited limited vision or ambition and a continual lack of urgency. A two-year project seemed far too long to determine already known issues and provide resolutions – until one realises that two years ago it was well known that a general election would be coming in exactly two years, allowing this particular can to be well and truly kicked down the road on its continuing odyssey to nowhere. Our comments on this initiative are under our Campaigning web page. During the hiatus caused by the pandemic we updated our 5-year plan – leaving major funding now the one missing element. Invest in ME Research Page 9 of 32

Journal of IiMER June 2024 Findings from the European ME Alliance PAN-European ME PATIENT Survey On World Health day 2024, the long-awaited findings of the European ME Alliance (EMEA) Pan-European ME Patient Survey were unveiled, painting a distressing picture of neglect and suffering endured by millions across Europe. The report - EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences - was the result of excellent work by the authors, Arild Angelsen and Trude Schei. Some of the items from the report, authored by Arild and Trude, are shown below. The report is available in full from this link - https://europeanmealliance.org/documents/emeaeusurvey/EMEAMEsurveyreport2024.pdf EMEA Pan-European ME Patient Survey Key Messages 'ME/CFS is a serious and debilitating disease ' '... profound disability levels and unmet needs among European ME/CFS patients' ' underscore the urgent priority for healthcare systems to recognise ME/CFS as a serious physical illness and provide better medical care, financial support, and social services' 'Keeping the activity level within the energy envelope (pacing) is the most helpful strategy ' 'Activity-based therapies do more harm than good' ' Almost half of survey respondents report a deteriorating course of illness ' ' Early diagnosis, activity management (pacing) and avoidance of over-exertion are key to preventing progression to severe disease ' ' Biopsychosocial (BPS) model - a failed and harmful approach to ME/CFS ' ' Therapies involving fixed increases in activity tend to worsen symptoms and risk a deteriorating course of the illness, rather than leading to improvement ' 'Access to medical care and social support varies across Europe, with different approaches taken by national health authorities impacting the course of illness and disease outcomes ' 'The health care system fails ME/CFS patients – and that has serious consequences ' Invest in ME Research Page 11 of 32

Journal of IiMER June 2024 Foreword from the ‘EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences‘ Report In the world of Myalgic Encephalomyelitis (ME or ME/CFS), where decades of misinformation, ignorance, bias and stigma have been allowed to develop and grow without challenge, and eventually influence and then swamp healthcare systems, government policies and media prejudice, people affected by this disease have been left without moral, economic and healthcare support. The advent of social media has levelled the field somewhat, allowing patient groups to challenge the orthodox view of ME/CFS. However, the continued lack of any adequate funding for research into the disease, and no serious attempt to find the cause of the disease by national research agencies or policymakers, has led to the lack of the one essential element that is needed to change policies in government. That element is evidence. The European ME Alliance (EMEA) survey of ME/CFS patients in Europe is a first attempt by patient organisations to bring forward information that can be applied by governments in Europe, and by EU institutions, in order for them to take responsibility for addressing this high burden, under prioritised disease and provide the needed research funding, medical education of physicians, and social support for patients. The objective behind the survey was to find out whether the situation for ME/CFS patients was similar across European countries. The survey originated from the excellent work already performed by the authors of this report – Arild Angelsen and Trude Schei – and their impressive work with Norges ME-forening (Norwegian ME Association), an EMEA member, where they have previously surveyed and reported on the situation with ME/CFS in Norway and Denmark and identified similarities between the onset of ME/CFS and other factors impacting people with this disease. Building upon their work, EMEA members came together to assist in conducting this ‘first ever’ European patient survey. The results show that patients everywhere in Europe face similar stigma regarding recognition and knowledge of the disease, with huge delays in diagnosis that may take up to 12 years in some cases. With patients in Europe often being forced into taking deleterious and flawed biopsychosocial-based therapies that are still recommended by some national healthcare authorities, it may be no surprise that the report shows only 7% of patients reporting improvement over the years, with many having to face health deterioration that can last a lifetime. The survey also indicated that patients who received early diagnosis had better outcomes and were able to manage their energy use earlier by using pacing techniques to avoid over exertion and repeated ‘crashes’. The lack of educated medical professionals leads to a failure of healthcare and welfare systems to provide adequate support – the report highlights the poor level of support for this disease being experienced everywhere. Invest in ME Research Page 12 of 32 Journal of IiMER June 2024 The results compiled here by Arild Angelsen and Trude Schei demonstrate that it is important that information about this disease is also to be collected from patients – to document their ‘lived experience’ as is the currently popular buzzword. The survey provides evidence. The survey results should be a call for action. Investing in ME research will greatly benefit not only the patients, but also the healthcare and social systems as, currently, it takes patients years of medical visits to receive a diagnosis or receive any symptom relief, and their inability to workplaces heavy strains on national insurance and welfare systems. It is important to note that the research community has the interest and the potential to tackle this disease. EMEA member organisations have established a network of experts – researchers and clinicians, namely the European ME Clinicians Council (EMECC), the European ME Research Group (EMERG), as well as an Early Career Researcher Network (Young EMERG). These are well connected internationally with world-renowned research institutes and already have the capability to coordinate the necessary research that can lead to a correct diagnosis and appropriate treatments for ME/CFS patients. In addition, EMEA supports the annual Invest in ME Research International ME Conference (IIMEC) which brings together world renowned researchers and also includes a 'patient day' which is open to the public where the latest advances related to ME/CFS are presented in a language patients can understand. Patient organisations play a key role in providing information, guidance and support to ME/CFS patients. EMEA is committed to continue surveying patients in order to provide ongoing data to support urgent and decisive action from policymakers in Europe in order to improve the situation for p eople with ME and their families in Europe. The EMEA survey of ME/CFS patients in Europe is a valuable part of the resources required as EMEA works to support the implementation of the UN Universal Declaration of Human Rights, the UN Convention on the Rights of Persons with Disabilities, and the UN Political Declaration on Universal Health Coverage, to respect patients’ rights and ensure that European government policies do not leave ME/CFS patients behind. Executive Committee, European ME Alliance Invest in ME Research Page 13 of 32

Journal of IiMER June 2024 Executive summary from ‘EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences‘ Report by Arild Angelsen and Trude Schei This survey of ME/CFS patients in Europe has been conducted by the European ME Alliance (EMEA), which gives a voice for people with ME/CFS in Europe and is the European partner for facilitating high-quality biomedical research. This report presents the findings from the survey of more than 11 000 ME/CFS patients. The aim was to compare patients’ experiences across countries regarding disease characteristics, course of illness, and access to healthcare and support. The survey The data are based on an online survey, conducted in May - August 2021. The questionnaire was translated into 15 languages, and the survey was promoted via patient organisations in European countries. The respondents spanned 44 countries, including responses from a few non-European countries. A total of 11 297 responses were analysed. The questionnaire covered illness characteristics, factors affecting disease course, therapies tried, and support received from healthcare and personal contacts. Potential biases due to non-random sampling are acknowledged. Severely ill and undiagnosed patients are likely to be underrepresented. However, the large sample size is viewed as providing useful insights into patients’ experiences across European countries. ME/CFS is a serious and debilitating disease ME/CFS is typically categorised into four degrees of severity: mild, moderate, severe, very severe It can be argued that the use of the term “mild ME/CFS” is an oxymoron, as even “mild” ME/CFS is a severe disease, with a major loss of function compared to before disease onset. Most patients cannot work and rely heavily on support. In the survey, 24.0% answered that they had mild ME/CFS, 53.8% had moderate ME/CFS (mostly housebound), 16.0% had severe ME/CFS (mostly bedbound), while 2.4% had very severe ME/CFS (bedbound and in need of continuous care). 3.7% described their severity as “better than mild”, while only 0.2% said they had recovered. Strong similarities were found among countries for several factors such as the distribution of degrees of severity, the positive correlation between early onset and disease severity, and the factors associated with a better course of illness, such as coping and support from family and friends. Almost half report a deteriorating course of illness Persistent myths exist about ME/CFS being an illness that gradually “burns out”. Some patients do indeed get much better or even recover, but most do not. As high-quality prospective studies on typical courses of illness are lacking, large patient surveys such as the present one may provide the best information available. Whether ME/CFS is seen as a temporary or chronic condition has major implications for welfare benefits and other services provided. In the survey, 46% described mainly deterioration (26% had initial fluctuations and then deterioration, and 20% have experience mainly deterioration), while 24% answered that they had experienced major fluctuation throughout their course of illness. In total, 70% of respondents described either deterioration or large fluctuations. Only 7% reported improvement. Many patients have a severe or very severe degree of ME early on. 33% among the very severely ill had an onset before turning 20 years old, compared with 14% among those with a mild degree. Invest in ME Research Page 14 of 32 Journal of IiMER June 2024 The health care system fails the ME/CFS patients – and that has serious consequences 3 out of 4 patients (74%) felt they received little or no health care support, while only 1 out of 8 (12%) had experience good or very good support. The dissatisfaction is high across most countries, and even in the best scoring countries (Norway, Iceland and Sweden), about 65% state that they received poor health care support. Yet some differences are notable, indicating that the public approach matters. This is illustrated by the difference found in an otherwise rather homogenous Nordic region. The portion of respondents reporting that they received no help varies from 15-21% in Iceland, Norway and Sweden, to 35% in Finland and more than half (53%) in Denmark. The latter is known for a strong biopsychosocial approach, where ME/CFS is considered a functional illness by the Danish health authority. On the positive side, patients with a more recent onset or diagnosis are less dissatisfied with the health care provided, which may suggest a modest improvement over time. While no objective diagnostic tests, verified biomarkers, curative medications or treatments for ME/CFS exist, health care support matters for the management of the symptoms and the improvement of functional capacity, and thus the course of illness. Respondents experiencing good support from the health care system in their country were more likely to report improvement and less likely to report deterioration. Early diagnostics and disease management critical to improve the course of illness Long delays in the diagnosis were common, with the diagnostic period (from onset to diagnosis) averaging 6.8 years across Europe and large variations across countries. Men are, on average, diagnosed one year earlier than women. Longer delays were associated with a worse course of illness. The risk of experiencing a course of illness characterised by deterioration is more than 50% higher among those with a late diagnosis (10 years or more) compared with those who received an early diagnosis (within 3 years). The survey confirms what several studies (with smaller samples) have found: delayed diagnosis is a risk factor for severe disease. Early and sound advice on the management of the disease, including pacing to avoid Post-Exertional Malaise (PEM), improves the prospects. Patients much more satisfied with support from family, friends and fellow patients 3 out of 5 (60%) stated that they received good or very good support from family members, while 1 out of 4 (25%) had received little or no support. There is a clear relationship between good family support and a lower probability of a deteriorating course of illness (similar to what is observed for health case support); good support in providing daily care and moral support helps staying within the “energy envelope” and avoiding PEM. A similar relationship is observed for support from friends and fellow patients. Keeping the activity level within the energy envelope (pacing) is the most helpful strategy Pacing to avoid post-exertional malaise (PEM) was viewed as the most helpful strategy. 3 out of 4 respondents (75%) considered pacing to have a positive or very positive impact on their course of illness. Successful pacing also requires that the patient knows what pacing is, and – critically – have sufficient help and support from the environment to make pacing possible. While pacing is critical to stabilise the illness, many struggle to find the right balance and adequate support, and experience regular “crashes” and deterioration of their symptoms (PEM). Caring for their family, their financial situation, and stress and worries are factors contributing to the worsening of their symptoms and the overall situation. Invest in ME Research Page 15 of 32

Journal of IiMER June 2024 Activity-based therapies do more harm than good With PEM being a characteristic symptom of ME/CFS, meaning that symptoms worsen upon even the slightest physical or mental exertion, therapies focused on increasing activity levels (Graded Exercise Therapy - GET) or changing illness beliefs (Cognitive Behavioural Therapy - CBT) were pe rceived as harmful by most patients. CBT is a highly controversial as a treatment for ME/CFS. In the survey we distinguished between CBT as a cure and CBT as coping. 3 out of 4 patients experienced a (very) negative effect of CBT as a cure, while 1 in 4 had a negative experience of CBT for coping. Only 5% reported that CBT as a cure to have had a positive effect, compared to 38% in the case of CBT for coping. The more severe the illness, the more negative experiences with CBT, both as cure and as coping. In short, CBT and GET are not only unsuccessful in improving the condition of ME/CFS patients but have a very negative impact on the course of illness. Both the CDC in the US and NICE in the UK have removed advice on CBT and GET from their guidelines for ME/CFS. The Biopsychosocial Model (BPS) – a failed and harmful approach to ME/CFS The dire situation for most ME/CFS patients across Europe is, in part, the result of both ignorance and lack of knowledge among health professionals, social workers, and policy makers. Moreover, the biopsychosocial (BPS) model claims ME/CFS to be psychological and linked to dysfunctional illness beliefs, a pathological focus on symptoms, fear of activity and resulting deconditioning. According to this model, the cure is teaching the patient to ignore, or not to focus on symptoms, and “push through” and follow an exercise program with set increments. This approach has not only failed to get support from interventional studies, or from research that finds critical biological anomalies in people with ME/CFS. It also lacks support from patients and has done harm in its promotion of CBT and GET. The model places the responsibility for both having ME/CFS and for recovery squarely on the patient. This may result in a lack of empathy and sympathy from others, both in healthcare and welfare institutions and within the patient’s family. Conclusions  The survey highlights profound disability levels and unmet needs among European ME/CFS patients. Findings underscore the urgent priority to recognise ME/CFS as a serious illness and provide better medical care, financial support, and social services.  Access to medical care and social support varies across Europe, resulting in both a general but dangerous neglect of the illness, with different approaches taken by national health authorities, impacting courses of illness and disease outcomes.  Therapies involving fixed increases in activity tend to worsen symptoms and risk a deteriorating course of the illness, rather than leading to improvement.  Early diagnosis, activity management (pacing) and avoidance of over-exertion (PEM) are key to preventing progression to severe disease. The full report is available in full from this link - europeanmealliance.org/documents/emeaeusurvey/EMEAMEsurveyreport2024.pdf The European ME Alliance has received ‘official Non-State Actor accreditation’ status from WHO’s Regional Office for Europe. This allows EMEA to participate in WHO Europe Regional Meetings and to make official statements on agenda topics of interest – allowing EMEA to increase awareness, recognition, and action on ME by WHO Europe’s 53 member countries. Invest in ME Research Page 16 of 32 Journal of IiMER June 2024 EMEA Commentary on Pan-European ME Patient Survey The long-awaited findings of the European ME Alliance Pan-European ME Patient Survey, initiated in 2021, have finally been unveiled, painting a distressing picture of neglect and suffering endured by millions across Europe. Drawing upon input from over 11,000 individuals, the report [' EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences'] lays bare the systemic failures and institutional neglect that have perpetuated the suffering for far too long and serves to sound the alarm to all stakeholders - including governments, healthcare providers, research agencies, policy makers, and global organisations - of the urgent need for concerted action to address the humanitarian crisis facing people with ME and their families. The report is an indictment of the status quo. Yet, by shining a spotlight on these issues, the report also seeks to catalyse meaningful dialogue and concrete steps towards redressing the injustices faced by ME patients. The stark revelations underscore the urgent need for concerted action. Key messages extracted from the report highlight the severity of the disease, with profound disability levels and unmet needs prevalent among European ME/CFS patients. Despite mounting evidence, healthcare systems continue to overlook ME/CFS as a serious physical illness, failing to provide adequate medical care, financial support, and social services. Incomprehensibly, it is not even recognised in some European countries despite it being listed under the World Health Organization’s ICD Codes, ICD-10 G93.3 and (later) ICD-11 8E49 as a neurological condition since 1969. This is a clear failing of EU healthcare provision and has resulted in the continued violation of patients’ human rights, especially to the best attainable health, a topic that EMEA is raising with the EU and WHO Europe. In response to these findings, the European ME Alliance has proposed a series of crucial actions to be undertaken. Invest in ME Research Page 17 of 32

Journal of IiMER June 2024 Action 1 EMEA urges all European countries to take immediate action in addressing Myalgic Encephalomyelitis and recognise ME/CFS as a somatic illness, as defined by the World Health Organization (WHO). ME/CFS requires standardised diagnosis and treatment protocols. It is imperative that all European governments swiftly adopt and implement WHO International Classification of Diseases (ICD) codes specific to ME/CFS within their healthcare systems. Action 2 EMEA urges a pan-European strategy of coordinated, collaborative biomedical research to be initiated across Europe, by all governments, using established or developing Centres of Excellence for ME. These centres would be adequately funded and perform translational biomedical research that will look at developing a full understanding of the disease and development of effective treatments to mitigate or cure the disease. Action 3 EMEA urges all European countries to take decisive action in establishing a specialist discipline for ME/CFS by creating academic consultant roles dedicated to ME/CFS and establishing at least one specialist clinical centre aligned with centres of excellence. Recognising the dangerously insufficient awareness and knowledge of ME/CFS, leading to misdiagnosis, missed diagnosis, or very late diagnosis (with an average delay of 6.8 years across Europe), concerted efforts are needed to include the latest scientific evidence on ME/CFS in medical curricula. Academic consultant roles specialising in ME/CFS would play a pivotal role in this effort, providing expertise and guidance to ensure the integration of ME/CFS education and research into medical curricula while utilising standardised diagnostic and treatment protocols for ME/CFS. Action 4 EMEA urges the EU to initiate a pan-European effort to implement accurate and correct recording of cases of ME/CFS, utilising the most up-to-date diagnostic criteria. This is crucial for understanding the full economic burden of the disease. As demonstrated in previous EMEA 'ME/CFS in Europe' webinars, EMEA has highlighted the feasibility for all European countries to implement SNOMED CT to record properly occurrences of ME/CFS, facilitating accurate prevalence figures. EMEA welcomes the opportunity to collaborate with EU institutions, European governments, and other stakeholders, leveraging the achievements of the EMEA pan-European survey, to ensure a thorough evaluation of ME/CFS prevalence and its economic ramifications. By taking these proactive steps, European governments can demonstrate their commitment to addressing the urgent needs of ME patients and improving their quality of life. While we recognise that it will take time to deliver and implement these recommendations their overarching aim is clear: to drive tangible change and improve the lives of ME patients across Europe. The urgency of this call to action cannot be overstated and demands immediate attention and intervention. Failure to act not only perpetuates the suffering of ME/CFS patients and their families but also undermines the integrity of our European healthcare systems. Invest in ME Research Page 18 of 32 Journal of IiMER June 2024 As part of its ongoing efforts to raise awareness and advocate for change, EMEA will also be hosting a webinar to delve deeper into the report's findings and explore potential pathways forward. This EMEA webinar will, again, bring stakeholders together, exchange ideas, and propose a course towards a more compassionate and inclusive healthcare system for all. The release of the report from the EMEA Pan-European ME Patient Survey marks a significant moment in the fight for recognition and support for ME patients in Europe and should be used by policy makers to enact change. It is incumbent upon all stakeholders to heed its findings, heed the call to action, and work collaboratively towards a future where the needs of ME patients are prioritised and their voices are heard. Background to the survey The idea for a pan-European survey among ME-patients originated when a patient survey carried out by Norges ME Forening - later supplemented with a similar survey in Denmark - identified strong similarities in the time of onset of the illness among ME-patients. This then led to a discussion and posed other questions on the similarities and differences across European countries. EMEA performed the pan-European survey in 2021 and, due to resource limitations with analyses, is now publishing the finalised report. We sincerely thank the authors, Arild Angelsen and Trude Schei, and Norges ME Forening for their support of the survey, analysis of the results, and production of the survey report. This survey was the first of its kind comparing the situation and experiences of ME-patients across European countries. As such, it permits cross-country comparison of a number of aspects, The results from the survey confirm much of what has been known by patients and, indeed, healthcare systems for many years but has been ignored. European ME Alliance Invest in ME Research Page 19 of 32

Journal of IiMER June 2024 Response to the 2023 Article in Scandinavian Journal of Public Health In September 2023, a group calling itself the 'Oslo Chronic Fatigue Consortium' issued a statement [OR1] entitled - Chronic fatigue syndromes: real illnesses that people can recover from - and supposedly concerning ME. This consortium ventured the notion that - "...the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation. Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities." One wonders from where this group of 'dedicated' researchers seemed to have arrived at the idea that people with ME are in favour of 'prolonged rest, social isolation and sensory deprivation'. As though patients had some choice in the matter. The article conveniently perpetuates the age-old gaslighting of patients by decrying an imagined 'dominant narrative' that - 'the prediction that patients cannot recover and that activity is harmful. This narrative is most commonly expressed by campaigners concerned with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME), but more recently by those writing about postcovid-19 condition ' Of course, this fits the same actual narrative that has been trotted out year after year for decades - and received the lion's share of funding from government agencies (oblivious to the needs and experiences of Invest in ME Research patients) - that try to prove the efficacy of the biopsychosocial ideology for ME. If it is not the patients who are causing themselves to be ill by their false beliefs then it is those patient organisations who have tried to do something to support the parlous status of treatment of people with ME in Europe! People with ME and their carers, along with most ME charities, will already be aware of the work of some of the people associated with this Oslo Chronic Fatigue Consortium. A handy reference to educate oneself on what has transpired over the years is available in the work of Margaret Williams over many years [OR3]- describing some of what patients have had to endure with these false ideologies. Nowadays the denigration of vulnerable patients is extended to include long covid - grudgingly acknowledged as an 'often referred' to condition. It would be expected that the European ME Alliance, as one of the oldest of patient organisations, would challenge this 'Oslo Declaration'. Therefore, instead of contending this latest misinterpretation of reality it was decided to support a counter-statement organised by researchers who were performing research into this disease or who were experienced in the real world of dealing with this disease. Last year Dr Jesper Mehlsen - co-chair of the European ME Research and Clinicians Groups (EMERG) - organised a reply to the Scandinavian Journal and EMEA helped coordinate signatories in support of this reply – ‘The Stockholm Declaration’ – recognising the genesis of the article Page 20 of 32 Journal of IiMER June 2024 coming from EMEA Sweden member RME, at their conference in that city last year. The response was submitted to the Journal last year - but no reply was received. Another response was sent and this will be published shortly - albeit forced into an abbreviated form before being accepted for publication. References: OR1 OR2 The original response, which was authored and co-signed by a long list of researchers, is shown below for all to see. This letter will be published on the EMEA web site when the abbreviated version has been published in the Scandinavian Journal of Primary Health Care. Scandinavian Journal of Primary Health Care Article https://www.tandfonline.com/doi/full/10.1080/02813432.2023.2235609 Scientific American 2024: People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System https://www.scientificamerican.com/article/people-with-myalgicencephalomyelitis-chronic-fatigue-syndrome-may-have-an-exhausted-immunesystem OR3 Margaret Williams Articles on ME https://www.margaretwilliams.co.uk The authors initially claim that the current public narrative on severe, persistent fatigue conditions are “most commonly expressed by campaigners concerned with chronic fatigue syndrome (CFS/myalgic encephalomyelitis (ME/CFS)), but more recently by those writing about post-covid-19 condition”. These “campaigners” include the Institute of Medicine and their 400-page review of ME/CFS [1] and the recent guidelines by the National Institute for Health and Care Excellence [2]. The prognosis of ME is not a question of “narratives” but of good, transparent, and reproducible empiric evaluation. The results of research are consistent, suggesting low rates of full recovery of between 5-10 % for adults [3-6]. In claiming a lack of specificity in the newer criteria including post exertional malaise (PEM) as a mandatory symptoms [2, 7], the authors are unaware of recent research, finding lower thresholds for lactate production8 and lower oxygen extraction9 during exercise in ME/CFS-patients as contributors to ME/CFS exertional intolerance-and thus to PEM. Other publications have identified mitochondrial dysfunction to be a likely explanation for PEM10 and have shown a correlation between severity and mitochondrial damage [10, 11]. The authors propose an alternative explanation based on questionable scientific evidence that purports to offer realistic hope of improvement and recovery. This scientific evidence comprises a study in 19 female CFS patients and 21 normal healthy controls showing significant changes in a single measure of heart rate variability after cognitive therapy [12], and a study of long-term follow-up in children and young adults13 that may have a much Invest in ME Research Page 21 of 32

Journal of IiMER June 2024 better prognosis. However, the latter study relies on limited data and is contradicted by a more recent and larger study [14]. Cognitive treatment plays a limited role in ME/CFS as pointed out in the NICE-guidelines [2]. In lumping patients with a diagnosis of ME/CFS in to one non-specific group of patients with fatigue clearly demonstrates the authors’ limited clinical and scientific experience in ME/CFS and the fact that several of the manifestations of this disease may be alleviated by targeted treatment [15-17]. The authors state that the approach often recommended by the public narrative of inactivity, isolation, and sensory deprivation, risks worsening symptoms and associated disability. Firstly, such a statement discloses the authors’ lack of clinical experience with the range of severity and phenotypes in ME/CFS requiring modifications in the therapeutic approach. Secondly, it is an unsubstantiated claim (no references) and for the potential risks, the authors refer to a meta-analysis on bed rest as a primary treatment in conditions such as acute low back pain, preeclampsia, and myocardial infarction [15] and to an unpublished study on long-term sensory deprivation related to space flights [16]. Sensory deprivation is not a choice but a necessity in ME/CFS-patients due to the general increased sensitivity of the nervous system to afferent input secondary to neuroinflammation. Symptoms of neuroinflammation are essential in the diagnosis of ME/CFS and different imaging techniques have shown neuroinflammation to be present in several studies [17,18] and that neuroinflammation is a common denominator in ME/CFS and longCOVID19. In the “Oslo Declaration’s” justification for a new perspective, the authors refer to chronic pain, fibromyalgia, and post COVID syndrome for support, but recent advances do not support their narrative. The “Oslo Declaration” is flawed, and the dismissal of biological evidence as non-specific associations is bewildering, with the authors seeking to replace it with a biopsychosocial model entirely based on associations. A recent study in fibromyalgia has demonstrated that patient autoantibodies mediate the sensory, motor, and anatomical symptoms and signs that patients present with [20]. Similarly, studies have revealed pathophysiological mechanisms including immune cell dysregulation and altered cortisol levels in post COVID patients [21]. The authors claim “After 40 years of research into CFS/ME … neither a specific biological defect or pathology, nor a specific biomarker, has been identified”. It is estimated that at least 10,000 scientific papers have been published on ME/CFS and several distinct biological changes have been discovered resulting in targeted interventions and thorough descriptions of the pathobiology of ME/CFS [22, 23]. In opposition to the vast amount of biopathological evidence, the authors refer to a publication where the initial part of the summary reads: “The basic assumption underlying the model presented here is that the brain makes sense of the internal state of the body by being sensitive to statistical regularities in its own neural activity” [24]. The publication title seems to state the validity of this concept by “Taking the inferential leap” perhaps not knowing that inferring denotes either a conclusion based on known facts or the act of passing from statistical sample data to generalization. The authors fail to provide any of these. Invest in ME Research Page 22 of 32 Journal of IiMER June 2024 Conclusion: The “Oslo Declaration” epitomises the dangers of extrapolating findings from a small underpowered, narrowly focused study with data from unrelated studies (disorders) to explain a complex multi-factorial disease comprising different clinical subtypes that ME/CFS represents. To quote the American literary critic HL Mencken: “For every complex problem there is an answer that is clear, simple, and wrong.” References: 1. 2. 3. 6. 7. 8. 9. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, D.C: National Academies Press; 2015. National Institute for Health and Care Excellence. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. 2021 Cairns R, Hotopf M. Occup Med (Lond). 2005 Jan;55(1):20-31. 4. Wilson A, et al. BMJ. 1994 Mar 19;308(6931):756-9. 5. Andersen MM, et al. J Psychosom Res. 2004 Feb 1;56(2):217–29. Ghali A, et al. Diagnostics 2022, 12, 2540. Carruthers BM, et al 2011 Oct;270(4):327-38. Lien K, et al. Physiol Rep. 2019 Jun;7(11): e14138. Joseph P, et al. Chest. 2021 Aug;160(2):642-651. 10. Booth NE, et al. Int J Clin Exp Med. 2012;5(3):208-20. 11. Tomas C, et al (2020) PLoS ONE 15(4): e0231136. 12. Hansen AL, et al. J Psychophysiol. 2013;27(2): 67–75 13. Rowe KS. Front Pediatr. 2019; 7: e00021. 14. Josev EK, et al. J Clin Med. 2021 Aug 16;10(16):3603. 15. Allen C, et al. Lancet. 1999;354(9186):1229–1233. 16. Arias D, Otto C. 2011 http://www.medirelax.com/v2/wp-content/uploads/2013/11/F.Scope-of-Sensory-Deprivation-for-Long-Duration-Space-Missions.pdf 17. Nakatomi Y et al.J Nucl Med 2014; 55:945–950 DOI: 10.2967/jnumed.113.131045 18. Mueller C, et al. Brain Imaging and Behavior 14, 562–572 (2020). 19. Tate W, et al. Front Neurol. 2022;13: 877772. 20. Goebel A, et al.: J Clin Invest. 2021;131(13):e144201. 21. Klein J, et al. Nature (2023). https://doi.org/10.1038/s41586-023-06651-y 22. Sotzny F, et al. Autoimmunity Reviews Volume 17, Issue 6, June 2018, Pages 601609 23. Stanculescu D, Bergquist J. Front Med (Lausanne). 2022 Mar 8;9:818728. 24. Fedorowski, A., Sutton, R. Nat Rev Cardiol 20, 281–282 (2023). 25. Franke, C., Berlit, P. & Prüss, H. Neurol. Res. Pract. 4, 28 (2022). 26. Möller M, et al.. J Intern Med. 2023 Sep 27. Invest in ME Research Page 23 of 32

16th International ME Conference - Presenters Professor Simon Carding Research Leader, Quadram Institute Bioscience, Norwich Research Park, UK Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body's immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Recently Dr Whittemore completed the NIH Roadmap for ME/CFS project having taken a leading role in developing the programme and project management. Invest in ME Research Page 24 of 32 Journal of IiMER June 2024 Dr Avindra Nath, NIH, USA NIH National Institute of Neurological Disorders, Bethesda, Maryland, USA Dr. Nath received his MD degree from Christian Medical College in India in 1981 and completed a residency in Neurology from University of Texas Health Science Center in Houston, followed by a fellowship in Multiple Sclerosis and Neurovirology at the same institution and then a fellowship in Neuro-AIDS at NINDS. He held faculty positions at the University of Manitoba (199097) and the University of Kentucky (1997-02). In 2002, he joined Johns Hopkins University as Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections. He joined NIH in 2011 as the Clinical Director of NINDS, the Director of the Translational Neuroscience Center and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases. Professor Lutz Schomburg Charité University Hospital, Germany Prof. Dr. Lutz Schomburg received his training in biochemistry at the University of Hanover, Germany. He completed internships at the Max Planck Institute for Biochemistry in Munich, the Waite Agricultural Research Institute, Adelaide, Australia, and King's College London, UK. He worked at the Max Planck Institute for Experimental Endocrinology in Hannover, Germany, and received his PhD in 1994. As a postdoctoral fellow, he worked at Brigham and Women's Hospital, Harvard Medical School, Boston, USA, with Prof. William W. Chin and at Julius Maximilians University, Würzburg, Germany, with Prof. Josef Köhrle. He is currently President of the International Society for Selenium Research and Deputy Director of the Institute for Experimental Endocrinology at Charité Universitätsmedizin Berlin. Professor Nancy Klimas Director, Institute for Neuro Immune Medicine, Professor of Medicine, Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University Professor Emerita, University of Miami Nancy Klimas, MD, has more than 30 years of professional experience and has achieved international recognition for her research and clinical efforts in multi-symptom disorders, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), Fibromyalgia, and other Neuro Immune Disorders. She is immediate past president of the International Association for CFS and ME (IACFS/ME), a professional organization of clinicians and investigators, and is also a member of the VA Research Advisory Committee for GWI, the NIH P2P CFS Committee, and the Institute of Medicine ME/CFS Review Panel. Dr. Klimas has advised three Secretaries of Health and Invest in ME Research Page 25 of 32

Journal of IiMER June 2024 Human Services, including Kathleen Sabelius, during her repeated service on the Health and Human Services CFS Advisory Committee. Professor Klimas has been featured on Good Morning America, in USA Today and the New York Times. Dr Rob Wüst Vrije University Amsterdam, Netherlands Rob Wüst is currently assistant professor at the Department of Human Movement Sciences at the VU University Amsterdam. He received a PhD in Physiology from the Manchester Metropolitan University and VU University Amsterdam, and completed postdoctoral training at the University of Leeds and Amsterdam University Medical Center. His research interest is in cardiac and skeletal muscle metabolism and mitochondrial physiology, in health and disease. Rob uses research methods, ranging from MR imaging and spectroscopy, fluorescence microscopy and cellular and molecular techniques. Professor Maureen Hanson Cornell University, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Dr. Hanson has a current project to examine the microbiome of ME/CFS patients and controls, in collaboration with Dr. Ruth Ley (Cornell Microbiology) and Susan Levine, M.D. (Manhattan, NY). Dr Levine is also collaborating with Dr. Hanson on an immune cell gene expression project that involves Dr. Fabien Campagne and Dr. Rita Shaknovich at Weill Cornell Medical School in New York City. Dr. Hanson's third project concerns analysis of blood samples from individuals performing a two-day cardiopulmonary exercise test at Ithaca College under the supervision of Dr. Betsy Keller. Dr Irina R Rozenfeld / Dr Violetta Renesca Institute for Neuro-Immune Medicine, Depart. of Clinical Immunology, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, USA Irina Rozenfeld is a Board Certified Nurse Practitioner committed to the health of her patients. Irina emphasizes patient-practitioner relationships, critical thinking and patient education to develop an optimal treatment plan and achieve sustainable results. She obtained her Bachelor's of Science degree from Nova Southeastern University and a Master's of Invest in ME Research Page 26 of 32 Journal of IiMER June 2024 Science in Nursing Studies from Florida International University. Additionally, she has obtained a Master's degree in Integrative Medicine from George Washington University School of Medicine and a Doctoral degree at the University of North Florida. Before joining the INIM, Irina worked for more than twenty years as a physician assistant in Russia. After relocating to Florida, she worked as a Clinical Research Nurse at Nova Southeastern University. Irina obtained an international certification as a Clinical Research Professional and has been involved in research in many roles. Irina teaches at Nova Southeastern University College of Nursing as an adjunct faculty. Irina's focus at the INIM includes myalgic encephalomyelitis/chronic fatigue syndrome, chronic infections, vector-borne illnesses, metabolic syndrome, chronic pain, environmental issues, detoxification and auto-immune diseases and her research interests include neuroinflammation, biotoxin exposure, detoxification, immune dysfunction, the stress response, neuroendocrinology and implementation of integrative medicine modalities. Violetta Renesca is a Board Certified Adult Nurse Practitioner focusing on functional and integrative approaches to treat patients with complex neuro-inflammatory conditions. She obtained a Bachelor of Science degree in Nursing from Nova Southeastern University and worked as a staff nurse and charge nurse on the Progressive Care Unit at Broward Health. After receiving her Master’s Degree from Florida International University as an Adult Nurse Practitioner, she joined a large multispecialty geriatric center in Fort Lauderdale. Violetta obtained a Doctorate in Nursing Practice from the University of North Florida. Violetta’s focus at the INIM includes myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War illness, chronic infections, metabolic syndrome, chronic pain, environmental illness, detoxification, and autoimmune diseases. As a certified practitioner for the Institute for Functional Medicine, she works with patients to create personalized treatment plans that addresses root causes of chronic illness. She is also the Director of the Veterans Clinic where she sees patients with Gulf War illness. Additionally, she is a member of the American Association of Nurse Practitioners as well as the Institute for Functional Medicine. Dr Jesper Mehlsen Copenhagen University Hospital, Denmark / EMERG Dr Jesper Mehlsen graduated as a medical doctor in 1979 and finished his specialist training in 1990. He has published more than 140 scientific papers in peer reviewed journals, mainly on the autonomic nervous system and more recently on complex diseases possibly resulting form HPV-vaccination. For more than 35 years, he has worked clinically and in research with dysfunction of the autonomic nervous system. Such dysfunction may lead to symptoms from a number of different organs often dominated by diminished control of blood pressure and heart rate. Over the past 5 years, he has worked clinically and in research with patients who suspect side effects due to HPV vaccination to be the cause of a number of symptoms, common to those seen in chronic ME. Dr Mehlsen is co-chair of the European ME Research Group (EMERG). Invest in ME Research Page 27 of 32

Journal of IiMER June 2024 Dr Dezső Modos, Imperial College London, UK Dr Dezső Modos is an Imperial College Research Fellow in the Systems Medicine division of the Department of Metabolism, Digestion and Reproduction. He completed his medical degree at Semmelweis University and a minor in bionics at the Pázmány Péter Catholic University. Later he obtained his PhD at the Semmelweis University on network biology. His primary focus was the intracellular signalling network in cancer and understanding the role of paralogues in signalling. After his PhD he moved to Cambridge and learned cheminformatics. He used network biology to understand and predict compound synergy in cancer. Here he also learned about various cheminformatic techniques, which he is adapting for his fellowship. The current inflammatory bowel disease (IBD) therapies maintain remission only in around 30% of cases forming therapeutic celling. His fellowship aims to find the right drug to the right patient in IBD. Similarly, we can use the targets of IBD drugs as a source node and build a drug specific network footprint. The comparison of patient-specific disease and drug networks, much like connectivity mapping, can aid in identifying the correct drug for each patient. Single nucleotide polymorphisms (SNPs) in inflammatory bowel disease are often in the non-coding region of the genome. He and his colleagues developed a tool called iSNP (https://github.com/korcsmarosgroup/iSNP) which can map these single nucleotide polymorphisms to regulatory regions and through that SNP affected genes. From the SNP affected genes, patient specific signalling networks, individual pathogenetic pathways and patient specific network footprints can be constructed. Already, he has used this method to understand ulcerative colitis pathogenesis. Precision Life, UK PrecisionLife is a precision medicine company focused on finding better, more personalised treatment options for complex chronic diseases such as Alzheimer’s, diabetes, and endometriosis. It analyses large amounts of data from sources such as clinical trials, patient charities, biobanks, and research organisations to stratify, or segment, patients into clinically relevant subgroups. It can then identify potential drug targets based on the cause of each subgroups’ condition and help healthcare providers diagnose these conditions more accurately and effectively. PrecisionLife received an Advancing Precision Medicine grant from Innovate UK to investigate the causes of ME and long Covid. One of the first project objectives will be for PrecisionLife to use its precision medicine approach to identify the biological mechanisms driving disease in different groups of patients. The results will be used to create the first predictive diagnostic tools and risk models that can rapidly triage patients presenting to a doctor with potential ME/CFS or long Covid symptoms. Invest in ME Research Page 28 of 32 Journal of IiMER June 2024 Dr Gunnar Gottschalk, Simmaron Research Inc., USA Carl Gunnar Gottschalk completed his BS in biology at Sierra Nevada College and MS in Biotechnology at Rush University Medical Center. He received his Ph.D. in Neuroscience from Rush University Medical Center. Prior to attending graduate school, Dr. Gottschalk was the lead research coordinator for Sierra Internal Medicine and was responsible for the execution of several large multi-centered investigations in ME/CFS. Dr. Gottschalk has been with Simmaron Research since its formation. In 2020, he was named the Foundation’s Executive Director. Since then, Dr. Gottschalk has served a dual role in the organisation as the Executive Director and Principal Investigator. At present, Dr. Gottschalk is the PI for Simmaron’s multi-centered clinical trial of Rapamycin in ME/CFS. His laboratory is located at the Indiana Center for Biomedical Innovation (ICBI) on the campus of the Indiana University Methodist Hospital in Indianapolis, IN. Dr David Systrom, Assistant Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA Dr. David M. Systrom is a physician at Brigham and Women's Hospital. He is also an assistant professor of medicine at Harvard Medical School where he directs the Dyspnea Clinic and the Advanced Cardiopulmonary Exercise Testing Program. He received his medical degree from Dartmouth Medical School (now known as Geisel School of Medicine). He has been on the Harvard faculty for over 35 years. He has used invasive cardiopulmonary exercise testing to investigate mechanisms underlying fatigue and orthostatic intolerance in ME/CFS and PASC. His recent work suggest commonality between the two, in particular neurovascular dysregulation and related hyperventilation underlying symptoms during exercise. He is the Principal Investigator of an ongoing $8 million study of limb skeletal muscle mitochondrial dysfunction and just completed the first ever randomised clinical trial of pyridostigmine, both in ME/CFS. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical genomics. Invest in ME Research Page 29 of 32

Journal of IiMER June 2024 #BRMEC13 PROGRAMME – Day 1 26th June 2024 Arrival Refreshments 08:55 Welcome to BRMEC13 09:35 How infectious diseases (IDs) together with environmental and genetic factors trigger the onset of noncommunicable diseases (NCDs) Underlying Mechanisms of Long Covid Chair: Simon Carding, Quadram Institute Chronic Infection Aetiology Starter (viral / non viral): Chair Fridbjorn Sigurdsson 09:10 10:00 ME/CFS and Long Covid: NIH study 10:25 10:45 Chaired Discussion 11:05 BREAK Physiology: Chair Jonas Bergquist 11:40 12:05 12:30 12:55 13:15 Acute and chronic infections in patients with post–infectious syndromes Diagnostic and potential relevance of autoantibodies for fatigue symptoms Dysautonomia and Results from ICOSS Chaired Discussion Chair: Opening Thomas Vogl, Medical University of Vienna, Austria David Price, Cardiff University Avindra Nath, NIIH A Systems Biology Approach to ME / AI and Phenotypes Tamas Korcsmaros, Imperial College London Discussion Branislav Milovanović, Institute for cardiovascular diseases-Dedinje Department of Cardiology, Serbia Insights from Invasive Cardiopulmonary Exercise David Systrom, Harvard Medical School Lutz Schomburg, Charite Berlin Markku Partinen, University of Helsinki Discussion 13:30 LUNCH Nervous System and Neuroinflammation: Chair Jon Brooks 14:30 14:35 15:00 15:25 15:50 fMRI Observations from NIH Intramural Study Innate immune activation in the whole body and CNS of ME patients using PET/MRI Using fMRI and PET imaging to study neuroinflammation in ME Chaired Discussion 16:10 BREAK Metabolism Body and Cell Chair: Rikke Olsen 16:35 Ancestral allele of DNA polymerase gamma modifies antiviral tolerance 17:00 Mitochondrial dysfunction in ME/CFS 17:25 17:50 18:00 Genetic predisposition to metabolic disturbances in individuals severely affected by long-COVID Chaired Discussion Adjourn Jon Brooks, UEA, UK Avi Nath, NIH Michelle James, Stanford University School of Medicine, USA Michael van Elzakker, Harvard Medical School & Massachusetts General Hospital/Tufts University Discussion Yilin Kang, Suomalainen-Wartiovaara Group, University of Helsinki Rob Wust, Virje University, Amsterdam, Kristoffer Hansen, Aarhus University Discussion Invest in ME Research Page 30 of 32 Journal of IiMER June 2024 #BRMEC13 PROGRAMME – Day 2 27th June 2024 Arrival Refreshments 08:55 Welcome to BRMEC12 Day 2 09:10 Regulatory T cells in the brain 09:35 tbc 10:00 Plasma Proteomics in Response to Exercise 10:25 Autoantiboidies in ME and Long Covid 10:50 tbc 11:05 BREAK 11:35 Discussion Immune System Primary and Secondary Chair: Eva Untersmayr-Elsenhuber , Medical University of Vienna 09:05 Chair: Opening Chair: Simon Carding, Quadram Institute Eva U, Medical University of Vienna Adrian Liston, University of Cambridge Simon Carding, Quadram Institute Maureen Hanson, Cornell University Nancy Klimas, Nova Southeastern University Johanna Rohrhofer, Medical University of Vienna Discussion Epigenomes and Transcriptomes: Chair Elisa Oltra, Univ. of Valencia 12:00 Single cell transcriptomics to reveal the role of thymus in autoimmune diseases, and potential implications for ME/CFS 12:25 Single-cell transcriptomics of the immune system in ME/CFS 12:50 Human endogenous retrovirus expression in the immune system of ME/CFS 13:10 Chaired Discussion 13:30 LUNCH 14:35 NIH / CDC /EMERG Phenotypes 14:55 Longitudinal Study of ME Patients 15:10 Identifying potential candidates for clinical trials using AI network medicine Benedicte Lie, University of Oslo, Norway Andrew Grimson, Department of Molecular Biology and Genetics, Cornell University, USA Karen Gimenez-Orenga, Department of Pathology, Universidad Católica de Valencia San Vicente Mártir, Spain Discussion Beth Unger, CDC Leonard Jason, Chicago De Paul University, USA Wenzhong Xiao, Harvard Medical School, USA Clinical Trials: Chair Jesper Mehlsen, Copenhagen University Hospital, Denmark / EMERG 15:30 Clinical Trials Design and Standards for ME 16:00 BREAK 16:30 Clinical trials Ad-hoc Presentations: 17:00 Involvement of BH4, NO and Oxidative Stress in ME/CFS 17:25 Clinical Trial of Rapamycin 17:50 Flash Talks Various Speakers building standards for clinical trials NIH / CDC / EMERG Continued + action plan + document Ron Davis, Stanford School of Medicine in Stanford, USA Gunnar Gottschalk, Simmaron Research Inc., USA Various speakers 18:00 Summary Day 2 – Chaired Discussion 1815 Adjourn - Discussions continue at the informal Researchers’ Evening Invest in ME Research Page 31 of 32

Journal of IiMER June 2024 #IIMEC16 PROGRAMME – 28th June 2024 Time Arrival Refreshments 09:00 Updates on research into ME 09:15 NIH Roadmap - Future Directions 09:40 Insight into mechanisms of ME/CFS 10:05 Autoantiboidies in ME 10:30 BREAK 11:00 Explaining skeletal muscle-related symptoms in patients with ME/CFS: from skeletal muscle to exercise immunology 11:25 Immune Exhaustion in ME 11:50 Comparing Long Covid and ME Phenotypes 12:15 Discussion 12:25 LUNCH 13:35 Treating ME in USA - A Clinician's Approach 14:00 Treating ME in Europe - A Clinician's Approach 14:25 Diagnostic Criteria and Challenges How to manage severe ME in hospital/care environment 14:45 BREAK 15:15 Precision medicine in complex diseases and AI 15:40 Identifying Genetic Risk Factors for ME/CFS and Long COVID: First Genetic Associations, Novel Targets, Actively Protective Biology, Diagnostics and Repurposing Opportunities 16:05 Update on Clinical Trial of Rapamycin in ME 16:20 Clinical Trial of LDN and Mestinon 16:45 Involvement of BH4, NO and Oxidative Stress in ME/CFS 17:15 Plenary 17:30 Adjourn Chair: Professor Simon Carding, Quadram Institute, UK Dr Vicky Whittemore, NIH, USA Dr Avi Nath, NIH, USA Professor Lutz Schomburg Charité University Hospital, Germany / EMERG Dr Rob Wüst, Vrije University Amsterdam, Netherlands Professor Maureen Hanson, Cornell University, USA Professor Nancy Klimas, Nova Southeastern University, USA Panel discussion Dr Irina R Rozenfeld / Dr Violetta Renesca Nova Southeastern University, USA Dr Jesper Mehlsen Copenhagen University Hospital, Denmark / EMERG Panel discussion Dr Dezső Modos, Imperial College London Precision Life, UK Dr Gunnar Gottschalk, Simmaron Research Inc., USA Dr David Systrom Harvard Medical School, USA Professor Ron Davis Stanford School of Medicine in Stanford, USA Panel Discussion Invest in ME Research Page 32 of 32

Journal of IiMER Volume 13 Issue 1 Invest in ME Research In this Issue In this Issue ............................................................... 3 FOURTEEN YEARS ..................................................... 4 Jonas Blomberg......................................................... 6 Fifty Years - and ME? ................................................ 7 A Centre of Excellence for ME .................................. 9 European ME Clinicians Council ............................. 11 Statement from EMECC .......................................... 12 Encouraging Young Researchers............................. 13 Denmark - Ærlighed varer længst ........................... 14 (HONESTY LASTS LONGEST) .................................... 14 UK - Parliamentary Debate ..................................... 15 Sweden ................................................................... 16 Perceptions of Care in a Hospital’s Emergency Department 20 Chronic fatigue syndrome in the emergency department .............................................................20 Medical Education ..................................................21 Education about ME has been one of the major objectives for Invest in ME Research ......................21 Doctors and Patients ..............................................23 Listen to the patients ..............................................24 Long term illness with ME ......................................27 Caring for someone with ME ..................................30 Disability and Human Rights ...................................33 ME and the EU ........................................................35 Children with ME ....................................................38 Removing isolation .................................................39 No Isolation & Invest in ME Research .....................39 Anne Ortegren - A Year On .....................................41 Conference Abstracts .............................................42

Journal of IiMER Volume 13 Issue 1 Invest in ME Research FOURTEEN YEARS Invest in ME Research is an independent UK charity facilitating and funding a strategy of highquality biomedical research into Myalgic Encephalomyelitis (ME or ME/CFS) and promoting better education about ME. The charity is run by volunteers - patients or parents of children with ME - no salaries, no government funding, but wonderful supporters. This is the fourteenth annual international ME conference that this small UK charity has organised - a fact which surprises us on many levels. It is a surprise that we have managed to continue to arrange these conferences, and even increased their scope - despite comparatively few resources. A surprise that there really has not been the progress in research that we believed would and should have come after all these years. A surprise that it has taken so long before any major national agency has taken this disease seriously. A surprise that many other national research councils, especially in UK, are lagging so far behind and have ignored this disease for so long. Yet where would we be now had it not been for the dedication and efforts of our supporters throughout these years who have made it possible for us to redirect research toward biomedical and influence and force a new direction for ME? These are not just mere words for us - not a fresh update to leaflets, not a soundbite to pacify ME patients in order to retain support, not a new tactic to attempt to maintain the status quo, not another strategy to do deals behind closed doors and maintain establishment influence on progress. During all these years the charity has consistently and unambiguously campaigned for dedicated biomedical research into ME and the necessary funding to achieve it. We believed progress would be more rapid and it is sad that the opportunities that we presented and the offers that we made to engage were not taken up by establishment organisations as so much more Invest in ME Research (Charity Nr. 1153730) might have been achieved in tackling this disease at that early stage, rather than waste lives by doing so little. Yet without the efforts of our supporters throughout these years the scene could have been quite different and far worse. We named the Colloquiums the “Biomedical Research into ME Colloquiums” as we wanted to make the point that we would not compromise. Biomedical research was the way forward to make progress. The conferences were designed for professionals in order to increase the education of healthcare staff and influence the future treatment of people with ME. However, we have always ensured that the conferences were also open to patients and carers, believing that having patients, carers, researchers, doctors, nurses and even the media interacting with each other was a good thing. The charity has facilitated the foundation for a sustainable strategy of biomedical research into this disease. Our plans for a Centre of Excellence for ME have captured the imagination and is clearly seen as the way ahead - and good progress on this has been made, although with more resources the charity could expedite this for the benefit of all patients. The Centre of Excellence for ME project began in 2010 and the charity was able to fund the first PhD studentship some years later. This approach to research offers the best way forward for ensuring biomedical research into ME can be maintained and treatments developed. Collaboration has been at the heart of the charity's innovation following a review after the 2007 conference and our strategy of bringing the best researchers from around the world together was formed. The acceptance of this vision and collaborative strategy has matured to the point where now the NIH is taking a lead in forming centres and collaborative strategies. Collaboration and working together have been themes for our Colloquiums - with real international cooperation forming which can only lead to a better future for patients than would otherwise be the case. To support this strategy the charity has investinme.org Page 4 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research continued to arrange the international ME conferences that have provided a platform for education about ME - with DVDs produced of all the conference presentations which have formed a historical record as well as providing knowledge of the latest research. The Colloquiums and Conferences have always had an international atmosphere – emphasising that international collaboration in research and treatment are necessary. Our original conferences have now developed into a unique conference week in the heart of London with delegates and colleagues and friends coming from over twenty countries around the world. ME Conference Week 2019 now includes a conference for young/early career researchers; a dinner where young researchers can meet more experienced scientists; a two day closed research Colloquium where researchers can share ideas and discuss and plan and collaborate; a researchers' dinner where more discussions can be had; a pre-conference dinner which allows a special gathering of researchers, clinicians, media folk, politicians, ME patient group representatives,carers and patients to interact; a public international conference; a post-conference dinner which allows researchers and patient groups to discuss further after the main events have finished and plan the next steps; and an annual general meeting for the European collaborative patient alliance. A small charity with wonderful supporters has achieved this. When people view charities as being "the largest" or "the main" organisations it is as well first to determine how those adjectives are measured. Is it by income, by number of staff, by the amount of media presence? Or by the amount of income spent on research, or on the least spent on admin and salaries, or on the achievements and ideas that actually are realised? It is achievements that count - always - and hopefully the ideas that actually are realised, where possible. The supporters of the charity may not get the publicity they deserve but actions speak far louder than words, or awards. In the recent parliamentary debate on ME, Invest in ME Research produced a document which Invest in ME Research (Charity Nr. 1153730) investinme.org Page 5 of 52 summarised the status of ME. It also laid out a bold vision for research – including proposing that £20 million be allocated every year for five years to kickstart biomedical research and support the foundations that have been laid. It is this vision that a small charity and dedicated supporters brings to the world of ME. We were happy to contribute to the parliamentary debate that originated from the early work performed by a supporter of Invest in ME Research who is a constituent of the SNP MP Carol Monaghan, who set up the debate. Being an independent charity allows a genuine approach to tackling the problems with ME that benefits patients and their families. As Dr Ian Gibson - our conference chair for all these years - has said "We can change things" As we host our largest ever “invite-only” closed research Colloquium (with more than 130 invitations being sent out) then the name of our charity truly becomes the main calling for all interested in resolving this disease. For our fourteenth conference, and our ninth international researchers' Colloquium, what better slogan to use at this point in time than the one that this small charity has uniquely been promoting for so long. Time to #InvestinMEresearch Kathleen McCall CHAIRMAN INVEST IN ME RESEARCH We would like to thank our friends from the Irish ME Trust, Norges ME Forening and the Open Medicine Foundation for donating to help fund the administration costs of the conference.

“He was a giant and his support for our endeavours was immeasurable. What a tragedy" - Dr Ian Gibson Jonas Blomberg Over the years, whilst the charity has been making huge efforts to encourage and facilitate international collaboration in research into ME, we have come into contact with hundreds of researchers in different research fields, in different institutes and in different countries. There are many researchers whom we have known who have become trusted friends. One of those researchers whom we have called a friend of the charity and a friend of people with ME was Jonas Blomberg. One liked Jonas instinctively from the beginning. He was the type of person who would always give an unbiased and objective view on science - with no pretensions or separate agenda. Jonas was the epitome of a researcher with integrity, honesty, approachability and scientific skills. Jonas came to one of our early international conferences after being encouraged by a member of RME Sverige. Invest in ME Research (Charity Nr. 1153730) Following that meeting we invited Jonas to every conference as our guest. He was also invited to our first Colloquium and attended every one of these events since that time. His was one of the first names that we entered when planning these events ten months before. Such was the level of trust and friendship that we asked Jonas to be a chair for many Colloquium sessions and sum up conclusions from the Colloquiums. Integrity – always. Jonas was scheduled to chair, once again, the Thinking the Future – Young/ECR Conference in London in May – having successfully chaired last year’s inaugural event. Jonas would also have been attending and chairing this year's 'Conference and Colloquium and Thinking the Future events. The news of his sudden death comes as a major shock to all at the charity. This affects all of us and is a great loss to ME. Our memories of Jonas are of the best - and he will be greatly missed by all. investinme.org Page 6 of 52 Fifty Years - and ME? In medicine, healthcare, technology and science the last fifty years have seen some dramatic developments that are nowadays taken for granted. Antibiotics dramatically reduced death rates due to infection and today even new classes of antibiotics are being produced – even synthesised versions – to tackle superbugs Organ transplants have become commonplace - with thousands of transplants being performed every year. Artificial organs have been developed. Anti-viral therapy for HIV has transformed the prospects of patients from a fatal to a managed condition. Vaccinations developed against many infectious diseases have changed society. Imaging technology such as CT, MRI, and PET has revolutionised the detection of disease. Anti-TB therapy practically eradicated tuberculosis, until recently. Major advances in knowledge of the genetic code has laid foundations for the -omics branches of science. Kidney dialysis, endoscopy and laparoscopic surgery, inhaled therapy, cataract treatment, statins, beta-blockers...etc. Invest in ME Research (Charity Nr. 1153730) Revolutionary developments now in everyday use, improving lives of patients. Technologies too have changed the world Computing power and development has turned the future into the present with technologies such as artificial intelligence. With the rapid pace of development in science and technology then this overflows into medicine. Unbelievable changes are being developed and tested - such as 3D printed body parts, new complex and even remote surgical procedures , gene therapy , gut bacteria treatments, cancer immunotherapy, synthetic cells, reprogrammed cells , mitochondrial replacement therapy ................it goes on and on. If one can dream one can think the future. It all seems possible. And myalgic encephalomyelitis? Well, all of the above have had great effects on society and even people with ME will have benefited from some of these developments. However, what of ME itself? investinme.org Page 7 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Fifty years ago, we celebrated the anniversary of the first moon landing. The amazing photograph showed earth as seen from the moon for the first time. How amazing, even today, to see this image and imagine that this could be achieved with computing power less than is now available in a mobile phone, and with technology that seems ancient by today’s norms. Yet who would have thought that fifty years would go by and people with ME would still have no specialist services, no treatments, no funding for fundamental biomedical research? For ME we are still discussing the criteria, the name, the politics. We are still frustrated that there is no adequate research funding. We still suffer – at least since the beginning of this decade – of the evil that is the biopsychosocial (BPS) doctrine. We should have made far more progress than has been the case in fifty years. Yet ME has failed to achieve the progress that other areas of medicine and science have enjoyed. ME has been forced into a retarded development due to the malign forces that have kept a few in positions of influence and power in order to support policies that have long been known to be damaging. Patients have been played. And who benefits from this continued stalling of progress? Progress with ME may well depend on some of the above mentioned developments in science, technology and medicine. The view regarding ME fifty years had seemed to be, until recent years, as bleak as the moon must have appeared to the crew of Apollo 8. Yet we can hope that even the most entrenched of establishment policies will finally be swept away. Fifty years ago we were amazed to see our world from another celestial body in all its splendour. Another fifty years cannot pass without seeing solutions to ME being realised. Status of ME 2018 - www.investinme.org/IIMER-Newslet-180601.shtml Invest in ME Research o an independent UK charity finding, funding and facilitating a strategy of high quality biomedical research into Myalgic Encephalomyelitis o focuses on biomedical research into ME and the education of healthcare staff, the media, government departments, patient groups and patients o run by volunteers with no paid staff - no funding from government or government organisations o overheads are kept to a minimum to enable all funds raised to go to promoting education of, and funding for biomedical research into, ME o a small charity with growing number of supporters with big hearts and determination to find the cause of myalgic encephalomyelitis and develop treatments o we have links nationwide and also internationally and facilitate international collaboration o founder member of the European ME Alliance (EMEA) o organises annual research Colloquium and public Conference attracting delegates from 20 countries o to bring best education and research to bear on ME and find/facilitate the best strategy of research o focused on setting up UK/European Centre of Excellence for ME to provide proper examinations and diagnosis for ME patients and coordinated strategy of biomedical research in order to find treatment(s) and cure(s) - http://www.cofeforme.org/centre o the charity welcomes support for our work – www.investinme.org/donate Invest in ME Research (Charity Nr. 1153730) investinme.org Page 8 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research A Centre of Excellence for ME The charity's proposal for a Centre of Excellence for ME was first made in 2010, after having sat in meetings with the NHS for several years - wasting time and effort where there seemed little progress in attempts to improve things for people with ME. The concept is designed to create a hub of high-quality translational biomedical research into ME using standard and up-to-date guidelines and protocols that allow accurate diagnosis based on relevant tests. These would consist of full examinations, clinical diagnosis, translational biomedical research, clinical trials, bioinformatics, biobank(s) to allow for more research opportunities and support) and improved education and training of healthcare staff. By using the facilities in the Norwich Research Park, the opportunity has been created for clinical trials to be carried out and a central point for medical education on ME to be established. With the help of the Let's Do It For ME campaign our foundation research project was funded and established and began in 2013 at University of East Anglia (UEA)/Quadram Institute (QI) in Norwich Research Park. This was the first crowdfunded PhD for ME. Further projects are now u Norwich Research Park. Concentrating on a Centre of Excellenc hub does not mean that all research must be performed at the one location. IiMER has also been funding research and a PhD studentship at UCL. Thanks to amazing support from The Hendrie Foundation B-cell research was initiated which allowed a preliminary study to be established and performed prior to the UK rituximab clinical trial. The charity had been keen to replicate the Norwegian Rituximab trial find and, in 2012, the charity announced its intention to facilitate and fund a clin trial of rituximab. Invest in ME Research (Charity Nr. 1153730) Dr Oystein Fluge and his team from Haukeland University Hospital in Bergen, Norway, visited Norwich in January 2017 to collaborate with the researchers from UEA/QI. Ultimately, the Norwegian Phase III rituximab trial proved negative but much was gained by establishing necessary collaborations that are needed in such a trial and the work was not wasted. Research, at least in UK, depends on rules, regulations, ethics etc. that all have to be fulfilled. Not often realised is that one of the biggest problems we have managed to overcome was the reluctance of established researchers to enter this field. Now that has been achieved then we have to and expand upon it. rituximab trial in Norway turned o be more positive then we could now have been seeing the elements e Centre coming into play to show what could be done. ertheless, new discussions are erway to achieve this. The new building for the Quadram Institute provides new facilities and new possibilities and publicity for research into ME, and a coordinated environment where the Medical School, Clinical Trials Unit and research lab will be located together. Park is described by Quadram r Ian Charles as follows - investinme.org Page 9 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research “The development of this new centre, together with the other expertise and facilities located at the Norwich Research Park, puts it in a very good position to lead a UK and European Centre of Excellence for biomedical research for M.E. to provide possible prevention and solutions.” - Journal of IiME Conference Abstract 2015 between UK, European and US researchers and institutes. All of this has been achieved without any government support. A sustainable Centre of Excellence for ME that can build on these foundations is now an entirely attainable objective - harnessing the benefits of As can be seen from the Quadram Institute web site ME is already firmly embedded as one of their “research targets” - facilitated by the groundwork performed already by the charity and its supporters. The head of Quadram has spoken twice at the Invest in ME Research International ME Conference and there is a major group performing research with international collaboration taking place - encouraged and facilitated by the charity. The collaboration with other UK and European researchers and institutes will create greater publicity and funding opportunities. In the last year the charity has not been idle. A number of proposals and requests are being looked at and several new ideas are being developed. We hope to be able to support an initial clinical fellowship in the research park soon. International collaboration between researchers is underway thanks to the initiatives facilitated by the charity and researchers. The funds raised by the charity have allowed a research group to be firmly established in the Quadram Institute that will allow clinical trials to be carried out in a state-of-the-art setting. Invest in ME Research has, since establishing this proposal, raised in excess of £900,000 for biomedical research into ME – mainly over the last 5 years. This has enabled new researchers to enter the field and firm collaborative links to be established Invest in ME Research (Charity Nr. 1153730) collaborative international biomedical research in modern facilities with world-class researchers. We aim to continue to support development of this world-class ME research centre based in Norwich Research Park that can form a hub of European research and treatment for this disease and produce a pathway to produce huge benefits for the nation and across the world. This will continue to influence other researchers and institutes in their perception of ME and provide a pathway for career development in researching this disease. This, itself, will allow new ideas to be formed in researching and treating the disease. The foundations are therefore already in place to advance science and provide the promise of better treatment and possible restoration of function and lives back to a section of the community who have received very little help in the past. We welcome all support to enable us to complete this project. investinme.org Page 10 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research European ME Clinicians Council One of the many failings in the way ME has been handled over the last decades has been the lack of education and specialisation in ME. Few clinicians have been able to accumulate enough experience and the disease is treated in healthcare with little regard, partly due to this failure and the lack of funding for fundamental research. Those clinicians who have gained experience in treating ME patients and collaborated with biomedical researchers need to be encouraged and supported. Our international conferences and research Colloquiums have brought together researchers from around the world and been instrumental in forging new and promising collaborations. Our European ME Research Group (EMERG) concept brought European researchers together. In a similar way, we feel it is important for experienced clinicians to share their knowledge on diagnostic and treatment methods and produce documentary aids for the research community focused on clinician guided treatment trials, identification of possible illness subsets, and observations of illness presentation. The charity has therefore facilitated the formation of a new European clinicians group. An inaugural CPD-accredited meeting took place in February 2019 in London. The charity sought out the leading clinicians in Europe who are treating ME patients and whom we felt will be supportive and constructive in going forward for the benefit of people with ME and their families. This meeting followed an American initiative that was started by Dr Lucinda Bateman and Mary Dimmock. We have used the name given to the American group that met in USA early 2018 under the chair of Dr Bateman and named this group the European ME Clinicians Council (EMECC). We have also borrowed from the Invest in ME Research (Charity Nr. 1153730) investinme.org USA experiences and documentation and liaised with Mary over the establishment of this group. We used the American meeting as a model and used similar objectives. We wanted to build a network of clinicians in Europe who could support each other, work together, and come together immediately. As Dr Bateman stated, aggregating the knowledge of experienced clinicians on clinical sub topics related to ME/CFS and providing patients, caregivers, advocates, clinicians and the researchers the most up to date information is a critical outcome. The aims of the inaugural meeting were therefore to bring together clinicians in the field of ME, to review the current state of knowledge, to present and discuss the latest initiatives, and to foster collaboration. Since the meeting the clinicians have been working together and this has become a formal group that will work with the American initiative and be supported by the European ME Alliance (now representing fifteen countries). This group will improve the knowledge of clinicians in Europe and act as a focal point for healthcare agencies, doctors and media outlets who wish to learn more from experienced clinicians about ME. The next meeting has already been planned in order develop the network and it has already increased in numbers since the first meeting. The first EMECC meeting took place over three days and a very positive and progressive atmosphere was created with a range of topics being discussed covering diagnosis, treatments, follow-ups, education, research and how the group continues and expands. One of the first items from EMECC is the following statement - Page 11 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Statement from EMECC LONDON, May 2019 International clinical and research experts participated in the first CPD-accredited European ME Clinicians Council (EMECC) workshop that took place over three days in London in February. EMECC has been formed to bring together clinicians from across Europe and from various disciplines to develop a European foundation of high-quality clinical expertise on myalgic encephalomyelitis (ME, also known as ME/CFS). Myalgic Encephalomyelitis (ME or ME/CFS) is classified as a neurological disease that affects patients’ lives profoundly. The USA Institutes of Medicine (IOM) stated in its 2015 report that “it is clear from the evidence compiled by the committee that ME/CFS is a serious, chronic, complex, multisystem disease that frequently and dramatically limits the activities of affected patients”. In view of this, we are concerned to note the longstanding and continued promotion in many countries of the psychosocial view of this condition, whereby it is regarded as a "non-disease" caused simply by a combination of falsely held patient belief systems combined with deconditioning. In our view, this belief system has done immense harm to both the patient community and the prospects for research on this condition. There is much misinformation for this debilitating disease where the current lack of any effective treatment aggravates patient suffering caused by mismanagement due to inadequate, and sometimes absent, policies of healthcare agencies regarding this disease. IOM state that physicians should diagnose ME/CFS if diagnostic criteria are met following an appropriate history, physical examination, and medical work-up. EMECC aims to harvest effective strategies for patient management and treatment from the pooled clinical knowledge of physicians working extensively with ME/CFS patients. A further important aim is to provide or refine ideas for research in all aspects of the disease based on the extensive clinical, handson clinical experience of the EMECC members. The meeting created a very positive and progressive atmosphere with a range of discussions around diagnosis, management and treatments, follow-up investigations, health personnel education and research and how the group will continue and expand. Arranged by UK charity Invest in ME Research and endorsed by the European ME Alliance this workshop involved leading clinicians from Europe who are treating ME/CFS patients and who will be instrumental in creating a sea change in clinical care for the benefit of people with ME and their families. The group will fill a vacuum in clinical expertise that has allowed false beliefs about the real nature of the disease to be propagated. This group will continue to meet in locations across Europe for follow-on meetings and be able to play an important role in clinical care, biomedical research and guidelines development. The workshop was CPD-accredited and we look forward to this group of clinicians/researchers making huge progress in developing sound clinical care for ME/CFS patients - and with the collaboration with our colleagues in the European ME Alliance. European ME Clinicians Council For more information, please contact info@euro-me.org or info@investinme.org Invest in ME Research (Charity Nr. 1153730) investinme.org Page 12 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Encouraging Young Researchers In highlighting some of the issues with ME a major problem is the lack of biomedical research into ME and the funding required for it. Another issue with ME that the charity has been attempting to resolve is the need for new research talent to enter the field. Medical students receive extremely poor education on ME in their curriculum - sometimes even nothing. Not only might this be negligent, as young doctors are subsequently unqualified to deal with ME, but it also means that potential recruits to ME research and treatment positions are discouraged due to ignorance of the condition. Medical students are unaware of the career opportunities. One way to get around this problem was to make students aware of the research that was being undertaken. With the help of the University of East Anglia Medical School the charity was able to fund and facilitate the participation of a number of medical students in the research being performed at Norwich Research Park. The idea was to fund the inclusion of medical students in research via a process of intercalation during their fourth year of medical studies. This led to collaboration with research at Oxford University with Professor Angela Vincent and with Dr Lesley Hoyles at Imperial College London. This has proven to be very successful. Apart from influencing opinions of their peers the medical students have been very active and well received in the research teams. Navena Navaneetharaja was one medical student funded by IiMER and Navena spent time with Professor Maureen Hanson at Cornell University in Ithaca, New York - developing another of IiMER's strategies in forging international collaboration in research. Thinking the Future network To ensure that a foundation of biomedical research into ME Invest in ME Research (Charity Nr. 1153730) investinme.org can be sustained and to encourage new ideas from new areas then we cannot rely just on this family of researchers that has been built up from all parts of the world at Colloquiums. We need to draw in knowledge and expertise from other areas – as we have been doing for many years with our research Colloquiums and international Conferences. Importantly, we also need to encourage early career researchers – and young researchers. In 2018 the charity initiated the young/early career researcher conference - Thinking the Future - an initiative to build a network of new and young research capacity for the future. The Thinking the Future network has the opportunity for developing this group of international, early career researchers which will, in turn, facilitate further international collaboration in research into ME and new ideas being formulated. In fact we have already had several meetings with NIH to collaborate on developing this network. Recently the Thinking the Future workshop was held by NIH in Washington and 40 young/ecr researchers attended. Dr Daniel Vipond from Quadram Institute represented the charity and spoke at the Washington TtF event. We are happy that eleven young/ecr investigators will be attending the TtF3 in London in ME Conference Week - funded by travel awards from NIH. We wish to facilitate and maximise the easy networking of attendees in order to build the network in USA and join it with the established group of European young/ecr researchers so IiMER will cover all registration costs for these delegates – to the TtF workshop and to the 2-day Colloquium and the public IIMEC14 conference. We hope this initiative will provide a focal point for all young/ecr researchers who wish to become involved in research into ME and help describe the exciting career path that this could become. Page 13 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Denmark - Ærlighed varer længst (HONESTY LASTS LONGEST) DANISH PARLIAMENT SEPARATES ME G93.3 FROM FUNCTIONAL DISORDERS Following excellent work by European ME AllianceDenmark member Dansk ME Foreningen, and work and input by those such as European ME Clinicians Council member Dr Jesper Mehlsen, there is now unified support in the Danish parliament for separating ME G93.3 from Functional Disorders and acknowledgment that the existing treatment of ME patients is inadequate and stigmatising. Specialist services are needed and the Department of Health needs to update its guidance regarding ME. Voting on the adoption of this proposal took place on Thursday 14th March. The Danish parliament voted unanimously for the separation of ME WHO ICD-10 G93.3 from Functional Disorders and called for the Department of Health documentation to be amended to reflect this. This discussion in the Danish parliament on classifying ME as a somatic and not as a functional disease is good progress. It was based on the case of a 29-year-old woman who has been lying in bed in a dark room since 2015, being taken care of by her parents without any help from the Danish healthcare system. Both the Danish ME organisation and Dr Mehlsen had been in contact with a number of politicians on both sides of the aisle and the results are positive. The Danish parliament voted unanimously in favour of ME as a somatic disease to be removed from the centres of functional diseases. That will be a great relief for the family concerned, for physicians, and for the Danish ME community. The result should help Finland too, as a team at Duodecim (Finland's largest scientific association) has been formed to look at Finnish guidelines and there was a proposal to adopt the previous Danish position. That cannot happen now and the Finnish authorities must change course accordingly. Invest in ME Research (Charity Nr. 1153730) investinme.org Page 14 of 52 In fact, the Finnish be improved for patien Duodecim will ne recent Swedish r says there is not to formulate adeq guidelines/propo One of the statem Swedish working guidelines was the f " Considering the situation as regard it is crucial that the interventions off patient diagnosed w ME/CFS or similar must be individu for the patient in q and evaluated. This patient grou need of care measures alleviate sympto improve quality o For the individual p different evidenc interventions can offered on the basis the symptoms presented in the patient in questio example, measur pain or sleep disturbances. The care provider mu be perceptive and take all aspects o the patient’s medical problem and healthcare needs into account." Journal of IiMER Volume 13 Issue 1 Invest in ME Research UK - Parliamentary Debate In UK a parliamentary debate in the main chamber held on 24th January 2019. The person responsible for getting all of this started, a supporter of IiMER, was a constituent of SNP MP Carol Monaghan who put forward the debate. This followed on from a previous parliamentary debate held in June 2018 on the PACE Trial. The debate was entitled - “That this House calls on the Government to provide increased funding for biomedical research into the diagnosis and treatment of ME, supports the suspension of Graded Exercise Therapy and Cognitive Behaviour Therapy as means of treatment, supports updated training of GPs and medical professionals to ensure they are equipped with clear guidance on diagnosis of ME and appropriate management advice to reflect international consensus on best practice, and is concerned about the current trends of subjecting ME families to unjustified child protection procedures.” IiMER made a document - The Debate is Over – Give ME Patients a Future - covering some of the issues relating to the parliamentary debate on 24th January 2019. This is available on our web site. In this summary the charity called for the following A Public Inquiry into ME  Implementation of revised CMO Report Recommendations  Removal of Existing NICE Guidelines for ME immediately  An annual Report to Parliament of the Status of ME  Transparency of Meetings Concerning ME by MRC  Removal of Those Previously Responsible for ME from positions of Influence  Research Funding - A five-year, ring-fenced budget of £20 million per year for biomedical research into ME should be allocated  Guidelines for diagnosis must be as accurate as possible and must be up to date  The CMOs of UK Must Report Annually on Prevalence of ME in UK  Patients Diagnosed with ME Need a Regular Follow-up Pathway Invest in ME Research (Charity Nr. 1153730) In 2018, IiMER carried out an extensive correspondence with the then director of NICE guidelines Professor Mark Baker. We made the case for removing both Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) as recommendations from the existing NICE guidelines immediately - whilst a new review was underway. This obvious necessity to remove recommendations which harm patients, something IiMER has called for consistently and which most now agree with, was met with disingenuous arguments from NICE as to why they would not be removed. The NICE review of guidelines for ME has now produced a guidelines working group. This has already been criticised by many for creating a “balance” between those who have a disposition to a Biopsychosocial view of ME, and those who believe ME to be a biomedical condition. The shambles of development group selection process reached farcical proportions during the setting up the group, with piecemeal announcements being made as to who had been selected for the development group and who had not, and background lobbying being conducted to get special places for certain individuals in this working group. The lack of transparency in the selection process was typified by the situation whereby some people who had applied to the working group and had been rejected could nevertheless conveniently be found a position connected to the working group. It demonstrates that the whole selection process is flawed. NICE has politicised this whole process where there was no need and really cannot be trusted. There are obvious conflicts of interest still left in place in this investinme.org Page 15 of 52  NICE Must Follow Department of Health View of ME  A specialism consultant needs to be established for ME  Medical curricula need to be revised education needs to extend to social care  Schools need to be educated about ME There are some clear signals for what needs to be done – as always we look for actions to replace words.

Journal of IiMER Volume 13 Issue 1 Invest in ME Research group where positions seem to be able to be negotiated. A “balance” was created where no “balance” was necessary. The Centre for Guidelines (CfG) develops guidance based on - • the promotion of good health • the prevention of ill health • the appropriate treatment and care for people with specific diseases and conditions • social care and service delivery We contend that retaining the existing guidelines – especially the recommendations for CBT and GET that are known to harm patients – is not promotion of good health. We also contend that retaining these recommendations is not preventing ill health. We provided a letter to Professor Baker from an ME patient who was a civil servant and who clearly described the harm done by CBT and GET. Professor Baker’s response was that the existing guidelines had “nuances” (nuances only perceived by Professor Baker it would seem) that apparently meant that patients did not have to accept CBT or GET. The fact is that insurance companies force people to go through these shambolic treatments precisely because they are recommendations by NICE. NICE seem to think that it would be possible for patients suffering from ME to have the capacity (either physically or financially) to fight the might of insurance companies. The level of puerile thinking on the part of NICE is unconscionable. The opportunity to withdraw these irresponsible recommendations from the existing guidelines has been lost and we are left with a shambolic working group selection process that augurs badly for the future. NICE could have removed the politics from this topic if it had approached the whole review with transparency. Now we are left with a compromised working group full of self-interest and conflicts of interest and we can only foresee another wasted opportunity and a fudges being formed for publication in 2020 that will serve nobody. At least NICE must accept all responsibility for any harm caused to patients who are forced into trying CBT and/or GET due to NICE retaining the existing recommendations for CBT and GET. Hopefully, other developments that may come to fruition over the next year will leave these farcical NICE tactics as a redundant relic from the past. One wonders what NICE can really imagine will be available for their review. The IOM carried out an extensive literature review in their 2015 report. Recently the Swedish authorities have examined ME. Their report follows – and it is doubtful that in one year NICE will deliver anything original – unless they remove CBT and GET completely, as many other countries have done or are doing. What NICE could have done is review the recent analysis by Sweden and their National Board of Health and Welfare. Sweden From Article number 2018-12-48 1(2) A review of the current knowledge status for Myalgic encephalomyelitis/chronic fatigue syndrome, ME/CFS Summary Socialstyrelsen (National Board of Health and Welfare) has been tasked by the Government to review the knowledge status and examine the prerequisites for providing support to healthcare professionals through guidelines and insurance medicine decision support (FMB) with regard to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Patients with ME/CFS have autonomous, cognitive and immunological symptoms. Typical symptoms are tiredness or fatigue, influenza-like symptoms with a feeling of fever, general pain in joints and Invest in ME Research (Charity Nr. 1153730) investinme.org Page 16 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research muscles, and disturbed sleep. The symptoms can be exacerbated by physical or mental exertion and the worsened state continues for more than 24 hours afterwards (post-exertional malaise, PEM). Descriptions of this disorder have existed since the 1950s. There are many hypotheses about what causes ME/CFS but up to now it has not been possible to prove any of them. Research is being done but currently there are no biomarkers for diagnostics, nor any medical treatment. The prevalence of ME/CFS depends on what criteria have been used and how data have been gathered. The figure varies from 0.1 percent to 6.4 percent of the population. When it comes to opinions regarding the cause of ME/CFS and its treatment, there are different standpoints: those who support a bio-medicinal view and those who support a biopsychosocial view. The question is whether the disorder should be explained purely through pathological biochemical and physiological findings, or whether mental and social factors must also be included in order to be able to explain certain medical problems. ME/CFS is an exclusion diagnosis. There are no biomarkers. Instead, the diagnosis is made with the help of diagnosis criteria that are only used when other physical or mental causes of the symptoms have been excluded. There are several different diagnosis criteria that overlap one another in part and there is no international consensus about them. There are also different standpoints regarding what illnesses/disorders are to be excluded before the diagnosis is made, and what comorbidity may exist. Patient representatives have pointed out the need for equal healthcare, guidelines and specialist care for this group. Patients’ experiences of healthcare vary both at individual level and according to geographical location in Sweden. Patients have also pointed out the need for more understanding treatment by healthcare professionals and for coordinated interventions. An overview of qualitative studies from SBU (Swedish Agency for Health Technology Assessment and Assessment of Social Services) regarding how adult patients diagnosed with ME/CFS perceive the care they are given shows that diagnosis, advice and support are essential. The patients have described the journey to a diagnosis as being cumbersome and that they have had to fight in order to get help. They feel that people are not interested in their problems and that healthcare professionals at primary care level do not believe the illness exists. Socialstyrelsen’s dialogue with the healthcare professional groups in question has shown that Invest in ME Research (Charity Nr. 1153730) there is a certain demand for national guidelines and insurance medicine decision support. However, specialists in general medicine seldom meet patients with ME/CFS, and no specific specialist field feels they have special responsibility for this patient group. This shows that these patients do not have any proper “home” in the healthcare system. The systematic overview conducted by SBU indicates that the scientific sup-porting documentation for the interventions offered in the relevant studies is insufficient. In addition, Socialstyrelsen’s survey shows that it is not possible to draw conclusions about the benefit of those interventions on the basis of proven experience since the prerequisites for consensus among clinical experts in this field are lacking. Therefore, Socialstyrelsen’s assessment is that it is currently not possible to draw up national guidelines with general advice in this area, as requested by the healthcare sector. Moreover, the basic preconditions for further work on insurance medicine decision support (FMB) for the diagnosis of ME/CFS do not exist. Socialstyrelsen emphasises that being on sick leave can be a correct intervention but no general recommendations can be given. Considering the current situation as regards evidence, it is crucial that the interventions offered to each patient diagnosed with ME/CFS or similar symptoms must be individually adapted for the patient in question and evaluated. This patient group is in need of care measures to alleviate symptoms and improve quality of life. For the individual patient, different evidence-based interventions can be offered on the basis of the symptoms presented in the patient in question, for example, measures for pain or sleep disturbances. The care provider must be perceptive and take all aspects of the patient’s medical problems and healthcare needs into account. The systematic overview and the qualitative report from SBU and this review by Socialstyrelsen can provide the healthcare sector with an up-to-date picture of the knowledge status, and indicate the need for more interventions and research for this patient group. Socialstyrelsen’s intention is to facilitate a dialogue between representatives for different professions in order to increase consensus in the long term. Here is the English version of the summary https://www.socialstyrelsen.se/Lists/Artik elkatalog/Attachments/21182/2018-12-48summary.pdf investinme.org Page 17 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Myalgic encephalomyelitis and Chronic Fatigue Syndrome (ME/CFS) - A systematic review sbu policy support december 2018 | www.sbu.se/295e Summary Aim The aim of this report was to investigate the available body of evidence for the treatment and prognosis of ME/CFS as well as a review of the health care experiences of patients. Background Myalgic encephalomyelitis, also called Chronic Fatigue syndrome (ME/CFS), was first described 70 years ago. The disorder often is preceded by an infection but the pathology and mechanisms behind ME/CFS are still unknown. People with ME/CFS can suffer from a broad spectrum of symptoms, e.g. prolonged fatigue, pain and post-exertional malaise (PEM). Individuals with ME/CFS have decreased activity levels and can have difficulty handling their everyday day duties, work, or studies and maintaining social relationships. For some, the symptoms can be so severe that they are home-or bedbound. There are no biomarkers for ME/CFS that can be used for diagnosis. The criteria for diagnosis have therefore developed over the years and are consensus-based sets of core symptoms. All the criteria include newly-onset severe and persistent fatigue and stipulate that core symptoms must have persisted for at least 6 months. The newer Canadian Consensus Criteria differs from previous criteria in that PEM lasting at least 24 hours after physical or mental exertion is required for a diagnosis. By applying the Canadian Consensus Criteria, the prevalence of ME/CFS is estimated to be about 0,1% of the population. Differentiating between ME/CFS and other diseases with long lasting fatigue, e.g. stress related exhaustion disorder, can be difficult. Studies show that half of patients referred to specialist clinics for suspicion of ME/ CFS were shown to have other diseases after closer examination, mostly sleep or psychiatric disorders. There is no curative treatment for ME/CFS. Health care therefore aims at relieving symptoms and supporting the patients in the management of their everyday lives. Content of the report This report is made up of four systematic reviews, conducted according to international guidelines. The first systematic review focuses on treatments and their effects on fatigue and PEM for persons with ME/CFS diagnosed with the Canadian Consensus Criteria. Treatments that aimed at relieving other symptoms, e.g. sleep problems or pain, or psychological therapies aimed at helping patients manage their disease were not included. Included studies were controlled clinical trials, with or without randomisation. The second systematic review assesses prognosis for recovery and return to work, while the third investigates whether there are any prognostic factors for improvement and return to work. In the fourth systematic review, we explore how patients experience their health care by reviewing studies that used qualitative methods, such as interviews, to address this question. The report only includes studies on adults. Main results A major finding was that the effects of treatments for patients diagnosed with the Canadian Consensus Criteria on fatigue or PEM cannot be estimated. Most studies used older criteria, mainly the Fukuda criteria, meaning there is a risk that the participants in the studies had other conditions, such as stress related exhaustion disorder or depression. Whether these results are valid for persons diagnosed according to the Canadian Consensus Criteria is therefore unclear. A small number of studies, most investigating pharmaceutical treatments, used the Canadian Consensus Criteria. None of these studies reported that the drug reduced fatigue. The prognostic studies identified applied older criteria. Two studies conducted in Scandinavian countries reported that a substantial proportion of the participants had not recovered at follow-up, around 10 years after symptom onset. One English and one Norwegian study found that many patients who had been diagnosed in specialist clinics after several years of disease and unemployment, had not yet returned to work or study at follow-ups conducted many years later. Prognostic factors for recovery or return to work could not be evaluated Invest in ME Research (Charity Nr. 1153730) investinme.org Page 18 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research as there were few studies, which were small and had substantial methodological limitations. The qualitative studies mostly described patient experiences in primary care. Many perceived that getting a diagnosis was a milestone and that individually tailored support was crucial for them to move on with their lives. They experienced the process of obtaining a diagnosis as burdensome and frustrating and felt that they were met with ignorance and lack of understanding. Discussion This report shows that there are many scientific evidence gaps regarding ME/CFS. Many gaps, such as methods for diagnosis and efficacy of curative or disease modifying treatments, are related to the lack of understanding of the aetiology behind ME/CFS. This report also indicates that a thorough diagnostic work-up is crucial. Multidisciplinary specialist competences are necessary to reliably exclude other disorders. Finally, the absence of evidence for effect of ME/CFS treatments does not mean that the treatments lack effect, but rather indicates that Project group Experts Per Julin, MD, PhD, Karolinska Institutet, Stockholm, and the ME/CFS-clinic, Stora Sköndal Per Lytsy, MD, Assistant Professor, SBU Marie Åsberg, Professor, Karolinska Institutet and Danderyd Hospital, Stockholm (advisory role in assessing differential diagnoses) SBU Agneta Pettersson (Project Manager) Susanne Gustafsson (Information Specialist) Caroline Jungner (Project Administrator) Lina Leander (Assistant Project Manager) Hanna Olofsson (Information Specialist) Scientific reviewers Kristina Bengtsson Boström, Skaraborg Kristina Glise, Göteborg Björn Mårtensson, Stockholm Anne Söderlund, Västerås SBU Assessments no 295e, 2019 www.sbu.se/en • registrator@sbu.se English Proofreading: Rebecca Silverstein, SBU Graphic Design: Åsa Isaksson, SBU Invest in ME Research (Charity Nr. 1153730) investinme.org Page 19 of 52 research is needed to clarify the effects of current treatments for people diagnosed with ME/CFS according to the Canadian Consensus Criteria. Meanwhile, it is important to support people with ME/CFS so they can attain the best quality of life, levels of function and participation in society as is possible. Since ME/CFS is relatively uncommon compared to other similar disorders, e.g. stress related exhaustion disorder or chronic pain, specialist clinics for ME/CFS would probably be advantageous, as they would be most likely to be able to closely follow the research and quickly implement new developments into clinical practice. Small charity BIG Cause With no major investment into correct research into myalgic encephalomyelitis during the last decades Invest in ME Research has, with a determined band of supporters, taken action for change in the absence of any coherent or scientific establishment policies. Funding has to be given to biomedical research and new knowledge from other disciplines such as virology, immunology, endocrinology etc. has to be brought in to help research into ME. Invest in ME Research has initiated and funded high-quality biomedical research at UEA and Quadram Institute Biosciences and at UCL - and facilitated development of international collaboration with other research institutes. Vision with action can change the world

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Perceptions of Care in a Hospital’s Emergency Department Division of Rheumatology, Immunology and Allergy, Georgetown University, Washington, DC, USA *Both authors contributed equally to this work A very useful recent paper published by Timbol and Baraniuk discusses Emergency Department visits by ME/CFS patients. "CFS patients present to the ED with a complex list of chronic symptoms, but the acute reasons for presentation are related to orthostatic intolerance, fatigue, PEM, and diarrhea." Professor James Baraniuk - Professor of Medicine at Georgetown University Medical Centre, Washington, USA - is a regular at IiMER colloquiums and conferences and always has very interesting and useful contributions. "This is of importance because it provides a starting point for diagnosis and treatment by ED physicians," Baraniuk said. "This condition is something that can be readily addressed by ED caregivers," he said. "There is a real need for physician education that will improve their efficiency in identifying and treating CFS, and in distinguishing CFS symptoms from other diseases in the exam room." "These patients should feel they are respected and that they can receive thorough care when they feel sick enough to go to an ED," Baraniuk said in a Georgetown news release." Here is the abstract. Chronic fatigue syndrome in the emergency department Available from DovePress https://www.dovepress.com/chronic-fatiguesyndrome-in-the-emergency-department-peerreviewed-fulltext-article-OAEM Christian R Timbol,* James N Baraniuk* Invest in ME Research (Charity Nr. 1153730) Purpose: Chronic fatigue syndrome (CFS) is a debilitating disease characterized by fatigue, postexertional malaise, cognitive dysfunction, sleep disturbances, and widespread pain. A pilot, online survey was used to determine the common presentations of CFS patients in the emergency department (ED) and attitudes about their encounters. Methods: The anonymous survey was created to score the severity of core CFS symptoms, reasons for going to the ED, and Likert scales to grade attitudes and impressions of care. Open text fields were qualitatively categorized to determine common themes about encounters. Results: Fifty-nine percent of respondents with physician-diagnosed CFS (total n=282) had gone to an ED. One-third of ED presentations were consistent with orthostatic intolerance; 42% of participants were dismissed as having psychosomatic complaints. ED staff were not knowledgeable about CFS. Encounters were unfavorable (3.6 on 10-point scale). The remaining 41% of subjects did not go to ED, stating nothing could be done or they would not be taken seriously. CFS subjects can be identified by a CFS questionnaire and the prolonged presence (>6 months) of unremitting fatigue, cognitive, sleep, and postexertional malaise problems. Conclusion: This is the first investigation of the presentation of CFS in the ED and indicates the importance of orthostatic intolerance as the most frequent acute cause for a visit. The self-report CFS questionnaire may be useful as a screening instrument in the ED. Education of ED staff about modern concepts of CFS is necessary to improve patient and staff satisfaction. Guidance is provided for the diagnosis and treatment of CFS in these challenging encounters. investinme.org Page 20 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Medical Education Education about ME has been one of the major objectives for Invest in ME Research. Dr Nina Muirhead and students at Cardiff University have been working on medical education. Invest in ME Research invited them to present poster presentations at the IIMEC14 conference in London. The studies demonstrate the following – 1) What is the Impact on Quality of Life of Family members with ME/CFS using the internationally validated QHOQUOL-BREF and FROM-16? Needless to say results show the negative impact of ME/CFS on family members is greater than any other medical condition. 2) What should medical students be taught about ME/CFS? This explores current teaching in 22 medical schools UK wide and uses qualitative information from patient surveys to make recommendations for not only what should be taught but how and when this could be delivered in the undergraduate medical school syllabus. 3) What is the role of the GP in care of ME/CFS patients in the community? This study draws together patient opinions in the form of 690 patient survey responses plus detailed ideas from qualitative analysis of telephone interviews of patients with a range of illness severity and duration. The patient voice is increasingly used in guideline development. We include here the abstracts for these presentations. The Impact of ME/CFS on the Family: Measuring Quality of Life (QoL) using the WHOQOL-BREF and FROM-16 Questionnaires Brittain EL, Muirhead NL, Finlay AY and Vyas J. ABSTRACT Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic condition Invest in ME Research (Charity Nr. 1153730) investinme.org Page 21 of 52 characterised by a multitude of symptoms, ranging from post-exertional malaise to cognitive difficulties. ME/CFS has been shown to significantly reduce patients’ quality of life (QoL) when compared to both healthy controls and patients with other chronic illnesses. To our knowledge, our study is the first to explore the impact of ME/CFS on QoL of both adult sufferers and their family members using the validated questionnaires: World Health Organisation Quality of Life - Abbreviated Version (WHOQOLBREF) and Family Reported Outcome Measure (FROM-16). The study information was posted on the website and social media pages of the charity WAMES (Welsh Association of ME & CFS Support). A total of 39 volunteers expressed an interest in participating in the study and were posted a questionnaire pack containing one WHOQOL-BREF and four FROM-16 questionnaires. People with ME/CFS completed the WHOQOL-BREF and up to four of their family members completed the FROM16 questionnaire. 29 participants returned the questionnaire packs (74% response rate), of which 5 were excluded due to incomplete data or not meeting the inclusion criteria. There was a negative effect on quality of life for both people with ME/CFS and their family members. People with ME/CFS, on average, scored substantially lower in the ‘Physical Health’ domain of the WHOQOL-BREF and scored highest in the ‘Environment’ domain. Conversely, the higher the FROM-16 score, the greater the adverse QoL impact on family members. FROM-16 total scores showed that the impact on QoL was very high (mean=19.86 SD=7.17 n=42) compared to previous studies of family members of patients with other diseases (mean=12.28, SD=7.47, n=120) and cancer (mean=11.75 SD=5.85 n=248). For people with ME/CFS: there was a strong correlation between health satisfaction and their perception of their QoL (rs=0.50, p=0.013) and none were ‘satisfied’ with their health nor rated their QoL as ‘good’. A significant correlation was found between the QoL of people with ME/CFS and their family members’ mean FROM-16 total score (rs=-0.41, p=0.047, n=24). This study has for the first time used FROM-16 to measure the impact of ME/CFS on the QoL of adults and their family members and highlights the need for additional larger-scale research into this area. The results of this study emphasise the importance of ensuring support is widely available to the family.

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Understanding the Role of the General Practitioner in Caring for Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Community Allwright EG, Muirhead NL Background Patients with ME/CFS are reliant on their GP for a diagnosis and early management but also holistic support, particularly where secondary services are limited. There has been increasing recognition of the importance of the patient voice. This study aimed to gain a better understanding of the patient perspective of GP care of ME/CFS with a view to identifying ways of improving the patient experience. Methods Information was gathered from: 1) an online question answered by 690 members of the ME Association 2) 47 written responses to this question 3) ten semi-structured interviews with patients with a diagnosis of ME/CFS. Qualitative, thematic analysis of both the written feedback and interview transcripts was used to identify themes. Results The online question demonstrated that patients prioritised the importance of GPs having an understanding of the symptoms of ME/CFS in order to make a diagnosis. Five themes were identified from the online free text responses and nine themes from the interviews. These covered the role of a GP in diagnosing and managing ME/CFS; the patients’ perception of their GP’s knowledge of ME/CFS; the broader role of the GP with links to social care and support to claim Disability Allowances; and patients’ reports of the relationship between patient and GP. The data also supported the concept of having a designated healthcare practitioner, be it a GP, therapist or practice nurse, who could offer consistent care and support. Conclusion Participants believed that their GPs did not have sufficient resources or knowledge to best manage ME/CFS however this was deemed less important to patients than a willingness to listen and sympathise with the patient, to understand their individual experience and work in collaboration with them towards recovery. Overall, participants emphasised the perception that a supportive GP, who is honest and open with patients, can make a significant Invest in ME Research (Charity Nr. 1153730) impact, regardless of their ability to cure the patient; “you hope you have a supportive GP because he will help you, even if he can’t treat you, he will help you”. What Should be Taught to Medical Students about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Lavery GE and Muirhead NL Introduction: The lack of understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) amongst health care professionals has been shown to cause delayed diagnosis, misdiagnosis and harm to people with ME/CFS (PWME). There is a paucity of data surrounding teaching on ME/CFS in UK medical schools. A small study undertaken in 2012 demonstrated that UK medical students 'were unconfident and uncertain around their understanding of CFS/ME, held varying models of aetiology of the illness and had limited knowledge of the symptoms and suitable management strategies’. A larger study conducted in the USA showed that only 28 percent of medical schools met the curricula criterion for ME/CFS teaching. Methods: 1) A quantitative analysis examining current teaching on ME/CFS at UK medical schools was performed. All 34 undergraduate medical schools in the UK were invited to complete an online survey through the website 'SurveyMonkey’, 22 medical schools (65%) completed the survey by the deadline. 2) A qualitative analysis exploring PWME’s perceptions of important topics to teach medical students was subsequently performed. PWME were invited to respond to a post on the Welsh Association of ME & CFS patient charity website (WAMES), entitled “What should medical students learn about ME?”. Thematic analysis applied both manually and using NVIVO 11 software identified key themes. Results: 1) Medical schools were able to skip questions if the answer was unknown. Data from the survey showed that 11 of 19 medical schools include formal teaching on ME/CFS in their curricula, the majority of whom deliver this teaching in lecture format. Only 3 of 12 medical schools spend more than two hours teaching on the topic and 2 of 10 include clinical contact with PWME. Only 5 of 19 include question(s) on ME/CFS in formal exams. Most investinme.org Page 22 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research medical schools expressed an interest in receiving videos, e-learning and lecture materials on ME/CFS. 2) Thematic analysis of 38 written responses from PWME identified three key themes that PWME believe medical students should be taught about: i) the definition and diagnosis of ME/CFS; ii) treatment options; and iii) the ways in which ME/CFS affects quality of life (QoL). Conclusion: The creation of e-learning or a short video to introduce ME/CFS followed by lectures or a teambased learning approach are suggested to improve teaching of medical students on the topic of ME/CFS. It was also concluded that a comprehensive basis for medical student ME/CFS teaching relies on a curriculum that encompasses accurate up to date information on the epidemiology, terminology, aetiology, treatment and effect on QoL of ME/CFS. presented with evidence of the damage caused, is negligent. There are also doctors who clearly remain ideologically challenged by this disease and continue to harbour false views about ME, fed by a Biopsychosocial (BPS) influenced healthcare system. Above all doctors seem to have lost any ability to say, "I don't know what is wrong" - as though this may be a shortcoming. So much easier to assign a diagnosis of the spurious Functional Neurological Disorder (FND). If only doctors would say, "I don't know what is wrong but will work with you to find answers". If only patients were believed. Much of this can be traced back to negligent policies from governments, health departments, research councils and clinical care organisations, and research funding bias that discourages biomedical research into ME. Doctors and Patients Many ME patients, at least those who are still being treated by a doctor, often comment on how doctors do not understand the disease. This itself compromises the future prospects for a patient to receive anything approaching adequate care. The reasons for this may be that doctors receive no training on ME - either during medical school due to flawed and sparse contingency in the medical curriculum for ME - or later during their career where there is little on offer. Invest in ME Research has, since 2006, been arranging CPD-accredited conferences for professionals in London and the participation of doctors has been gradually increasing. Yet there remains a great deal to do. Medical education about the realities of ME is essentially missing - with what is on offer being either inadequate or incompatible with the true requirement to understand this disease and be aware of what can make patients worse. Doctors also may be constrained by NICE guidelines in what they feel they are able to offer. NICE guidelines are currently being reviewed yet the farcical set up of the guidelines development group augurs badly for any positive outcome. NICE’s refusal to remove CBT and GET immediately from the existing guidelines, despite being Invest in ME Research (Charity Nr. 1153730) Despite this, there have been signs of light coming through as more education and more research, funded by organisations like Invest in ME Research, changes the barren landscape that has existed in the UK healthcare system. And there are doctors who think for themselves and listen to their patients. And there are pioneers in treating people with ME. Two such doctors were Dr John Richardson and Dr Irving Spurr. Dr John Richardson had a distinguished career as a physician and published numerous papers. He was a founder member of the Newcastle Research Group in which he was very active and the primary organiser of their annual international conferences. He was also a member of the Melvin Ramsey society and the Environmental Medicine Association as well as other medical research organisations. Following his retirement from the NHS, he continued to see patients privately on a voluntary basis regularly seeing in excess of thirty per day. Many travelled considerable distances from the UK investinme.org Page 23 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research and abroad for his specialist advice and treatment and frequently were referred by hospitals and their own doctors. Dr Irving Spurr was a GP in the rural Weardale Practice in County Durham for 28 years until his retirement in 1997. Listen to the patients Stories of ME Over the years Invest in ME Research has received many stories of people enduring ME, and who have experienced the lack of knowledge about the disease, the ignorance. Some long stories, some short. He was committed to doing his very best for his patients and this led him to become a pioneering researcher into ME. During the early Eighties, a boy of 14 came to see him with all the symptoms. Irving wanted to get to the bottom of what was causing it, but ME was, at the time, belittled in NHS circles as not a ‘real’ condition (some would say little has changed). He became heavily involved in the fledgling John Richardson Research Group, a medical charity in the north-east of England, ultimately leading its work to promote greater understanding and awareness, as well as more effective treatment. His commitment included running ME clinics, with his nurse wife Eileen at his side, but it was extended to delivering lectures all around the country and building links with colleagues in Norway, Canada and Israel. He continued with the clinics until the onset of the ill-health that preceded his peaceful death. In recent years his view on ME — once a lonely one — increasingly become more accepted and mainstream, to the benefit of many sufferers from this disease. Yet he never let his crusade for ME cause him to short-change his other patients. The John Richardson Research Group made a wonderful donation to Invest in ME Research to continue to establish a national and international centre for ME and translational medicine in this area. All underlying the incomprehensibility of retaining the status quo in terms of research, treatments and services – that has suited some organisations, and individuals and benefited those taking salaries or maintaining careers based on this state of affairs. So it is always surprising that the old adage “listen to the patients” is something often ignored. We pointed this out in Listen to the Patients http://www.investinme.org/IiMER-Newslet-180901.shtml where it seems to go wrong, even in a country which has everything required for providing an example of how to perform research into ME, how to develop services for people with ME and how to treat ME as the organic illness that it is. It is sobering to read some of the stories from patients, and carers – even just clips. We alluded to some in them in the Advent Calendar Day 14 article Humour and ME article But definitely not with any humour is the story of the family of Rose - "The consultant said that the some of the symptoms Rose had were not due to ME (i.e. memory loss and paralysis) and that her ME could be a cloak for PRS (Pervasive Refusal Syndrome)." from ‘An ME Carer’s View’ http://www.investinme.org/mestory1019.shtml Invest in ME Research (Charity Nr. 1153730) investinme.org Page 24 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Here we have some, just a few of the many stories written or told or emailed over the years – Some examples – Dr D. "I saw 2 GP's in the summer holidays. They were cold to the point of hostile when I had the temerity to suggest that I had ME/CFS." Sandra "I was interviewed by this supervisor every Monday and every Friday from then on. I felt like I was a criminal. She took me into a small office and every time asked how I was doing and how long would it be before I worked full time again because I was straining the section as they had to cover for my absence" Jim "And because of my test results, they no longer tell me my illness is in my head, they just won't accept ME as the cause.” C "I hope it demonstrates how utterly distressing it is for sufferers to not only cope with their ever deteriorating health, but to cope with supposedly professional people who use every opportunity to psychologically batter them into submission. " R ""you have ME, I am not going to waste time doing tests on you" " Julie " I felt humiliated and ridiculed by someone who was clearly a psychiatrist of some description " Cindy “Being in the medical profession I am angered and embarrassed by the way I'm treated with this illness." Shelley " I went to a Manchester hospital. That’s when my nightmare began. I felt really ill at that time and a sister said it was all in my mind. " There are longer stories too - see Further Reading below. The stories above reflect decades of suffering and are a call for doctors and healthcare staff to believe in patients. Healthcare staff need to remember -nobody really wants to live like this. Rose "So Rose had to do a 6 week diagnostic test for PRS with two 6-second sessions of physio, adding on 10% each week and starting with 10 minutes high activities. This included education, art therapy and visitors. Even if Rose was unconscious from blacking out then someone had to read to her and the curtains had to remain open - 10% each week." Invest in ME Research (Charity Nr. 1153730) investinme.org Page 25 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research One Stupid D ٜt Stacy Hart aka @MamaChill hip hop/rap artist, diagnosed with M.E. in 1991. Stacy still has M.E., 24 years after being diagnosed. Invest in ME Research (Charity Nr. 1153730) investinme.org Page 26 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Long term illness with ME Having ME for decades brings with it many different issues. Apart from obvious direct effects of the illness on one's life, with the impact on family, on career, on financial situation - there are the more insidious and rarely mentioned issues - loneliness, isolation from society, further health issues with new symptoms and possible co-morbidities developing, invisible to healthcare systems due to the label of ME. Care and compassion may also be casualties of health systems that are influenced by commercial or career interests and have no funding and no time for patients suffering from long term ME. People who currently have had an ME diagnosis for several decades will know of all of these issues. If a patient is "lucky" enough to receive attention then they are quite likely to be at the end of a long queue. Healthcare systems that cannot understand the disease, let alone treat it, will have no capacity for managing the longer term consequences. For those recently diagnosed with ME the thought of the situation getting worse, or being long-term, is something that does not initially come to mind. Long term illness from ME is something that is not discussed much - although one can often hear of stories of those who have to endure this disease for decades. Even with their disease these long-term sufferers will have hoped for recovery, for research that brought forth treatments. Many might also have become advocates and contributed what energy they had to changing things for the better, to raise hope that things would be different. It is testimony to the courage and resilience of those long-term ill that they continue to hope, to campaign, to trust for a better life. It is a sad and continuing indictment on successive governments and health departments and, especially, on research councils and their appointed guardians of research into ME that they have failed these people. We invited Dr David Bell (Lyndonville NY, USA) to speak about his longitudinal study at our IIMEC6 conference in 2011. Dr Bell presented his work on the 25-year follow-up of the young people from the initial illness that triggered his research. He described this initial outbreak in 1985 in a small rural community just south of Toronto. 210 people remained ill following a flu-like illness. Many more had the illness, but had recovered by 6 months. Those remaining ill were finally diagnosed as suffering from ME/CFS. 60 were children and adolescents. The 13 year follow-up was written up in the Journal of Paediatrics. 80% described themselves as doing well. Half of these still had symptoms but leading a reasonably normal life, the other half seemed OK. 20% had ongoing illness and were "disabled". The book Lost Voices from a Hidden illness eloquently brought out some issues regarding longterm illness. Those patients who have had ME for several decades were young at the beginning, had dreams and ambitions, aspired to do more. Invest in ME Research (Charity Nr. 1153730) He then asked, "How should recovery be defined?" - "Is it absence of symptoms or adaptation?" If the answer is adaptation, this leads to confusion and a false perception of health. Factors included here would be: patient looks OK, tests are normal, specialists come up with no diagnosis and there is a lack of evolution into an illness such as MS. This confusion is damaging for adolescents. The current study included a follow up of 28 people, and a wide range of assessment tools was used. 3 had developed malignancies (thyroid cancer, cervical cancer and leukaemia) and were excluded. investinme.org Page 27 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research The remainder (25) were represented by 3 groups. 2/25 (8%) were well. 18/25 (72%) had remitting illness - they considered themselves all right, but scores indicated they were not well. The third group - 5/25 (20%) had persistent ME/CFS. They considered themselves disabled with severe symptoms and reduced activity. These people were on disability pensions, but ME/CFS was not used as the diagnosis to be eligible, and the illness was often called other names to ensure the benefit. Dr Bell pointed out how people do learn to adapt to this illness. Many seem to recover but then slide down again. The worst symptoms seem to be associated with sleep and pain. He described his disability scale from 0-100 with 100 being entirely well. Many of these patients scored around 30. He felt one of the most important questions for the clinician to ask was the number of hours of upright activity attainable each day. In his current study, controls scored 15 hours, the persisting severe group 1-5 hours and the remitting group 13 hours. In summary, Dr Bell concluded that at follow up 72% had mild to moderate illness, although considered themselves OK. There was health identity confusion, by remembering self being much worse, and now considering self "well". Time will tell the long-term outcome. He felt strongly that he was looking at the natural history and course of the illness rather than any medication or vitamins promoting recovery. The long-term ME patients constitute an area which is almost totally neglected - something that should be of major concern to healthcare providers, along with the severely ill and children with ME. The long-term ill from ME are not only those in old age either. Younger people are included in this group if they were diagnosed with ME in their early teens. Yet it is ignored, buried in the soundbites of the media who remain oblivious to the reality of ME; callously removed from the policies of research councils and government health departments due to apathy; unable to be researched properly due to the lack of funding from those agencies responsible for funding; and often let down by support organisations who take subscriptions but do little to Invest in ME Research (Charity Nr. 1153730) investinme.org Page 28 of 52 convince anyone of this neglected section of society. We can only hope that we can soon get to a situation where all people with ME will get adequate treatment based on results from wellfunded biomedical research. This subject needs to be included in debates about ME in any parliament setting. It needs to be recognised and addressed in healthcare systems. The long term ME patient needs to be represented. In the meantime, we recognise the courage of those who have had to endure ME through many years with little or no support and yet who continue to remain hopeful and try as best they can to help to change things.

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Caring for someone with ME "She was gradually deteriorating. Every tiniest activity (physical, cognitive and sensory) from washing her hair to rubbish collection day, had devastating results. Sometimes she could recover in a few days, other times it would take months, but often the cumulative effects of the noisy, smelly, bright, sunny, loud, vibrational, fast, chemical based world we live in were all too much and disease progression with permanent damage resulted. Doctors always amaze me when they are puzzled by her severity and wonder why it's taking so long to 'pick up her bed and walk". - Lili It is difficult to convey fully the overwhelming effects of severe ME – on the patient or on carers. We can only allude to the horrendous course that ME can take, point out at how little has been done to address this particular issue of ME, and state what we, as a charity, are trying to do to change things. The odds are stacked against carers if the person(s) they are caring for suffer from ME. Carers have to stop their normal life to try to come to grips with the effects of this disease on themselves as well as the patient. Lack of understanding about the disease by the public – a great deal of which has been caused by misinformation from media centres and compromised media editors - can even affect relationships. If a carer/partner does not understand the illness or has been misinformed due to the media propaganda then subsequent strains on relationships can take its toll – thus further aggravating the situation for the patient. Apart from having to research oneself what this disease is, and what treatments there may be, a carer/parent may suddenly be met, not with compassion or understanding, but with the full force of social services intervening and suddenly becoming victim to the ignorance that pervades society. The other insidious effects of ME that the patient experiences – such as isolation – may also come into play for carers. Kjersti Krisner gave a moving testimony of issues with severe ME in her pre-conference dinner Invest in ME Research (Charity Nr. 1153730) presentation prior to the 11th International ME Conference in London in 2016. If one wished to see all that has been wrong with research policies toward ME by establishment organisations over the years then one would only need to see Kjersti's presentation Kjersti's family of three severely affected children was highlighted in Norwegian TV with the NRK channel Pulse program in 2009. Meridian TV aired a series of programmes in 20052006 covering the effects of ME on severely affected patients. A reporter from Meridian interviewed a number of ME sufferers in Hampshire as well as at the regional ME centre. This set of interviews conveyed the suffering and lack of action regarding ME. One of the most shocking and heart-breaking cases involved Sophia Mirza. The full force of establishment ignorance about ME came crushing down on one poor girl and her family. Had this story occurred today, with all of the effects of social media, then the story would have been a national scandal with resulting action being taken. Instead, Sophia's mother, Criona, had to continue to campaign for years to try to get justice. Invest in ME Research organised a conference call in 2013 with Dr Martin McShane, Director of Domain Two, NHS Commissioning Board, after a supporter contacted her constituency MP (which happened to be the Prime Minister at that time). In that meeting the parents of the very severely ill young person gave a presentation of their experiences since their child became severely ill at the age of 8 in 2000. The presentation was very powerful and was conveyed in a very professional manner despite the obvious anguish and distress that it caused the parents. - There was a cluster of 5 people who became ill at the same time in the small village in which they lived - Not one GP took it upon themselves to investigate - Life was a living hell as their child could not talk, could not swallow and was sensitive to light and noise - Severe ME causes panic in healthcare professionals who want quick fixes, and look around investinme.org Page 30 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research for some other causes in parents or patients (Munchausen’s by Proxy, Pervasive Refusal Syndrome and so on ) despite the CMO report recognising ME as an organic illness - Good doctors who kept children safe from the threat of child protection orders have now retired or passed away so the parents have nowhere to turn to for support - OTs were helpful but in their experience GPs had been terrible - Advice/information given by unhelpful GPs and consultants, paediatricians over the years included removal of parental support, physiotherapy, stating that ME is not a real disease, that it was an illness caused by exam nerves etc. - GP visits were unannounced, and the family was reported to social services for neglect and the family were then asked to leave the GP service - In 2012, after a fairly stable period, tooth surgery caused a severe relapse and the GP decided to resurrect the earlier accusations - The family had kept quiet for 12 years but felt now that enough was enough. They had sent complaints to PALS. The doctors had refused to comment. This representation was enough to convey what many in the UK had felt for a generation and for which little has, or is being done. Dr McShane commented that to change the quality of life with long-term conditions we have to accept what we do not know. IiMER felt this was not good enough. We explained how we had sat in countless meetings, with words said, promises made and nothing ever changes. It was unacceptable. Empathy was fine, and we were grateful for Dr McShane’s acknowledgement of the poor service given to ME patients and their families. However, we needed to progress – and we had ways, proposals which could be used to progress this. Invest in ME Research (Charity Nr. 1153730) IiMER pointed out the difficulties in getting anything done and we did not want to go away from yet another meeting with nothing, and no action plan. The local commissioner at the meeting had promised education of GPs. However, we all felt that there is a major problem in the lack of accountability. Nobody seems to want to take responsibility - and this extends from the local level right the way up the chain to the CMO and the Minister for Health. (IiMER mentioned that CMOs had been invited to every single one of the eight (at that point in time) IiMER annual conferences - without any sign of leading or an agenda for ME) IiMER suggested using this area (ME) as an example of a difficult area of medicine and use it as a model for nationwide services. Dr McShane promised to promote Dr Terry Mitchell’s approach (kind, caring, patient centred). Whilst we felt Dr McShane was genuinely empathetic to the plight of ME patients and their families we saw no appetite from any direction in the NHS to invoke change, to rectify the inadequacies in the NHS or to initiate any visionary approach to progressing ME. And so it proved to be. At the meeting our overriding feeling was that we would have to continue to make the changes necessary ourselves. And so it proved to be. “The carer of an M.E. loved one is like no other carer. Not only is it imperative to learn about myalgic encephalomyelitis in order to give the specialist care required for M.E. (to avoid causing them further harm), it is also necessary to become their protector” Dr Amolak Bansal spoke at the #IIMEC8 conference in 2103. After the conference Dr Bansal added the following especially for Invest in ME for a forthcoming news article (which subsequently was not used), explaining severe ME in the following way - “While it is presently very difficult for modern medicine to fully explain all severe ME symptoms, disordered neural function within the brain and spinal cord would come close. How this occurs is unknown but there are counterparts in certain newly described autoimmune conditions and viral infections of the nervous system. In addition to a direct stimulation of neurones in different parts of the brain and spinal cord there is investinme.org Page 31 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research also an impaired filtering function of the brain stem and a reduced threshold for neurones to fire off. This allows external stimuli such as movement, light, sounds, touch and sometimes even worrying thoughts to produce widespread neuronal activation with ultimate excitotoxic damage to these cells. The consequence is impaired activity of the brain generally but particularly the hypothalamus and prefrontal cortex leading to fatigue, disordered sleep, impaired memory, attention, faintness, palpitations, disordered respiration, temperature dysregulation etc. Outwardly, many patients appear well and routine blood and other investigations are normal. Internally there are severe symptoms that, if unchecked, escalate leading ultimately to immobility and increasing pain and spasms in a proportion of patients. Clearly a greater understanding of this highly disabling condition is required with a greater focus on disrupted immune and neural pathways and not just psychosocial factors as has previously been the case.” Sidsel Elisabeth Kreyberg carried out a small survey on Caring for seriously ill ME-patients that showed how important experience was in the work with ME. Severe ME patients have not often been included in research into the disease. This may be necessary on occasions, depending on the type of research or the logistics of accessing the patients in their delicate state. But IiMER has always stated that severely affected patients should not be excluded from research. Invest in ME Research are currently funding research into ME with severely affected patients being included. Diane - the carer/mother of severely affected daughter Lili, eloquently described her caring for her daughter and how her whole life was lived from her bed. Diane describes her GP "as an aggressive rude man who insulted Lili to such a degree that I wanted to throw him out". Invest in ME Research (Charity Nr. 1153730) Attempts to change things resulted in a different GP being arranged - one who visited Lili but had seemingly already prejudged both carer and patient and who was very keen for Lili to do Graded Exercise Therapy (GET). This already horrendous situation for Lili and Diane turned ever darker when social services intervened amid doctors' allegations of abuse. In Dianes's story of Lili Diane writes – "The carer of an M.E. loved one is like no other carer. Not only is it imperative to learn about myalgic encephalomyelitis in order to give the specialist care required for M.E. (to avoid causing them further harm), it is also necessary to become their protector. This serious illness is very misunderstood, even by doctors. Society as a whole has a very misguided view of M.E. and so the carer has to do all they can to keep this harmful ignorant tribal thinking from entering the world of the M.E. sufferer. They need to protect their healing space from influences, opinions and 'treatment' that will cause disease progression and maybe even death. But who protects the carer? In some ways the carer is as vulnerable as their loved one." ".....the carer is as vulnerable as their loved one....." That says it all about ME And Lili? "Lili collapsed after her last hospital visit. She passed out with a seizure, her body violently shook, and paralysis spread throughout her body. It was an extreme reaction to the overload of physical, cognitive and sensory attack on her body during that year, but this last journey to the hospital was the straw upon the last straw that broke her body down. She never recovered." investinme.org Page 32 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Disability and Human Rights ME is not alone in being an easy target for the DWP to unleash its draconian and ideologically driven policy assault on disabled people. Yet no other disease has had funding from the DWP given to a research team to prove that simplistic therapies could be used to make patients better – or at least avoid them using funds from the public purse. The PACE Trial had DWP funding included in the £5 million that was wasted to prove that Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) were beneficial for “treating” ME. The tale is rich in irony as it was due, predominantly, to the work of patients that the PACE trial was found to be flawed and totally unusable. The DWP were actually found to have a target of 80% to refuse mandatory reconsideration requests as a Key Performance indicator. Both government contractors have previously been found to have bungled disability tests. Invest in ME Research were long ago told by an ex-member of the DWP fraud team that the actual fraudulent element from benefits was less than 3% and the official government figures for fraud now are far less. The Press Association revealed in 2017 that Atos and Capita were set to be paid more than £700 million for their five-year contracts One is left to wonder if these external profit centres are really required, especially when so many appeals against denial of benefits are eventually won. What of the effect on society? The whole benefits system for disabled people – including ME patients – is in disarray and produces an anxiety-ridden exercise which may further exacerbate a patient's condition. Universal Credit rollout has turned into an exercise in incompetence. And some charities cannot complain as they take money from the government and are under contract not to criticise. ME patients know well what it feels like to be at the sharp end of DWP coercion. The current benefits system means that ME patients are likely to be judged by a third-party subcontractor who is totally clueless when it comes to knowing anything about the disease or its effects. Of course, the DWP keep making the point that they judge on disability not on condition. Yet how can a patient be judged fairly when the person judging them has no idea of the illness and how it affects the person attending the benefits review, either then or days after the interview? The corporate parasites that DWP subcontracts to do the deeds presumably do not have to care about the effects on patients – they just carry out their instructions. Perhaps the DWP (which is effectively the government of the day) and the ministers who decide DWP policies feel cleaner, less soiled this way - yet continually forget that they are servants of the public. In a recent article, “Britain’s most senior tribunal judge says most of the benefits cases that reach court are based on bad decisions where the Department for Work and Pensions has no case at all. Sir Ernest Ryder, senior president of tribunals, also said the quality of evidence provided by the DWP is so poor it would be “wholly inadmissible” in any other court.” And the effects were expertly captured by this tweet from a doctor - Invest in ME Research (Charity Nr. 1153730) investinme.org Page 33 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Professor Tom Shakespeare at University of East Anglia has researched and published work on the biophysical explanation for disabilities and how benefit awards have arisen from the WaddellAylward model. In his preface to book Science, Politics,.......and ME, by Dr Ian Gibson and Elaine Sherriffs, Professor Shakespeare wrote the following – “Rather than judging whether a person has a practical chance of being able to find a job they can do in the actual labour market, the Work Capability Assessment investigates whether the person has the ability, in theory, to do any form of work at all, thus tightening the eligibility criteria substantially and making it more difficult to qualify for Employment Support Allowance.” Another change has been introduced, as he says: “A second change is that instead of using a person’s regular GP, who knows them and their difficulties, an ‘independent assessor’ is used, who does not necessarily understand how illness or impairment impacts their life.” This can result again in the denial of benefits..." The UK welfare system's' treatment of poor people (and that includes disabled people) in recent years has drawn attention from unlikely sources. Philip Alston, "the UN’s rapporteur on extreme poverty and human rights, warned that poverty in the UK is a “political choice” and that compassion and concern had been “outsourced” in favour of tax cuts for the rich.". Of course all of these things overlap when we discuss ME – all interplay – and one can imagine it is all part of the grand establishment strategy. The benefits scandal that denies disabled people what they deserve by using non-medical subcontractors to assess people; where targets are set to deny benefits and make patients undergo unnecessary duress to overcome a pre-conceived outcome for their disability assessment; where the DWP fund research aimed solely at proving ME can be “fixed” by simplistic approaches that fund careers and assist insurance companies; where the official flawed guidelines are rigidly decided by an institute that claims to be responsible for clinical excellence yet seems to ignore patients' experiences and aligns more with the BPS lobby; where insurance companies deny benefits to patients if they choose not to try the recommendations in the flawed official guidelines Invest in ME Research (Charity Nr. 1153730) World Human Rights Day, like many grand ideas, has a noble purpose. Yet despite their profound messages and campaigns the basic rights to health of ME patients are continually infringed and discarded. Lip service only is paid to the world quangos such as WHO and UN by governments and establishment organisations. For ME there is never any follow up on the implementation. Where was the UN when poor ME patient Karina Hansen was incarcerated in Denmark? Who covered the human rights of Sophia Mirza when she was forcibly sectioned? Where have the Governments, DoH, CMO, NICE been in protecting human rights? Who are they serving? Can one think of another case where it is so detrimental to patients when one doctrine is forcibly imposed on vulnerable people by establishment forces against common sense and when there is no evidence base that stands up to proper scientific scrutiny? From the charity's' response to the 2007 NICE Draft guidelines we have reused the comments on human rights provided by R. Mitchell and V.Mitchell. Private Health Insurers cannot force an M.E. client to undergo unwanted treatment before making a payment, unless those treatments are specified in the contract. Unless the contract of a company states clearly that M.E. clients must undergo CBT and/or graded exercise before a payment is made, the company could well be in breach of contract. Also, every individual has freedom to express views as stated by investinme.org Page 34 of 52 that propose harmful therapies such as CBT and GET as treatments; and the possible payment of government funds to charities to avoid criticism by buying their silence. Played out using ME patients as the pawns. Quod erat demonstrandum Journal of IiMER Volume 13 Issue 1 Invest in ME Research The Human Rights Act 1998. If an insurance company ignores a client’s reasons for refusing CBT and/or graded exercise, a client could claim their ‘freedom of expression’ has been violated.2 The Human Rights Act 1998, European Convention for the Protection of Human Rights and Fundamental Freedoms, Section 1, Article 10, no.1 The guidelines should have had a significant increase in evidence-based assessment and treatments beyond the psychosocial model and CBT/GET treatments before it can be accepted as an independent, expert guideline for the treatment of ME/CFS. In 2007 the recommendation from NICE to use psychological therapies for treating ME contravened the human rights of patients. It was stated that by ignoring the serious issues with regard to CBT and GET the NICE guidelines would violate the right of clinicians and patients to the highest, safest standards of medical practice and care, amounting to a violation of their Human Rights, apart from major concerns about the efficacy of use of CBT or about the danger in the use of GET. There was no regulatory framework governing the development and use of CBT and GET thus leaving ME patients vulnerable to exploitation and abuse at the hands of the vagaries of power, politics and prejudice (which has been proven correct). In respect of informed consent for using these therapies the issue did not arise as there simply cannot be informed consent since there are important ethical, safety and regulatory questions arising from these treatments, to be addressed. It was hard to envisage any Independent authority clearing a drug for Human testing or use without ethical and safety issues, like those surrounding Psychological Therapy, being resolved. By ignoring these serious issues with regard to psychological therapy the NICE guidelines violated the right of clinicians and patients to the highest, safest standards of Medical practice and care, amounting to a violation of their Human Rights. This was a Human Rights issue. And what of today when one sees NICE retaining these harmful therapies as recommendations for treatment for ME despite being told they are harmful? Invest in ME Research (Charity Nr. 1153730) ME and the EU What has been causing billions of pounds of damage to the economies of Europe, and affects the lives of hundreds of thousands of people? Yes, ME - of course. However, rivalling it in recent years has been Brexit. Brexit may mean Brexit for some – but leaving the EU does nothing to help patients with ME. Research itself suffers due to the lack of EU funding available and UK researchers will be excluded from leading EU projects. We have already seen examples of how this is affecting research plans. We were hoping that one advantage of Brexit, at least for the remaining EU countries, was that other European healthcare systems would no longer pay any attention to UK’s NICE and its flawed guidelines for ME. Instead new policies could be formed. We may be being led headlong into the Brexit abyss but IiMER does not intend to break links with Europe. IiMER is part of the European ME Alliance (EMEA), now fifteen countries working together on ME and including groups and advocates with the same objectives. EMEA is a member of the European Federation of Neurological Associations (EFNA), with a member on the board representing ME, and works together to improve recognition of ME within Europe. What is clear is that the same problems that exist with ME in the UK also exist, to a greater or lesser extent, in all other European countries. One of IiMER's great supporters – Mike Harley – is running 28 EU marathons to support the charity in raising awareness and developing a Centre of investinme.org Page 35 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Excellence for ME that can perform translational biomedical research in a European hub, able to develop treatments for ME. Apart from raising funds and enormous awareness of ME Mike has also been able to look at issues in each European country. His blog not only details his marathon events. He has also made an effort to report on the situation with ME around Europe by discussing with ME patients in the country in which he is running. And it is very illuminating. Different countries, but all sharing the same problems. Politics, the influence of Biopsychosocial (BPS) doctrine, the lack of funding for proper research, recommendations from official bodies for deleterious Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET), the lack of belief of doctors in the disease, the stigma and mistreatment around ME, patients having to research themselves, the problem not being dealt with and not going away.......... Let us look at some of the comments that Mike brought back from patients in the countries in which he ran. DENMARK “Very few doctors in Denmark know that ME is a biological illness, so most patients do not get an ME diagnosis.” "Instead, when a patient presents with ME symptoms, they are told that they are stressed, just need to pull themselves together and get some exercise. “ “The main reason for this overwhelmingly negative attitude about ME, is a long campaign by a group of psychiatrists who are working to have ME seen as a form of somatoform disorder" AUSTRIA "A doctor in Vienna, recommended to me by a ME / CFS group, made a diagnosis of CFS, amongst other things. I cannot obtain a second opinion, because according to ME / CFS Help Austria, this doctor is the only one in Vienna!" Invest in ME Research (Charity Nr. 1153730) investinme.org “…hardly anyone takes you seriously, you are usually left totally alone, especially by doctors, you are ridiculed, accused of just being lazy, not wanting to get better, and told that you should just make more of an effort. !” MALTA "There is no study or any estimates to show or at least a demarcation if there ever was any study to establish a percentage of how many ME sufferers there are there. Some doctors say it is approx. 0.02 % same as in Europe. Due to unwillingness to diagnose and lack of knowledge on ME, it's difficult for doctors to give an accurate figure." SLOVENIA "They don't support us too much around this disease, like we're nothing. We are not noticed even though we are very tired and we are hurting. We are invisibly ill, like a house that has a nice facade, but you can’t see that inside it has a fallen staircase and a broken sink." NETHERLANDS “I was denied help for cleaning as it was considered anti rehabilitive and a house because a psychologist told me that he didn't see anything wrong with me or my situation. Financial support went well but for many it's very difficult, more often than not people even need to fight it out in court. Very sad”. FINLAND "CFS/ME is classified as a psychiatric disorder by most of the doctors and they tend to treat it with antidepressants and graded exercise therapy (GET) which are potentially very harmful to patients and may permanently worsen their condition. Fortunately for the patients even these harmful therapies seem unavailable as there are no experts even to carry out GET-therapy. Patients are totally left without any care." IRELAND "Our own Department of Health tends to follow the advice given by the UK Department of Health. Page 36 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Following the 2002 CMO report in the UK, our then Chief Medical Officer told an IMET delegation that they wouldn’t intend to reinvent the wheel, but would follow the course laid down by the UK." GREECE "As far as the Government is concerned, it doesn’t have a clue about ME/CFS Greece does not have a specialist clinic for the diagnosis and treatment of ME/CFS" SWEDEN "..the psychosocial view is common, and there is a disturbing tendency to clump ME/CFS together with medically unexplained symptoms (MUS). However, there are a minority of doctors who recognise ME/CFS as a biomedical illness." POLAND "In Poland, the illness is largely perceived as being in the mind and not a biomedical condition. there is one center in Bydgoszcz where ME is diagnosed, but they then tell people to exercise" BELGIUM "ME is being perceived as a psychological disorder treated with CBT and GET despite the fact that the KCE (Federal Knowledge Centre for Health) issued a report in 2008 stating that this therapy given in the reference centres, wasn’t effective Getting diagnosed in Belgium usually takes a lot of time. With the available care facilities being ineffective and insufficient, patients with CFS have to wait sometimes years to receive a diagnosis." FRANCE "Support for ME/CFS patients in France is still very uncertain and often very difficult to obtain. Despite suffering very severely patients often find that their doctors willing to be updated at the international level with the fingers of a hand I've seen/read many other experts in the country say things that are completely out of tune with the international conception of the illness. lot of doctors have laughed at me when I told them I had CFS, others have told me I just needed to get a boyfriend... " LITHUANIA "Some doctors want to get rid of you as quick as possible, because your results are good. They think you are pretending or something. .......... I don’t think the government care, because this illness is invisible and there is not enough proof that it’s real." CZECH REPUBLIC "No diagnostic and therapeutic standards for ME / CFS have been introduced into clinical practice in the Czech Republic. Patient care depends on their luck whether they can find a doctor who does not solve whether or not he is diagnosed (and does not send everyone to psychiatry immediately), but he is treating real problems." We know that the evil of BPS has been allowed to spread its insidious network throughout Europe – like a cancer through each health system, corrupting doctors and research councils everywhere. At a time where the mess of Brexit seems like a microcosm of the unpredictability and the unravelling of the world today then one thing is certain – IiMER will still stay close to Europe via EMEA and other initiatives such as the European ME Clinicans Council (EMECC) concept. Leaving the EU will make no difference to the actual

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Children with ME Losing school, losing contact to friends, losing any social life - isolation. Could it get any worse? In the UK yes! A child may be branded with the scandalously contrived soundbite of Pervasive Refusal Syndrome or some other such nonsensical catchphrase? “There is clear evidence of the impact of ME/CFS on the education and social development of these young people. The stigma and social effects of pediatric ME/CFS include the loss of normal childhood activities and in some extreme instances, inappropriate forcible separation of children from their parents” - Institute of Medicine (IOM) Report - “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” February 2015 For any parent the event of their child being diagnosed with a disease is one of the worst of experiences that they will ever have. To then discover that there is no treatment, let alone a prospect for any cure, will likely make them search for the reason(s) why - expecting to find answers, but instead finding more questions. To realise that this disease is ignored by governments, restricted from any level approaching adequate funding by research councils, treated inappropriately by institutes supposedly responsible for excellence in care, and used as a means to build careers and support egos for others – all this makes it even more incomprehensible. To learn that a powerful and influential lobby has been largely responsible for maintaining the above and even influencing the establishment policies and the media portrayal of this disease as a condition that can be changed just by trying harder or thinking differently – then the nightmare turns into a continuous horror. For children, of course, the future is often upended - with possible additional consequences caused by the disease, apart from the direct symptoms from the condition itself. Invest in ME Research (Charity Nr. 1153730) Yet, despite this surreal and sometimes ugly scenario, we see many examples of the resilience and courage of children with ME - young people who deal with the effects of ME on their health and their lives and yet continue to hope and believe in a better future. The great majority remain positive and maintain an unbelievable lack of any resentment for their situation - blaming nobody, stoically handling this disease . Quite remarkable. We have many examples also of young people supporting the charity and using what possibilities they have to raise awareness and funds. Some take action themselves. Last summer we received this image from Professor Kristian Sommerfelt in Norway - a drawing by young Emma who so clearly explained in her image here what ME is like for a young person. In the UK an estimated 25,000 children have ME - but nobody knows for sure as data is not currently collected! There are so few paediatricians that understand ME - another failure of establishment policies. Even those who are qualified, knowledgeable and appreciated by parents of children with ME are given a hard time – see http://www.investinme.org/IIME-Newslet-1604NS999.shtml investinme.org Page 38 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research As for paediatric research - well, the less said about that the better. We have commented before on the appalling SMILE trial and on pyramid businesses that are unregulated, unaccountable and unscientific. Junk research that attracts funding thanks to a rigid system that defies any logic or concern for children. It also recreated the social relationships. We feel that it also educated other children – and their families, and teachers and possibly SENCOs. No Isolation & Invest in ME Research Removing isolation Most of the effort from Invest in ME Research in recent years has been aimed at trying to get research into ME started that looked at the long term. However, we have also looked at other issues – the consequences of ME. One insidious consequence is isolation – affecting young and old patients. Little had been done to tackle this. This year we wanted to change how young people may be affected by this. A disease such as ME presents many challenges to a patient and to a family. It can provide challenges also to schools when a child or young person is unable to continue full time education. In such situations families can find themselves on the receiving end of the ignorance about ME that pervades our society where social services and education authorities may use a one-size-fits-all attitude to treating families where the child must remain at home. Children and youths with long-term illness such as ME do not need to be excluded from their friends’ activities and progress and schools have a responsibility not to ignore them – something which can otherwise lead to long term discrimination. We started a trial of remote participation by working with Norwegian company No Isolation to conduct a trial for young people with ME and the results were very good. This trial not only facilitated the re-connection of young ME patients to their schools. Invest in ME Research (Charity Nr. 1153730) No Isolation is a Norwegian-born start up founded with the aim of reducing loneliness and involuntary social isolation through the creation and implementation of warm technology. Its first product is a physical avatar named AV1, which allows children and young adults, who are forced by illness to take extended time away from school, to maintain a presence in the classroom and communicate with friends. In 2017, to expand the number of children it could help, No Isolation launched in the UK, and today, over 900 children use AV1 across Europe. While in the Nordics, AV1 was largely used by children suffering from leukaemia; however, since its arrival in the UK, AV1 has fast become an invaluable lifeline for children with Myalgic Encephalomyelitis (ME) thanks to Invest in ME Research. One of the UK’s most avid users is 15-year-old Makayla Nunn, who was first diagnosed with ME aged eight. Makayla was introduced to the technology through the trial arranged by Invest in ME Research. Her family and school saw how essential AV1 had become to help Makayla maintain the increased attendance in class, and subsequent increase in grades and social confidence. Makayla has been using her AV1, who is lovingly named Robbie, for well over a year now. There is no better way to explore the AV1’s success in transforming the life of someone with ME, than to speak with a real-life user. Ahead of this year’s Invest in ME Research conference, we caught up with Makayla and her mother about their experiences with the technology. Hi Makayla, can you tell us a little bit about your journey with ME? I was diagnosed with ME at eight years old, and since then I have been unable to attend school full time due to tiredness, flu-like symptoms, and brain fog. I also suffer from hyper-mobility syndrome, meaning that it often hurts to move my joints, and POTs (postural orthostatic tachycardia), which causes a spike in my heart rate, leading to dizziness and fainting. As well as missing out on school, I had to give up sports and hobbies, including dancing and investinme.org Page 39 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research swimming. I can’t horse ride as much as want to, either. When did you first encounter AV1? I saw on the news that Jade Gadd had used a robot called Bee (her AV1) to assist her with a different condition, then Invest in ME Research asked me if I would like to try an AV1 out for three months. As I was behind at school, my mum and I thought that the robot could help me attend extra hours of school from home, taking the pressure off my education. I got my AV1 in January 2018, and now, Robbie is part of the family! How did your class react to having AV1 in the classroom? It was quite strange at first. Robbie used to get a lot of attention from my class when we were attending the lesson. My class really like him being there, it was the school that named him, and one of the staff members even made Robbie a cape to keep him warm when he's going between buildings! How has AV1 helped you better cope with your condition? If I am having a day where I am feeling very tired or ill, I often don’t feel up to going into school. With Robbie, I can now work from home on these days, rather than having to miss out entirely. This helps me hugely, because to do this, I don’t have to physically push myself too much, which can make me feel worse. Using Robbie is just like being in class, because when I need to get my teacher’s attention I can light up Robbie’s head, just like putting a hand up. I can also put the ‘sleep mode’ on if I want to be in the lesson but don’t feel up to saying too much. Do you think that your AV1 will give you more opportunities for the future? I'm not as behind in school any more, my grades have improved and I feel more confident. This is good because exam work has started for my GCSE’s, so Robbie is helping me to catch up on the stuff that I have missed previously, having been on reduced hours of school for the last 7 years. We were also lucky enough to catch up with Makayla’s mother, Michelle, too. Hi Michelle, how has AV1 changed family life? AV1 has made me more confident about Makayla’s education. When she is struggling at school she gets Invest in ME Research (Charity Nr. 1153730) frustrated and upset; falling behind the rest of the class. By giving her the ability to attend more lessons through Robbie, it gives her more control, which is a massive boost for Makayla. How has AV1 changed Makayla’s education? Robbie has helped Makayla beyond my expectations! When she’s having a bad day she knows she’s not under pressure to go in anymore, because we can send Robbie in. This has taken a lot of pressure off her and having Robbie as a safety net has made the world of difference. She’s not forcing herself to go to school on days when she needs to rest, which in turn makes her worse in the long run. In a way, Robbie is helping her overall health. How has AV1 changed Makayla’s daily life? As a parent, I am always being told ‘you should limit this’ or ‘Makayla can’t do that’. Robbie has really helped to take the ‘you can’t’ away. Robbie has given hope to other children and parents too, as most with ME have had to drop out of education. Aside from education, Robbie helps Makayla see her grandmother. When illness has prevented Makayla visiting her grandmother (for the worry of contagion), a remote visit through AV1 can help Makayla and her grandmother spend more time together. What do you hope for the future? We are hoping technologies like the AV1 will change people’s attitudes towards ME. Clarifying that the illness is not about people not wanting to do things, but it is about them not wanting to be sick. They have had to give up so much. This is a real illness that affects so much more than just their health - it affects life. I’ve been so surprised at how well Robbie has supported Makayla. Allowing her to carry on with her education has made Makayla far more confident. It has also given Makayla had one less thing to worry about: the isolation that she felt and the awkwardness of feeling left behind. investinme.org Page 40 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Anne Ortegren - A Year On It is a year since news came of the passing of Anne Örtegren. The lives of those who have passed away are placed in the memory of the living. A year passes and the shock of the news of Anne's death may have ebbed away somewhat - yet the void remains, covered by the memory of one woman whose courage, dignity and influence were evident always - and continue to inspire. Reading Anne’s Last Post - an articulate, reasoned and eloquent article that gives insight into the loss of this amazing person - it may seem that she was recounting the situation that she found herself in and reasons for her course of action. That, itself, would have been an enormous effort. Yet, with Anne, this article was also likely to have been written to help so many others in the future - so typical of Anne’s selfless actions. In her last post Anne wrote – “If you are a decision maker, here is what you urgently need to do: - You need to bring funding for biomedical ME/CFS research up so it’s on par with comparable diseases (as an example, in the US that would mean $188 million per year). - You need to make sure there are dedicated hospital care units for ME/CFS inpatients in every city around the world. - You need to establish specialist biomedical care available to all ME/CFS patients; it should be as natural as RA patients having access to a rheumatologist or cancer patients to an oncologist. You need to give ME/CFS patients a future.” Invest in ME Research (Charity Nr. 1153730) A year on. We would have liked to have written that things have changed, that a new path is opened, that Anne's experiences will never have to be repeated. We cannot state this. Our status report from summer of 2018, prior to the UK parliamentary debate on ME, highlighted a picture of wasted lives and wasted opportunities over these many years where little has changed, thanks to establishment apathy. Yet we remain hopeful of change coming - albeit far too slowly. Therefore, the charity is developing a new initiative that will build on Anne's influence and may, in some way, honour her memory. We will continue to arrange for the Anne Örtegren Memorial Lecture to be given at our annual international ME conference in. In memory of Anne we released the tribute to her from last year’s IIMEC13 conference DVD that occurred prior to the inaugural Anne Ortegren Memorial Lecture. Here, quite appropriately, a distinguished Swedish scientist – Professor Jonas Blomberg – spoke of Anne. Little did we know then that a year later we would be mourning the sad loss of Professor Blomberg himself. As we wrote last year - when we lose a friend we lose a part of ourselves. Anne's influence on the lives of others lives on. http://investinme.org/AnneOrtegren.shtml investinme.org Page 41 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Conference Abstracts Dr Ian Gibson Former Dean of Biological Sciences, UEA Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, became Dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Professor Markku Partinen University of Helsinki, Finland Prof Markku Partinen is a neurologist and an internationally well-known opinion leader and expert in sleep research and sleep medicine. Professor Partinen is currently Director of the Helsinki Sleep Clinic, Vitalmed Research Centre, Invest in ME Research (Charity Nr. 1153730) and Principal Investigator of Sleep Research at Institute of Clinical Medicine, Clinicum, University of Helsinki, Finland. He has been the coordinator of the NARPANord Narcolepsy Consortium. He has published more than 330 original articles in peer reviewed Journals in addition to writing many book Chapters and editing several books. He has been President of the ESRS congress in 1992 (Helsinki), the World Congress of Sleep Apnea in 2003 (Helsinki), and the WASM congress in 2007 (Bangkok). Currently he is a Member of the Board in the ESRS EU-Narcolepsy Network (EU-NN) and Chair of Scientific Board of the EU-NN, President of the Finnish Parkinson Association and President of the Finnish Sleep Research Society. Professor James Baraniuk Professor of Medicine at Georgetown University Medical Centre, Washington, USA James N. Baraniuk was born in Alberta, Canada. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, investinme.org Page 42 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his longstanding collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. Dr Elizabeth R. Unger Chief of Chronic Viral Diseases Branch, National Center for Emerging and Zoonotic Infectious Diseases, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention Elizabeth (Beth) Unger, PhD, MD received an undergraduate degree in Chemistry at Lebanon Valley College, Annville, PA. She then earned her PhD and MD in the Division of Biologic Sciences at the University of Chicago where she also began residency in pathology. Her residency and fellowship was completed at Pennsylvania State University Medical Center. During this time, Dr. Unger developed a practical method of colorimetic in situ hybridization. This work led to interest in tissue localization of HPV and ultimately to her initial appointment to CDC in 1997 to pursue molecular pathology of HPV and CFS. Dr. Unger has served as the Acting Chief of CVDB since January 2010 and has 13 years of experience in CVDB, where she has participated in the design and implementation of CFS research and HPV laboratory diagnostics. During this time, she was coauthor on 25 peer-reviewed manuscripts related to CFS, including the often-cited descriptions of the Wichita and Georgia population-based studies. In addition, Dr. Unger has been instrumental in efforts by WHO to establish an HPV LabNet and serves as Invest in ME Research (Charity Nr. 1153730) lead of a WHO HPV Global Reference Laboratory. She is co-author of 142 peer-reviewed publications and 24 book chapters and serves on the editorial board of six scientific journals. In 2008, for her HPV research accomplishments, she received the Health and Human Services (HHS) Career Achievement Award. Dr Unger has been selected to serve as the Chief of the Chronic Viral Diseases Branch (CVDB) in the Division of High-Consequence Pathogens and Pathology (DHCPP), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for Disease Control and Prevention (CDC). Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States. Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by postdoctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. investinme.org Page 43 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Professor Maureen Hanson Director, Center for Enervating Neuroimmune Disease. Liberty Hyde Bailey Professor, Department of Molecular Biology and Genetics, Cornell University, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Associate Professor Mady Hornig Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with Invest in ME Research (Charity Nr. 1153730) environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Professor Don Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Professor Staines has been a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as crossdisciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. He is now Co-Director at The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University in Australia investinme.org Page 44 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Abstract: Role of transient receptor potential ion channels in the etiology and pathomechanism of ME/CFS Staines D1,2 Cabanas H1,2,, Muraki K2,3 , Balinas C1,2, Eaton-Fitch N,1,2, , Marshall-Gradisnik S1, 2. 1.The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, Southport, QLD, 4222, Australia. h.cabanas@griffith.edu.au. 2. Consortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia. h.cabanas@griffith.edu.au. 3. Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Chikusa, Nagoya, Japan. NCNED has confirmed the pathology of transient receptor potential (TRP) ion channels in ME/CFS. TRP Melastatin 3 (TRPM3) impairment has been identified in three separate cohorts of patients. TRPM ion channels are non-selective calcium ion channels increasingly associated with systemic, particularly central nervous system (CNS), pathology. TRPM3 is highly concentrated in the CNS, (autonomic) ANS and (peripheral) PNS. The observed changes in gene structures and TRP receptor ion channel proteins are reflected in perturbations of intracellular calcium signalling. These findings have been demonstrated through electrophysiology patch-clamp technology, the gold standard for research into ion channel function. Drugs are now being analysed in this research context regarding suitability for pharmacotherapeutics and hence treatments. The demonstrated pathology of TRPM correlates with symptom presentation in ME/CFS. Patch clamp identification of impaired TRP ion channels, the findings of drugs in a therapeutic context and the known roles of TRPM ion channels in systemic diseases establishes TRP pathology as the underlying cause of ME/CFS. Additional data demonstrating changes in other TRP sub-family members is currently under publication. Whether these additional changes reflect compensatory mechanisms is being investigated. Invest in ME Research (Charity Nr. 1153730) Dr Jesper Mehlsen Bispebjerg Hospital, Copenhagen, Denmark Jesper Mehlsen graduated as a doctor in 1979 from the University of Copenhagen and became a specialist in 1990. For 35 years he has been working clinically and in research with patients with disorders of blood pressure control, with dizziness, fainting (syncope) and near-fainting in upright position. He is author / co-author of more than 140 articles in international journals and has been the leader of a number of research projects in these fields and with projects related to HPV vaccination. Over the past 5 years, he has performed clinical research with patients who suspect vaccine damage as the cause of the development of a number of symptoms that are often common to those seen in chronic fatigue syndrome / ME. His expertise is in Autonomic nervous system, Heart rate and blood pressure control, Cardiovascular physiology and pathophysiology, HPV vaccines and -complications His Main research areas relate to methods for the study of autonomic cardiovascular control; Mathematical modelling of cardiovascular control; Autoimmune response to vaccination; Mathematical modeling of the neuroinflammatory reflex. His current research involves mathematical analysis of hemodynamic adaptations to the upright posture; mathematical analysis of hemodynamic response to Valsalva manoeuvre; dynamic T-wave alterations and the autonomic nervous system; mathematical analysis of cytokine response to LPS in humans; autoimmunity in patients with possible side effects to HPV vaccination. He places great emphasis on taking time to listen, investigate, explain and find treatment options based on a holistic assessment and in close interaction with the patient investinme.org Page 45 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Dr Øystein Fluge Haukeland University Hospital, Bergen, Norway Oystein Fluge received medical degree in 1988 at the University of Bergen, and is specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. For example, TRPV1 is activated by noxious high temperature (>42°C), TRPM8 by cool temperatures (<~28°C) and TRPV3 by warm temperatures (>32°C). TRPA1 can also be activated by noxious cold temperatures. TRPV1 and TRPA1 are expressed by sensory nerves that respond to noxious stimuli and these two channels are also sensitive to pungent chemicals such as capsaicin found in chilli peppers (TRPV1) and allyl isothiocyanate found in mustard and wasabi (TRPA1). His interest is to determine the roles of TRP channels and other ion channels and receptors in normal physiology and in disease states. The activities of channels and receptors are studied using electrophysiological measurements from native cells (such as sensory neurons) and cells heterologously expressing molecules of interest. Professor Simon Carding Research Leader, Quadram Institute Bioscience Professor Stuart Bevan Professor of Pharmacology at the Wolfson Centre for Age Related Diseases, Kings College London, UK Professor Stuart Bevan is Professor of Pharmacology at the Wolfson Centre for Age Related Diseases. From 1997 to 2005, he was Head of the Chronic Pain Unit for Novartis based in the Novartis Institute for Biomedical Research laboratories on the UCL campus. Our studies are focused on sensory transduction in neuronal and non-neuronal cells, the transduction and transmission of noxious and innocuous stimuli in peripheral sensory nerves and mechanisms of pain and analgesia. These investigations are carried out using a combination of in vitro and in vivo approaches. Transient receptor potential (TRP) channels Much of our current research involves studies on TRP Channels. TRP channels have diverse roles in sensory transduction and cellular regulation. We have a specific interest in TRP channels expressed by peripheral sensory neurons and interacting cells such as keratinocytes as well as non-neuronal cells in the gastro-intestinal tract. Several of these channels are important sensors of thermal stimuli. Invest in ME Research (Charity Nr. 1153730) Upon completing postgraduate work at the Medical Research Council’s Clinical Research Centre in Harrow, Simon Carding took up a postdoctoral position at New York University School of Medicine, USA,and then at Yale University as a Howard Hughes Fellow in the Immunobiology Group at Yale University with Profs Kim Bottomly and Charlie Janeway Jr. While at Yale an interest in gamma-delta (γδ) T cells was acquired working closely with Adrian Hayday on molecular genetics and then with Prof. Peter Doherty to establish their role in (viral) infectious disease. He left Yale after five years to take up a faculty position at the University of Pennsylvania in Philadelphia where he developed a research interest in mucosal and GI-tract immunology, performing studies in germfree mice with Prof John Cebra that helped establish the role of gut microbes in the aetiology of inflammatory bowel disease (IBD). After 15 years in the USA, he returned to the UK to take up the Chair in Molecular Immunology at the University of Leeds where he established a new research programme on commensal gut bacteria and Bacteroides genetics leading to the development of a Bacteroides drug delivery platform that is being used for developing new interventions for IBD and for mucosal vaccination. investinme.org Page 46 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research In 2008 he was recruited by UEA and IFR to develop a gut research programme, taking up the Chair of Mucosal Immunology at UEA-MED and the position of head of the Gut Biology Research Programme at IFR, which later became part of the Gut Health and Food Safety (GHFS) Programme. GHFS research covers a broad area of gut biology including epithelial cell physiology, mucus and glycobiology, mucosal immunology, commensal microbiology, foodborne bacterial pathogens, and mathematical modelling and bioinformatics. The success of this programme has led to the establishment of the Gut Microbes and Health research programme that is integral to the research agenda of The Quadram Institute. Within these programmes, much of the work undertaken in his research group builds upon that carried out in the USA and latterly in the UK with a major focus on understanding the mechanisms of intestinal microbial (bacterial and viral) tolerance. In particular, identifying the pathways and mediators of microbe-host cross talk and the role they play in establishing and maintaining gut health and in diseases that not only affect the gut but other organ systems. This has led to the development of new research projects relating to the gut-microbiomebrain axis and understanding how the intestinal microbiome impacts on mental health and the development of neurodegenerative diseases, and the intestinal virome and the role that prokaryotic and eukaryotic viruses play in microbial homeostasis and dysbiosis. Professor Karl Johan Tronstad Professor Institute for Biomedicine , Tronstad Lab, Bergen, Norway Prof. Tronstad completed his graduate studies in biochemistry at the University of Bergen (UiB) in 2002. As postdoc at the Haukeland University Hospital, he studied bioactive compounds with the potential to modulate mitochondrial functions in cancer cells. In 2005 he was recruited to the Department of Biomedicine, UiB, where he started his research group to investigate metabolism and mitochondrial physiology. His laboratory seeks to better our understanding of how defective mitochondrial homeostasis may disturb cell physiology, and how this may be involved in mechanisms of cancer and Myalgic Invest in ME Research (Charity Nr. 1153730) Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Karl was involved with the recent paper to come from Bergen - Journal of Clinical Investigation Insight. The Tronstad Lab investigates cell metabolism and mitochondrial biology and we are very fortunate that he can spare time to participate in the Colloquium. Professor Nancy Klimas, Director, Institute for Neuro Immune Medicine, Nova Southeastern University USA Nancy Klimas, MD, has more than 30 years of professional experience and has achieved international recognition for her research and clinical efforts in multi-symptom disorders, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), Fibromyalgia, and other Neuro Immune Disorders. She is immediate past president of the International Association for CFS and ME (IACFS/ME), a professional organization of clinicians and investigators, and is also a member of the VA Research Advisory Committee for GWI, the NIH P2P CFS Committee, and the Institute of Medicine ME/CFS Review Panel. Dr. Klimas has advised three Secretaries of Health and Human Services, including Kathleen Sabelius, during her repeated service on the Health and Human Services CFS Advisory Committee. Dr. Klimas has been featured on Good Morning America, in USA Today and the New York Times. Dr Ron Tompkins Director of the Center for Surgery, Science and Bioengineering, Massachusetts General Hospital, USA Ronald G. Tompkins, MD, ScD, is the Sumner M. Redstone Professor of Surgery at Harvard Medical School, Founding Director of the Center for Surgery, Science & Bioengineering at Massachusetts General Hospital, and Chief of Staff Emeritus at Shriners Hospitals for Children―Boston. investinme.org Page 47 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research The Center, a division of Surgery at Mass General, is a newly established center for research and innovation based upon the Mass General Burns Division’s collaborative track record and expertise in securing more than $200 million in federal, foundation, and industrial support for basic research and clinical programs. It is a clinically-driven enterprise that engages in the basic sciences and engineering to solve everyday challenges in clinical medicine. The center promotes the development of new approaches to healthcare delivery and personalized medicine, minimally invasive therapies, as well as a myriad of new technologies such as re-engineered organs, smart nano-pharmaceuticals and nano-diagnostics, and living cell-based microfabricated devices for diagnostics, therapeutics, high-throughput drug screening, and basic and applied biomedical investigation. He is a board-certified general surgeon with a doctorate in chemical engineering, which provides him with expertise not only in the clinical evaluation of critical care patients, but also in inflammation biology, genomics, proteomics, and computational biology. Elected as a Director of the American Board of Surgery in 1994, he has received multiple honors including a fellowship from the American Institute for Medical and Biological Engineering and an honorary M.A. from Harvard University. He has served as an officer including as President and Board Member of more than a dozen national and international academic societies. Dr. Tompkins has published more than 450 research papers in medicine and engineering journals and has contributed to the advancement of science and engineering through service on institutional advisory panels, moderating mini-symposia and workshops on biotechnology, and studying the genomics and proteomics of immunology and metabolism resulting from injury. Together with his Division colleagues, nearly 300 fellows have been mentored in the Division’s training programs with many excellent success stories. Professor Michael VanElzakker Massachusetts General Hospital/Tufts University, USA Dr. VanElzakker received a master's degree in behavioral neuroscience at the University of Colorado, Invest in ME Research (Charity Nr. 1153730) working in Dr. Robert Spencer's neuroendocrinology laboratory, and a PhD in experimental clinical psychology at Tufts University, working in Dr. Lisa Shin's psychopathology neuroimaging laboratory. His postdoctoral fellowship is at Massachusetts General Hospital/ Harvard Medical School, at the Martinos Center for Biomedical Imaging, in the Division of Neurotherapeutics. Dr. VanElzakker is interested in uncovering the mechanisms of post-traumatic stress disorder (PTSD), and of myalgic encephalomyelitis - also known as chronic fatigue syndrome (ME/CFS). His PTSD research uses functional and structural brain imaging, behavioral attention tasks, blood, and genetic data to investigate what makes some individuals vulnerable to PTSD following trauma. He is interested in using non-invasive electroceutical medical devices to enhance safety learning, which may eventually serve as an adjunct to enhance exposure-based therapy for PTSD. His ME/CFS research uses functional and structural brain imaging to look for abnormal patterns in brain metabolism and inflammation in this patient population. This research focuses on dysfunction at the intersection of the nervous and immune systems and posits that ME/CFS may be what happens when the nervous system detects an exaggerated and ongoing innate immune response. He is interested in using non-invasive electroceutical medical devices to enhance the antiinflammatory vagus nerve reflex. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis investinme.org Page 48 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research focuses on the interface of nano-fabricated state devices and biological systems. He and his research team also develop no technologies for the genetic, genomic, and molecular analysis of a wide range of mo organisms as well as humans. The team's focus on practical application technologies is setting the standard for clin genomics. The genomic revolution has been spurred technological advances that made nucleo sequencing inexpensive, high-throughpu accessible. The next phase in this revolut the way for personalized health entails si breakthroughs in biosensor technologies personal molecular monitoring. Just as w sequencing, the key features to optimize accuracy, sensitivity, cost, and accessibili close collaboration between engineers, biochemists, geneticists, and clinicians, o has developed several such technologies devices. The technologies target the bioph properties of the cells and molecules, and do not rely on introducing labels or other c sample preparation techniques. We have successfully applied these technologies t drug resistance, resolving cells and molecules in bodily fluids and tissues, and engineering multiparametric, wearable biosensors. W begun applying these methods to unders chronic fatigue syndrome, one of the last diseases about which almost nothing is k anticipate that these technological break coupled with data integration of personal profiles will play an instrumental role in t realization of personalized health regimens and disease prevention strategies. Invest in ME Research (Charity Nr. 1153730) investinme.org Page 49 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Start Presentation Presenter 07.45 Registration 08.45 IiMER 09:00 #InvestinMEResearch 09:10 CDC update 09:25 NIH Update 09:45 Immune Dysregulation in ME/CFS 10.10 Fingerprinting the Phenotypes of ME/CFS Along the Gut-Immune-Brain Axis 10:35 Refreshments Break 11:05 Transient receptor potential ion channels in the aetiology and pathomechanism of CFS/ME 11:30 Pathophysiological Basis of Fibromyalgia 11:55 Characteristics and pathophysiologic changes in a large cohort of Danish ME-patients. 12.20 Lunch 13.20 Anne Örtegren Memorial Lecture: Pain and ME/CFS 13:45 Developments at Quadram Institute 14:05 Rituximab in ME/CFS: a randomised, doubleblind and placebo-controlled trial 14.30 Metabolic profiling and associations to clinical data in ME 14:55 Refreshments Break 15:25 Integrative Medicine Approach to Treatment of ME 15:50 Harvard Plans for Clinical Research 16:10 Physiological and fMRI measures before and after symptom provocation by invasive cardiopulmonary exercise testing 16:35 Stanford Metabolomics & Genetics Study Update 17:10 Plenary Session 17.30 Adjourn Invest in ME Research (Charity Nr. 1153730) investinme.org Professor Nancy Klimas Dr Ron Tompkins Dr Michael VanElzakker Professor Ron Davis Panel discussion Page 50 of 52 Professor Stuart Bevan Professor Simon Carding Dr Oystein Fluge Professor Karl Johan Tronstad Professor Don Staines Dr David Andersson Dr Jesper Mehlsen Opening Dr Ian Gibson Dr Elizabeth Unger Dr Vicky Whittemore Professor Maureen Hanson Assoc. Professor Mady Hornig Journal of IiMER Volume 13 Issue 1 Invest in ME Research Invest in ME Research (Charity Nr. 1153730) investinme.org Page 51 of 52

nal of IiMER Journal of IiMER Volume 12 Issue 1 May 2018 Research into ME Published by UK Charity Invest in ME Research www.investinme.org

“This organization has been working in the trenches of ME, and it has been a notable and significant contribution to the field. Invest in ME has been able to increase awareness and disseminate knowledge to scientists, clinicians, and patients within the ME community. With limited resources, but unlimited creativity and imagination, these patients and their supporters have showed the world what can be done.” - Dr. Leonard A. Jason Invest in ME Research o an independent UK charity finding, funding and facilitating a strategy of high quality biomedical research into Myalgic Encephalomyelitis, as defined by WHO-ICD-10-G93.3 o focuses on biomedical research into ME and the education of healthcare staff, the media, government departments, patient groups and patients o run by volunteers with no paid staff - no funding from government or government organisations o overheads are kept to a minimum to enable all funds raised to go to promoting education of, and funding for biomedical research into, ME o a small charity but we do far more than most with growing number of supporters with big hearts and determination to find the cause of myalgic encephalomyelitis and develop treatments o funding more biomedical research than many other organisations o we have links nationwide and also internationally and facilitate international collaboration o founder member of the European ME Alliance (EMEA) o organises annual research Colloquium and public Conference attracting delegates from 20 countries o to bring best education and research to bear on ME and find/facilitate the best strategy of research o focused on setting up UK/European Centre of Excellence for ME to provide proper examinations and diagnosis for ME patients and coordinated strategy of biomedical research in order to find treatment(s) and cure(s) - http://www.cofeforme.eu o the charity welcomes support for our work – www.investinme.org/donate www.investinme.org Page 2 of 56 Invest in ME Research (Charity Nr. 1153730) www.investinme.org Page 2 of 56 Invest in ME research (Charity Nr. 1153730) 3 Chairman of IiMER 6 Progress in ME 12 NICE Review Comments 18 Centre Research Blog 20 Thinking the Future 21 Quadram Institute Bioscience News 22 UK Biobank: An Open Access Resource 29 Farewell to a Friend – Anne Örtegren 36 A Harsh Debate about ME in Norway 41 Letter from America 43 IiMER’s Own Film Star 45 Conference Abstracts All content in the Journal of IiMER is copyright to Invest in ME Research and/or the authors. Permission is required and requested from Invest in ME Research before republishing from this Journal. DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME Research. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME research (Charity Nr. 1153730) Welcome to IIMEC13 A Foundation of International Collaboration in Biomedical Research From the Chairman of Invest in ME Research Invest in ME Research is an independent UK charity facilitating and funding a strategy of biomedical research into Myalgic Encephalomyelitis (ME or ME/CFS) and promoting better education about ME. The charity was built on the firm belief that biomedical research into ME was crucial in order to make progress in treating this disease. The education of healthcare staff, the media, government departments, patient groups and patients was also to be a priority - but something that would develop from the research being undertaken. Although forcing research into ME into the mainstream of academic and clinical consideration has taken too long we do sometimes wonder where we would be if we had not started our conferences and, later, our research Colloquiums. The international conferences were organised from the beginning to provide a platform for research and a means of facilitating education about ME. The research Colloquiums now attract researchers from around the world to a meeting where they are free to discuss, share and collaborate. Collaboration and working together have been themes for our Colloquiums - with real international cooperation forming that can only lead to a better future for patients than would otherwise be the case. www.investinme.org Page 3 of 56

This year we again have representatives from both the USA National Institute of Health (NIH) and Centres for Disease Control (CDC) attending our Colloquium and Conference - endorsing our view of international collaboration as a critical means to an end. We can also see some of the spin-offs that have occurred due to our Colloquium taking place - either research projects, collaboration in planning projects or in other events taking place. Both the Colloquium and Conference are high quality, forward-looking events that serve to improve knowledge of this disease and generate and improve international collaboration into ME. As always the charity takes on the task of producing a high-quality DVD of the conference with all of the presentations included. This serves as a historical record and is an educational tool for doctors and clinicians - demonstrating the seriousness of this disease. For 2017, our conference DVD reached even more countries and allowed us to inform a wider audience. Yet how do we speed up research and move the direction away from the flawed approach to ME research that has been the strategy of establishment organisations that have not responded to the needs of patients? The strategy that Invest in ME Research has created is to develop a Centre of Excellence for ME based on highquality biomedical research and international collaboration. There are now four PhD students performing biomedical research into ME at the Norwich Research Park, where the hub for the UK Centre of Excellence for ME is proposed. The charity continues to fund research at UCL also by supporting the remainder of another PhD studentship there. The charity is doing more than most to provide a sound foundation for research into ME and spends more, proportionately, of its income on biomedical research and associated activities than any other UK charity. The Invest in ME Research strategy of bringing in researchers from other fields to help and improve biomedical research into ME is working. Our conferences bring together patients, researchers, clinicians and healthcare staff and allow knowledge and Page 4 of 56 www.investinme.org experiences to be shared – and IIMEC13 and BRMEC8 will see us entering our thirteenth year in doing this. Our BRMEC8 is again a two-day event with biomedical researchers invited from around the world. This year will be the biggest yet with almost 100 top biomedical researchers participating from over a dozen countries. The IIMEC13 Conference allows researchers, clinicians and patient/ groups/patients and carers to mix with each other, discuss together and network with unique opportunities – all enabling a greater understanding of this disease. In order to bring the best education and research to London each year we welcome all support for these events as there are significant costs involved in achieving this. We are therefore extremely grateful to our friends and supporters who have helped us via online donations. We also wish to thank our sponsors for IIMEC13. The Irish ME Trust A word of thanks to the Irish ME Trust who, yet again, will be sponsoring one of the speakers to the conference. IMET have been a constant friend and supporter of IiMER, and of ME patients. They have been a leading member in the European ME Alliance. The Irish ME Trust has sponsored a speaker at all of our conferences and we would like to thank them for their continued support. Norges ME Forening Norway's ME Association (Norges ME Forening) is sponsoring the IIMEC13 conference. Norges ME Forening has been a long-standing supporter of IiMER we are very grateful for this kind donation. Thank you NMEF. Invest in ME research (Charity Nr. 1153730) Solve ME/CFS Initiative Solve ME/CFS Initiative (SMCI) has sponsored an IiMER conference for the first time but has already granted awards to two of the research groups which currently have research underway that is being funded by IiMER. Thank you SMCI. The Only Form of Graded Exercise Therapy Acceptable for People with ME Thanks to Paul Kayes Welcome to those attending Thinking the Future 2018, BRMEC8 Colloquium, IIMEC13 international ME Conference and European ME Alliance AGM. Welcome to London, Kathleen McCall In This Issue This issue of the journal contains views on the current state of research and advocacy in ME, looking at past mistakes and false views that still pervade the landscape today and have affected the perception and treatment of ME, and especially the research. Has research moved on? We have an opinion piece from Professor Ola Didrik Saugstad on the situation in Norway. If anyone were in doubt of the danger from lack of progress then the story of our friend, Anne Örtegren, is sobering. It is easy for patients to continue to believe in those who have failed them but we feel there are better choices. News from the Quadram Institute Bioscience ahead of their move to a state-of-the-art research, researchers such as Leonard Jason who still provides input to ME research. We have the UK Biobank presenting at our Colloquium – an article of the work of this national/international resource is in the Journal – answering the question what can the UK Biobank do for ME. IiMER continue to use our efforts to develop the UK/European Centre of Excellence for ME in Norwich Research Park. Exercise can be really beneficial for people with ME, but it needs to be the right kind of exercise. This is a list of activities for us to work through as part of a Graded Exercise programme. Don't take it on all at once, aim to undertake one exercise daily - IT WILL make you feel better, promise. ....................……................................. Exercises: Beat around the bush. Jump to conclusions. Climb up the walls. Wade through the morning paper. Drag my heels. Push my luck. Make mountains out of mole hills. Hit the nail on the head. Bend over backwards. Jump on the band wagon. Run around in circles. Toot my own horn. Pull out all the stops. Add fuel to the fire. Open a can of worms. Put my foot in my mouth. Start the ball rolling. Go over the edge. Pick up the pieces. What a Workout! Rest At Last. Face Book Time. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 5 of 56

Although, to be fair, it is maybe not the MRC with whom we take issue as it does some excellent work in many other fields. It is, instead, those whom the MRC have charged with responsibility for ME. They have failed miserably - or succeeded completely - depending on whether the objective was to make progress in research or to be gatekeepers for stalling any progress. If anyone doubts the lack of progress made let us look back to a time long before the disastrous PACE Trial, way before the worthless “expert panels”, before the Gibson Inquiry, even before the CMO report of 2002. In 1988 in Parliament MP Jimmy Hood tabled a motion – “to require an annual report to Parliament on progress made in investigating the causes, effects and treatment of myalgic encephalomyelitis” 30 years ago! It is worthwhile reading again. https://api.parliament.uk/historichansard/commons/1988/feb/23/myalgicencephalomyelitis#S6CV0128P0_19880223_HOC_296 Myalgic Encephalomyelitis HC Deb 23 February 1988 vol 128 cc167-81674.36 pm §Mr. Jimmy Hood (Clydesdale) I beg to move, That leave be given to bring in a Bill to require an annual report to Parliament on progress made in investigating the causes, effects and treatment of myalgic encephalomyelitis. First, I should like to pay tribute to the many sufferers who have written to me in the past few days telling me of their personal suffering from the illness myalgic encephalomyelitis—an illness that is also known as post-virile fatigue syndrome. ---------------------------------------------------------------The ME illness was first observed in Britain 33 years ago in 1955, but it was observed in other countries as early as 1939. Research into the disease is being carried out in Britain at St. Mary's hospital in Paddington, Glasgow university and establishments elsewhere. Research is also being carried out abroad, notably in Australia and the United States of America. Research shows that ME appears to be caused by virile infection, combined with a disfunction of the immune system. There is no doubt that ME is an organic disease. The nature of the disease is such that it primarily strikes the central nervous system, the brain and body muscles. Its most common symptom is a profound weakness of the body, which results in even the most active of people being confined to their bed for long periods, sometimes years. Another symptom that is more distressing than that is the illness's effect on the brain. Some normally bright, alert people find themselves unable to function. Their concentration goes; they have difficulty speaking; and even conversation leaves them completely exhausted. Sufferers lose their jobs and their lives come to a halt. Children affected lose out on their Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 7 of 56

education, sometimes for years. For many children the disease totally devastates their lives. The greatest suffering of all is the anguish caused by misdiagnosis. On top of the physical and mental stress caused by the disease, sufferers' agonies are compounded by being told that they are well, that there is nothing wrong with them, that they are malingering, or that they are neurotic. It is widely acknowledged that many incidences of suicide result from the refusal of doctors to accept that sufferers are ill from myalgic encephalomyelitis. The Bill is a simple measure which merely requires the Secretary of State to make an annual report to Parliament describing the progress that has been made in investigating the causes, effects, incidence and treatment of ME. Such 168a report would be of enormous value in drawing the attention of the medical profession, sufferers themselves and others to whom sufferers may turn for help to what is known about the illness. I cannot emphasise enough how vital it is to give proper recognition to the condition, as the failure to recognise the reality of the illness causes sufferers such great and wholly unnecessary distress. The following are authentic examples of suffering caused by ME. A mother wrote to me saying: My son aged 18 died from this miserable illness last March. He was away at university and had been ill on and off for two years. It all started with an attack of glandular fever. Now we look back over this time and so many things fit into a pattern. He was an active, bright young man with a zest for living and life. This illness got in his way. She concluded by telling me that her son committed suicide. Then there was Jill from Sussex, who said: I have been to hell and back with this devastating illness. I am still not recognised or getting proper benefits. I have received hundreds of letters about similar experiences from all over Britain, as well as Northern Ireland and the Isle of Man. Many well-known persons are afflicted with the disease. Sufferers include the Dean of Westminster; David Provan, a Scottish international footballer who had to retire from a promising career; a famous ballet dancer who is now confined to a wheelchair; and Clare Francis, a well-known adventurer and authoress. I inform the House that one of its Members, my hon. Friend the Member for Pontypridd (Mr. John), who is a sponsor of the Bill, is a sufferer. I submit that the case for justice for ME sufferers is proved beyond all doubt. I have tried today to resist the temptation to speak in strong terms about the failure of the medical profession to recognise myalgic encephalomyelitis and the failure of the Department of Health and Social Security to recognise the plight of ME sufferers. The sufferers are denied proper recognition, misdiagnosed, vilified, ridiculed and driven to great depths of despair. They look to this House for justice. For them all I commend the Bill to the House. Question put and agreed to. Bill ordered to be brought in by Mr. Jimmy Hood, Mr. Alfred Morris, Mr. Jack Ashley, Mr. Brynmor John, Mr. Don Dixon, Mr. Alan Meale, Dr. Lewis Moonie, Mr. Sam Galbraith, Ms. Harriet Harman, Mr. Jimmy Wray, Mr. Tom Clarke and Mr. Jerry Hayes. Look again at the first two paragraphs of the above motion - and this is from 1988! The sad fact is that the above motion could have been brought before parliament today. Page 8 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) In fact, this motion from thirty years is far more advanced than some recent motions that have been brought before parliament. And what was the request from this bill from 30 years ago? “The Bill is a simple measure which merely requires the Secretary of State to make an annual report to Parliament describing the progress that has been made in investigating the causes, effects, incidence and treatment of ME.” An annual report into progress! Logical, simple, coordinated. Something that any health department of chief medical officer might well see as common sense for a disease that affects so many and costs so much. Yet thirty years on we have nothing of the sort. We can wonder how things may have been if this request had been enacted. Thirty years have passed since the above motion was made, and very little has changed, and the scale of the failure of those chosen to deal with ME is apparent. So many false starts and disingenuous actions by those in influential positions! Since the CMO report on ME from 2002 people in positions of influence have had adequate opportunity to support biomedical research into ME. Instead, we witness dead-end “expert” panels and collaboratives formed – coming and going every few years, ending in failure, before another dead end initiative is set up. This pattern of stalling tactics is there to be seen and should fool no one. It is tempting for some to believe those who perform a 180o change of direction to embrace “biomedical research” into ME, or issue statements that CBT and GET should not be offered as treatments – despite having promoted these views for decades. We do not believe in these epiphanies. After years of collaborating or supporting those proponents of the biopsychosocial theories of ME, the motives for changing of views has more to do with selfinterest and less than the good of mankind at heart. Continually offering second chances to organisations that repeatedly failed people with ME is a perverse form of Stockholm syndrome. As we stated in our letters to NICE we would advise people not to believe these statements and only give trust when one sees concrete action and permanent change. Invest in ME research (Charity Nr. 1153730) Are we any closer today to joining the pieces together and creating the bigger picture than we were twelve years ago when the Gibson Inquiry of 2006 suggested that “£11 million should be made available for research to redress the balance in an illness where too much emphasis had been put on psychological ‘coping strategies’ ”? Yes and no. IiMER were probably one of the first to begin discussing the idea of international collaboration in research into ME many years ago as the way forward. We embedded this concept in all we do following the 2007 conference. Now this term is being used more and more. Yet, if we are honest, it is still not how we wished things to be. If we discount the doubtful areas of research that have received large funding in the past – what IiMER refers to as the “Wrong Stuff” – then rather than real coordinated collaboration what we see at the moment is still largely sets of disparate research threads and “territories” which continue to be, to a great extent, competing rather than joining together. Perhaps it is just the phase we are going through where everyone is finding their place in the new world www.investinme.org Page 9 of 56 Research into ME But what of research into ME? This brings us on to our cover image – which sums up the state of current research into ME.

following the decimation of the flawed PACE Trial and glimpses of realisation by the establishment that things must change. IiMER were arguably the first to develop the idea of a Centre of Excellence for ME in UK – started almost a decade ago – a while after the Gibson inquiry and after that charity had sat in interminable meetings with the NHS for years and which had achiev by the time we walked out in disgust. senseless meetings are still going on wi sign of any progress. The Gibson Inquiry recommended an investigation of those vested interests in ME that have so manipulated the research and treatment services. Dr Gibson suggested a standards committee because too often patients had to live with the double burden of fighting for both their health and their benefits. This has not occurred. Instead, it has been left to an independent journalist from outside the UK to expose the flawed PACE Trial and all of its underlying intrigue. Yet, compared to even five years ago there are changes which have occurred. Thanks to leading organisations, such as Invest in ME Research, a great deal of international collaboration has been initiated, some more funding has been found (though still mostly from philanthropic and charitable sources). The recent NIH award is encouraging but far less than Invest in ME Research suggested in our response to IOM and P2P Reports ($250 million dollars for the next five years). However, our cover image shows the reality of the state of research into ME today – lots of pieces to a puzzle, without anyone really knowing what the bigger picture will look like, even though there are hints. The landscape for ME still seems like a jigsaw puzzle with an historical lack of funding meaning that relatively few players have been able to start to create the big picture. In research it is common for false starts to occur when attempting to find the cause(s) and treatment(s) for a disease. The fact that ME has had far fewer false starts, let alone breakthroughs, than other areas of research is also an indication of the pitiful attention that has been given to it by successive governments and health departments and by disingenuous establishment representatives. Biomedical research into ME has not been well served in UK or elsewhere for a generation. Patients are (literally) sick of the biopsychosocial approach to ME and fatigued by the constant false belief that exercise will make them better. r lack of funding have been political n part, and more to do with reasons ated from researching this disease. s has had consequences in scaring off new research interest, in avoiding ME being brought into mainstream biomedical research and lacking any sort of strategy. gress from seed funding research ccasional philanthropic means has ed. is has done is to create more puzzle pieces and nothing has been joined together. So many disparate pieces of research – uncoordinated, using precious funds raised mainly by patients and poor use of the comparatively small research capacity available. Until very recently nobody has been looking at the whole puzzle, with genomics technologies now assisting. This is why Invest in ME Research has been developing a strategy since 2010 to develop the UK/European Centre of Excellence for ME – where a hub of research, based in Norwich Research Park, can be created to build up the bigger picture and then add research onto to it as knowledge develops. To create hypotheses to establish how things may link up. Already, in recent discussions on research, we can see that our Centre approach is functioning and addressing other missing aspects of the big picture that have been allowed to be ignored – such as overall standards and outcome measures which can be used by all. The basics are still lacking and there is an urgent need to raise the standards. This is why Invest in ME Research has spent so much effort in facilitating international collaboration between trustworthy biomedical researchers who wish to work together – such as the European ME Research Group (EMERG) concept. This is why common data elements is required and why the recent NIH work on that may be crucial to move forward. Page 10 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) This is why we need a specialism in ME – a clinical consultancy attached to the research. And this is why we need up to date information that is not serving the biopsychosocial ideology or some careers. These are all elements that Invest in ME Research have been developing for years, with few resources and with little support other than from the great supporters that we have. It is why we need to complete the establishment of the foundation for the Centre of Excellence that we have started - to join research and create the future rather than rely on the status quo that benefits some organisations and individuals – but not patients. An organisation can achieve a lot in five years – or it can achieve nothing. appreciate. We need momentum and international collaboration in research – and this is what Invest in ME Research provides with its cpd-accredited Colloquiums that are designed to bring together researchers, clinicians, patient groups and patients/carers in order to make progress in research into ME. This year’s Colloquium has almost one hundred biomedical researchers from around the world, from all of the main centres of research into ME and the CDC and NIH, binding these research elements together and creating new ones. The Colloquiums are created by a small charity with great supporters without support from large establishment organisations or paid employees doing the work. But then the Colloquiums are the real thing – not carrying any baggage from the wrong stuff or weighed down by affinities to the BPS lobby. Moreover, they are successful – often even helping those who choose not to support the charity. It is five years since we began funding the first biomedical research project at Norwich Research Park. An organisation can achieve a lot in five years – or it can achieve nothing. The difference is often down to individuals – those who have the passion and dedication to make change - or those who fail to do anything and are comfortable with seeing no change, merely making disingenuous platitudes aimed to assuage patient opinion. We have been reminded in recent times of how fragile life is and how healthcare is so important for a just society. Even “established” diseases that have comparatively large research funding and correct The NIH initiative is along the lines we foresaw when we initiated our proposal for a Centre of Excellence. The IiMER concept and development is based on a sound foundation and trusted biomedical researchers who are not serving their own agendas and has no baggage associated with it that can cause harm to people with ME. The key to making ME a disease that receives the highest priority is an objective that we need to attain by establishing basic building blocks and a foundation on which to progress – funding for proper, high-quality biomedical research; education about the disease; and correct perception of the disease. These aforementioned building blocks happen to be the basic objectives of the charity. We do believe that a corner has been turned and more good news is coming – some from IiMER. However, time will tell if we are heading for a new dawn – or watching the stars circle. perception amongst health departments are not without issues. We have seen examples of this close up. The negative early results from the Norwegian Phase III trial has created a vacuum in research into ME. It directly affected the charity’s plans for research and forced a major reassessment of our strategy and that of our supporters. We were recently grateful to learn that the pledge that was provided for the rituximab trial from the Hendrie Foundation has now been granted for use by the charity in other, future biomedical research. The Hendrie Foundation has been an incredible supporter showing not only advice and support but also huge integrity – a particular attribute that we Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 11 of 56

National Institute for Health and Care Excellence Guidelines for ME Correspondence with Professor Mark Baker Centre for Guidelines Director Whilst preparing for the planned NICE Stakeholders' Workshop in January to review the NICE guidelines for ME it was, in our opinion, necessary to make one request to NICE which we felt could not be delayed. We requested that NICE remove the recommendations for Cognitive Behaviour Therapy (CBT) and Graded Exercise Treatment (GET) immediately from the existing guidelines due to the possible deleterious effects on people with ME. All of the correspondence can be seen on our website here - http://www.investinme.org/IIMER-Newslet-180101.shtml. We felt that it must have now surely been realised by all that CBT and GET are inappropriate for treating ME and in many cases have proven to be deleterious to the health of patients. The PACE Trial, which was supposed to prove the efficacy of CBT and GET for ME, has been sown to be flawed and a complete waste of taxpayers’ money. Reanalysis of PACE Trial results by Matthees et al (once the data was forced to be released from the authors following a legal challenge) stated - "This re-analysis demonstrates that the previously reported recovery rates were inflated by an average of four-fold." The PACE Trial is now being used as an example of how not to perform research – and it is widely seen as flawed and is ridiculed. Several articles by David Tuller academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley, have exposed these flaws and demonstrated that the PACE Trial cannot be considered valid. We believe that a full review of the NICE guidelines, that may take two years or more, will leave patients exposed to these harmful treatments (CBT and GET) and it is not acceptable. By removing the recommendations for CBT and GET from the existing guidelines now, with an addendum or correction of some sort, it could go a long way to establishing some trust in NICE from patients that was forfeited when the previous guidelines were published and the views of patients were ignored. Thus began an exchange of letters between Professor Mark Baker of NICE and Invest in ME Research. The final letter from Professor Baker and our summary are illustrative of a system that has failed people with ME in the past and risks continuing to fail them in the future By retaining CBT as a recommendation then this only helps those organisations and individuals who continue to promote biopsychosocial theories about ME for their own vested interests and will continue the threat to the welfare of ME patients. CBT in the existing NICE guidelines is tightly connected to GET as it asserts that fear of exercise and false illness beliefs perpetuate the condition. If the treatments mentioned (CBT and GET) are already accepted to be “inappropriate”, “unacceptable” or “unsuitable” as recommended by the existing guidelines then your (and NICE’s) duty and obligation to sick and vulnerable patients is to remove them immediately. There is no other logical course to take. Summary from Invest in ME Research 9th February 2018 Following the exchange of letters with Professor Baker we have summarised our views on the statements we have received. The replies we have received force us to be very concerned about influences still affecting NICE guideline development for ME.  Professor Baker believes withdrawal of the guidelines would result in the entire support structure being removed. He has said that the services that are now provided to patients will be withdrawn if the existing guidelines are withdrawn immediately. Page 12 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730)  We have said we disagree with that. The reality is that the services offered currently are sparse at best and detrimental to patients’ health at worst and rarely meet the needs of patients. It now must surely be recognised that, in fact, there is a distinct lack of services for ME patients, then we do really think it again illogical to worry about services disappearing. To what majority view is Professor Baker referring? Is the majority view that of doctors? We doubt it! Is the “majority view” that of the lobby of psychiatrists who have so dominated the debate regarding what guidelines are imposed on people with ME, and what research is to be funded? This seems a very odd conclusion in the circumstances.  As all doctors will be told that a new set of guidelines will appear then new services will result from that. CCGs still have a responsibility to patients. In addition, we have suggested that NICE has a choice of action – if NICE does not wish to remove the existing guidelines then just adding the addendum that CBT and GET are no longer valid recommendations would be appropriate. The extremely poor or inappropriate services currently offered should not be a reason to retain flawed guidelines that harm patients.  Professor Baker stated that “the actions of some service agencies (health care commissioners, children’s services, schools and benefits agency amongst others) ”....is not something which NICE has direct influence over”.  Professor Baker claims that NICE guidelines are responsible for services being provided because they will disappear without them – whilst at the same time claiming that NICE has no direct influence over those services using them. It is hard to follow this reasoning.  The actions of some service agencies (health care commissioners, children’s services, schools and benefits agency amongst others) are the direct result of the NICE guidelines and the recommendations therein and NICE must be held accountable and take responsibility.  Despite admitting the unpopularity of the guidelines with patients, which Professor Baker and NICE state they "clearly now empathise with", Professor Baker states that the majority view has been that they have done some good.  The guidelines must surely be created to benefit patients. Professor Baker admits that they are unpopular with patients. Yet patients are only offered empathy - not action. Mere words being thrown around without any substantiation or detail is not just careless - in this situation it is disingenuous and maybe even dishonest. If Professor Baker and NICE state that a majority view supports the retention of the existing guidelines then they must provide details of whom that majority consists of. For it is not amongst patients.  Professor Baker believes that the guidelines legitimise the diagnosis.  Yet how could that be when few services have been offered, when the services that are offered are inappropriate and when Professor Baker acknowledges the horror stories confronting him where patients are not treated seriously? How can it be when the diagnosis of ME is so unreliable and unclear?  In short, we contend that the NICE guidelines have done nothing to legitimise the disease.  In fact, they have maintained an ignorance of the disease and allowed patients to be harmed - and continue to allow patients to be harmed.  Legitimation is not what patients feel.  We also contend that doctors have been ill served by these existing guidelines and cannot help their patients. After two or three decades of seeing this disease mishandled and starved of funding for proper research then we can attest to the fact that it has been anything but legitimised. Even the main protagonists of the BPS ideology, an ideology that has so completely raped this illness with its misinformation and vested interests, have stated that they do not see ME as being a disease – but instead a behavioural illness that can be cured by quack treatments. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 13 of 56

 The existing NICE guidelines have done nothing to legitimise or help ME patients and the services that are on offer are mostly inappropriate or sparse – influenced totally by the existing NICE guidelines.  Professor Baker has stated that the existing guidance is carefully worded with the implication that doctors are somehow not only aware of the “nuances” mentioned by Professor Baker, but are also understanding them.  We have to disagree. If NICE recommend CBT and GET and if these therapies harm patients then no amount of crafted wordsmanship in the world will avoid the situation where patients are harmed.  We have stated that the “nuances” and “craftsmanship” of the wording in the existing NICE guidelines to which Professor Baker refers are lost on doctors, and on almost everyone, except NICE.  Professor Baker states that the (existing) guidance is very carefully worded to protect patients and is "deeply concerned" at the actions of some service agencies (health care commissioners, children’s services, schools and benefits agency amongst others) which clearly do not represent the wording and intentions of the guidance. Professor Baker then states that this is not something which NICE has direct influence over and can only suggest that we direct our ire on those responsible for irrational decisions and the misquoting of our guidance.  This is an astonishing statement to make - and far from true.  Of course NICE directly influences what doctors prescribe.  It is NICE who are responsible for the recommendations which doctors are compelled to take into account.  This statement demonstrates that NICE still really has no idea at how much damage these existing guidelines have done, and no idea of what damage they continue to do.  Professor Baker suggested that we direct our ire on those responsible for irrational decisions and the misquoting of our guidance.  Our "ire" is actually directed at those responsible for irrational decisions or decisions that make ME patients worse. Page 14 of 56 www.investinme.org Professor Baker admitted that the guidelines would be replaced entirely. Professor Baker has agreed that CBT and GET are perceived and experienced by patients as harmful. We believe that Professor Baker accepts the claims that patients have been harmed by CBT and GET It therefore defies logic to retain harmful recommendations for two more years or morewhen it is clearly understood that patients are being harmed by these recommendations.  Professor Baker stated that the PACE Trial has had no effect on the recommendations of NICE (despite last summer the surveillance review quoting the PACE Trial).  In our letter to Professor Baker we did not refer to PACE as being the base of evidence for NICE guidelines. We only intended to refer to PACE in case Professor Baker came back to us to deflect our argument that CBT and GET need to be dropped by referring to PACE.  Yet NICE did use it to base its decisions in the surveillance review of 2017  We have stated it is illogical, and harmful to patients, that NICE retain the existing guidelines when it is admitted they are not fit for purpose, are not what patients want and potentially harm patients, and will be discarded in any case.  NICE must follow the USA and remove recommendations for using CBT and GET as treatments for ME with an addendum to the existing guidelines.  We have requested that this addendum is communicated to other healthcare agencies around the world who have misguidedly used the existing NICE guidelines as any basis for their own treatment of ME patients.  We began this series of letters to Professor Baker due to the comments attributed to him and NICE. These comments have made us wonder how these would be translated into action.  Professor Baker’s reply to us – a few hours before the stakeholder meeting – clearly seemed to be contradictory to the comments that Professor Baker made to the participants in the stakeholder meeting and raised major concerns for us as to the actual way NICE were intending to proceed. Invest in ME research (Charity Nr. 1153730)  This, and further replies to our initial request to remove CBT and GET from existing guidelines, baffled us.  The fact that Professor Baker has stated that the existing NICE guidelines will be torn up indicates this realisation that NICE and the existing guidelines have failed.  What patients have said has proven to be true. Yet NICE did not listen.  We detect even now that these messages still have not been taken on board.  Comments such as “we will tear up” the existing guidelines need to be translated into immediate action.  We have words from NICE - but no action.  NICE must separate the decision on the continuation of the existing guidelines from the review of them. These are two separate matters – linked by the fact that NICE has already decided to tear up the existing guidelines and that Professor Baker accepts that CBT and GET are harmful to ME patients.  The existing guidelines must be withdrawn or NICE must add an addendum that CBT and GET are no longer recommendations.  The refusal to add an addendum to existing guidelines to remove BOTH CBT and GET is illogical in the context of the remarks made by Professor Baker/NICE. To avoid further harm to patients they would remove the drug immediately.  This is the same situation that NICE now face with CBT and GET for ME.  Professor Baker has written to IiMER that he “will discuss at the highest level at NICE what remedial action to help patients we can take in the meantime.” We hope that this will result in issuing the addendum to the existing guidelines that removes CBT and GET as recommendations for ME – or otherwise the withdrawal of the existing NICE guidelines for ME immediately.  We do not share the euphoric tributes to NICE for arranging a workshop where the audience is told everything that they want to hear. Our recommendation to ME patients and their families is not to trust comments by NICE and not to trust NICE at all – until the day arrives that NICE actually deliver and The refusal to withdraw the existing guidelines whilst they are torn up and new guidelines are developed carries a level of illogical reasoning. Professor Baker has admitted the existing guidelines are unfit, he has accepted the horror stories of patients being coerced into trying CBT and GET and being harmed by them, he has heard of insurance companies denying benefits when people refuse to agree to try these flawed theories recommended by NICE. operationalise guidelines for ME that really do reflect the reality and needs of ME patients and their families.  Years of experience of establishment tactics involving wasting several years on initiatives that are already designed to deliver nothing of consequence have made us wary of the corrupt systems in place.  Based on their track record NICE do not yet deserve any such trust.  ME patients have had very little bargaining power over the last decades thanks to the insidious and immoral network of BPS protagonists who have influenced all policies on ME in the UK and taken over decision making in weak and apathetic research councils and government departments. In all of this how can it be logical, or moral, or safe, to retain these existing guidelines, and especially the disastrous and damaging recommendations for CBT and GET? If a drug is recommended by NICE for a disease and some time later the drug is found to be harming patients then surely NICE would take steps to remove that drug. They would not retain it as a recommendation, to be in use for two years whilst they developed a new guideline for the disease. Invest in ME research (Charity Nr. 1153730)  What patients have been able to retain is the ability to give or withhold their trust in new initiatives that promise change to improve their lives. In the world of social media, where the playing field has been levelled in recent times and allowed patients to challenge biased research, this provision of trust by the patient community can be a useful commodity.  We therefore do not give NICE our trust. Our recommendation to ME patients and their families is not to trust comments by NICE and not to trust NICE at all – until the day arrives that NICE actually deliver and operationalise guidelines for ME that really do www.investinme.org Page 15 of 56

reflect the reality and needs of ME patients and their families. Currently that date would be somewhere in two years time. NICE can bring forward that date by acceding to our request to add an addendum immediately to the existing guidelines to remove recommendations for BOTH CBT and GET - or by withdrawing the existing guidelines for ME immediately, and issuing a press release to doctors in UK and abroad that NICE has found the existing guidelines to be unsatisfactory, that they are going to be torn up and completely revised. If NICE do this then trust will surely be given by ME patients. Sir Andrew Dillon might even find it within himself, on behalf of NICE, to issue an apology to ME patients for the wasted years and the distress and the harm which the existing guideline recommendations have caused. If NICE do not take this eminently logical and fair decision immediately then there is no reason to give that trust. We really do hope that NICE now act in a logical and fair way with the patients in mind - uninfluenced by the evil of the BPS network that has been allowed to flourish over the last decades. Add the addendum to remove CBT and GET – or Tear It Up! Now! Finally, look at a communication below, from a patient, that has come to Invest in ME Research in the last month - a letter which neatly describes the appalling consequences of recommending CBT and GET - something for which Professor Baker and NICE cannot pass on responsibility to others. This is the result of NICE's recommendations in their existing guidelines - and this just underlines everything we have been trying to make Professor Baker, and NICE, understand. This letter alone is a testament to the failure of NICE to help people with ME and their families - and a decade on from the creation of the existing guidelines there is enough of an indication that no lessons have been learnt - or any real intent is underway to correct the failings. Throughout our correspondence it seems clear that Professor Baker is oblivious to the elephant in the NICE room - no matter how much damage it is doing to patients. NICE must serve the needs of patients. Page 16 of 56 www.investinme.org Unfortunately, we fear that NICE will not do as we suggest and will not act for the interests of patients. We can only surmise that more influential forces are still present, continuing to force more CBT and GET on to patients. If that were so it would be shameful. NICE, and those deciding on the future for people with ME, must be held accountable if more people are harmed by retaining the existing damaging recommendations for using CBT and GET for another two or more years. Further Reading 1/ 2/ NICE Campaigning Notes on BPS Model From a Patient: To Invest in ME Research I have been closely following your continuing correspondence in relation to the call for revision of the NICE guidelines. In particular the removal of CBT/GET. I have had M.E. for almost four years and am quite severely affected. I am housebound most of the time and often bedbound. I was previously a 'high flyer' (my neurologists' words) and a civil servant with a social work background. Due to my illness I am no longer able to work, and have just been through the very painful process of applying for ill health retirement. My pension provider (through the (name provided) pension scheme) has a two tier system for pension awards in the circumstance of ill health retirement. I have undergone five medical assessments during the process and have been assessed as permanently incapacitated in terms of employment. However, as I have not completed the treatment, as recommended in the NICE guidelines, I cannot obtain the higher rate pension. The treatment namely being CBT and GET. I have engaged with the specialist M.E. service in (location provided) but was unable to continue as attending sessions made me more unwell. I tried CBT through my local mental health service, attending three out of six sessions, this made me more unwell and put me back into bed for weeks. I am in receipt of the highest rate of both ESA and PIPS. These were both awarded following the first medical assessment, which I understand is not the position for far too many M.E. sufferers. Invest in ME research (Charity Nr. 1153730) I have taken my ill health retirement case to appeal within my pension service. The position of the original decision not to award me the higher rate pension has been upheld on the grounds that I have not completed CBT and GET. which takes around three hours to get me ready for, with lots and lots of assistance from my wife, who is also my carer and carer to our 18 year old disabled son. My pension provider will now escalate my appeal to stage two of the process. However, the decision makes it clear that, in order to succeed, I need to prove that I have completed CBT and GET. I am faced with a position that is unfair and takes away any right I have not to undergo treatment that exacerbates my illness. I have had support from my union (name provided), however they aren't familiar with the fight that M.E. suffers like myself face. Please please continue the fight for those of us struggling to do it for ourselves I often find it difficult to construct challenges around my illness as i simply can't find the words due to my diminished cognitive functioning. This is one of the hardest symptoms to deal with. The loss of intellect. It's in there somewhere, I'm in there somewhere, but I just can't get the words to make sense. It is imperative that someone listens to our voices and I am so thankful for your determination in challenging the medical profession around our treatment options. It will probably be too late to make any difference to my case. I have previously had a life where i travelled up and down the country for my career, helping to make a difference in the lives of vulnerable children. I had authority and was very much a professional. I have always worked within the public sector, both local and central government. I had a lively social life, always on the go with my partner and family. Now my life revolves around my bedroom. I rely on pillows, blackout curtains and strong medication to try and control my pain. If I journey out, it is to visit my G.P. I hope that in the future no one will be penalised for not undergoing treatment that is harmful to their health as a result of your campaigning; that CBT and GET will be removed from the guidelines with immediate effect, rather than waiting for years while the guidelines are revised. Please please continue the fight for those of us struggling to do it for ourselves Little more needs to be said. IiMER Conference DVDs The Invest in ME Research conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo and available in PAL (European) or NTSC (N. America) format. They contain all of the presentations from IiMER International ME/CFS Conferences (2006 – 2013). Also included in the DVD sets are interviews with ME presenters, news stories and round-table discussions. The Invest in ME Research conference DVDs have been distributed to more than 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at http://www.investinme.eu/IIMEC13pastconferences.shtml or via emailing Invest in ME Research at info@investinme.org Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 17 of 56

Research News from Katharine Seton “Defining autoimmune aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)” I would like to introduce myself to you all. I am Katharine Seton, a 22-year-old PhD student and I have just began the second year of my PhD. I originally came from Cumbria and studied Biomedical Sciences at Newcastle University before starting my PhD funded by Invest in ME Research. I have always had a strong interest in the immune system and ME research. I have a personal investment and interest in ME research, because in January 2009 I was diagnosed with ME, when I was just 13 years old. It was both physically and emotionally challenging to make the transition from a very active and musical child, regularly competing in basketball, swimming, orienteering, hockey, netball and athletic events, to a child too ill to attend school more then 9 hours a week. Up until my ME diagnosis, I had always dreamt of being a stunt woman and having a very active career. When I developed ME, I had to cut out sport, music and socialising, which meant I became focussed on my education. I realised after I managed to achieve 11 GCSE’s grades A* to A whilst attending school on a part time basis that I am academically able, something I did not realise prior to my ME diagnosis because I was always so focussed on sport. It was only once I was at University, studying my undergraduate degree, that I came to the realisation that I could contribute to the ME research field. In the summer of my second year, I had a Wellcome Trust funded Vacation Studentship, researching the heritability of ME with Professor Julia Newton at Newcastle University. I loved every minute of this placement, although it was computer based, and after this valuable work experience I realised that I would love to contribute to laboratory research into the cause of ME. I aspire to help find a cure for ME … so watch this space! The research that I am focussing on in my PhD is the immune system and its interaction with gut microbes, specifically, whether there is an inappropriate immune response triggered by bacteria that has leaked across the gut wall. There is current evidence of an inappropriate immune response and gastrointestinal involvement in ME Page 18 of 56 www.investinme.org patients and I endeavour to find out whether there is a link between the two, and if this link is blocked, would it lead to symptom improvement. As ME patients experience a wide range of symptoms, and have different onset patterns, it is a scientifically challenging area of research to study, often yielding different results between different research groups. The first year of my PhD was focussed on creating a plan for recruitment, sample collection and sample analysis. This study has received ethical approval from the Health Research Authority, and participant recruitment is underway. It has been agreed that this study will focus on the recruitment of severe ME patients and their household controls, recruited through East Coast Community Healthcare Centre and through Dr Bansal at Epsom and St Helier CFS Clinic. As this is a longitudinal study, blood and stool samples will be collected on up to six occasions. Now that we have received ethical approval for this study, the second year of my PhD will be focussed on participant recruitment, sample collection and processing, and sample analysis, hopefully leading to the generation of some interesting, valuable, results. Katharine Seton - Quadram Institute, Norwich A Study Update Posted by: Katharine Seton Post Date: 8 February 2018 With regards to the human study being undertaken at the Quadram Institute, “Defining autoimmune aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” progress has been made, despite hold ups. 50% of the target number of patients have volunteered to participate in the study. The main study obstacle was identifying a trained person for blood sample collection. Invest in ME research (Charity Nr. 1153730) A trained person has been identified at the Quadram Institute to take blood. An amendment application and approval from the Health Research Authority has been obtained, and a contract delegating study responsibilities between the University of East Anglia and the Quadram Institute is underway. Once this is in place, home visits and sample collection can commence. Despite not being able to collect samples yet, major progress in method development and optimisation has been made. This was done using banked samples from Daniel Vipond’s PhD. Between (fellow PhD students) Fiona Newberry, ShenYuan Hsieh and myself we have optimised the following: isolation of virus particles from stool samples, viral identification based on unique sequences, and a method to screen for antibody responses to gut microbes. I have recently had a review with my PhD supervisors, the purpose of which is to identify how much progress has been made. I received positive comments that have given me some added motivation: “The quality of the work undertaken to date is also very good with considerable careful and detailed effort being put into evaluating multiple experimental variables to optimise the assay”. Looking forward, the next couple of months entail home visits, sample collection and sample processing, all of which take a considerable amount of time. While this is occurring, method development will be continued and progressed. In addition, we have also been very kindly invited to give a presentation at the Shropshire ME Group Conference in May. This is a great opportunity to communicate our research to the public, and to engage with the public to hear their thoughts. The move in date to the new Quadram Institute building is now August 2018. This provides us with plenty of time to do the first round of sample collection. On a finishing note, I would really appreciate those who received a study invitation, and are interested in participating in the study to please contact myself soon to register your interest. Bye for now – Katharine Katharine Seton - Quadram Institute, Norwich A New Paper from Fiona Newberry et al IiMER-funded PhD student Fiona Newberry has recently had a paper published - “Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?” – with an interesting observation “..as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. " https://ueaeprints.uea.ac.uk/66615/ Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 19 of 56

Thinking the Future - Young/Early Career Researchers for ME Research into Myalgic Encephalomyelitis Prior to the conference Invest in ME Research organised the inaugural meeting of a new international network to encourage young and early career researchers to this field. Despite the seriousness of this disease still very little biomedical research is funded or performed on ME. An international family of researchers working together has been facilitated by the Invest in ME Research Biomedical Research into ME Colloquiums. However, the charity felt that we needed to do more to attract and encourage new, younger researchers or those at the early stages of their careers. To ensure that a foundation of biomedical research into ME can be sustained and to encourage new ideas from new areas then we cannot rely just on the family of researchers that has been built up from all parts of the world. We need to draw in knowledge and expertise from other areas – as we have been doing for many years with our Colloquiums and international conferences. Importantly, we also need to encourage new researchers – and young researchers. Now in its eighth year we wish to introduce another level to the Biomedical Research into ME Colloquium to address these points. As part of the European ME Research Group (EMERG) concept - which is building a network of close European biomedical research collaboration to make rapid advances in research and funding for ME - we introduced a new idea. Thinking the Future. An Early Careers Researcher is defined an individual who is within a few years of the award of their PhD or equivalent professional training, or their first academic appointment. IiMER has created this additional event to encapsulate the need to bring in new faces and new ideas to the field of ME research - and initiate a network for new research talent. The charity made this event free for young/ecr researchers in order to facilitate the establishment of these links and it is open to postgraduate students and postdocs involved in biomedical research, and also medical students with an interest in biomedical research into ME. Page 20 of 56 www.investinme.org We will establish this international forum where research into ME can be discussed, ideas can be generated and a network built to allow opportunities for those young or early career researchers who are already involved in research into ME, or involved in another research area which may be of relevance to understanding ME. Importantly, it will provide more awareness of the exciting possibilities of researching this disease – for the betterment of patients and carers. To make this an international group with events being held elsewhere, and in other countries, we have contacted research groups and our friends in other likeminded charities and organisations who have the same objectives as us. We welcome all support for this and hope that more early career researchers and research departments will begin to appreciate the interesting and challenging opportunities that exist for biomedical research in this field. Help us Think the Future - for ME Invest in ME research (Charity Nr. 1153730) Quadram Institute Bioscience News Opening fully in mid-2018, the Quadram Institute will be at the forefront of a new era of food and health research, working at the interface between food science, gut biology and health. It will develop solutions to worldwide challenges in food-related disease and human health, with a lifelong focus from establishing optimum health at birth through to ensuring we age healthily. The Quadram Institute is assembling interdisciplinary teams and working with appropriate international organisations to address these major issues. Scientists and clinicians working together under one roof will deliver innovative new healthcare solutions. Based on the Norwich Research Park, it is a partnership between Quadram Institute Bioscience, the University of East Anglia (UEA) and the Norfolk and Norwich University Hospitals NHS Foundation Trust. This brings together excellent research, teaching and patient care, synergising collaborations between the 3,000 scientists and clinicians working in six world class organisations clustered on the Norwich Research Park. This concentration of interdisciplinary expertise is needed if we are to solve complex health problems facing society. The Quadram Institute, supported by the charity Invest in ME Research, has established a programme of biomedical research addressing the complex causes of Myalgic Encephalomyelitis (ME). Our ME studies are led by Professor Simon Carding, who leads QI’s Gut Microbes and Health research programme, and is also Professor of Mucosal Immunology at the Norwich Medical School at the University of East Anglia. The research builds on recent evidence that ME/CFS has a basis in the immune system. Our focus is on the interactions between the immune system and the microbiota in the gut. Many ME Invest in ME research (Charity Nr. 1153730) sufferers also have gut-related conditions and several studies have recorded altered microbiota communities. The gut is a major focal point of the body’s immune system. It must deal with a constant barrage of potentially harmful microbes taken into the body with our food, whilst also supporting a large community of microbes that benefit health – the microbiota. Part of the Quadram Institute’s mission is to understand how this balance is maintained, and how changes in this balance lead to diseased states. One aspect of this includes the study of what happens when the lining of the gut, the intestinal epithelium, fails to act as a barrier and members of the microbiota are able to cross. This is known as leaky gut syndrome and may be important in a number of conditions, including ME/CFS, as it abnormally presents microbes to the immune system and potentially triggering an autoimmune response. With partners at University College London, we are looking at the nature of autoimmune reaction in patients with ME. An important aspect of our research into links between the microbiota and ME/CFS is to understand better the role played by viruses in the microbiota. Much research has focused on the bacterial populations, but the microbiota contains many other organisms, including fungi and viruses, as well as bacteriophages (viruses that infect bacteria). Viruses in particular are of interest in the study of ME/CFS as there has been evidence suggesting a viral role in triggering ME/CFS without being able to identify specific causes. Working with colleagues at UEA, we are looking to fully study the viral component of the microbiome, the virome, and its relevance to ME/CFS. Much of our work to date has been supported by the charity, Invest in ME Research, who, as well as raising funds for biomedical research are working to raise awareness of the condition and supporting collaborative efforts across the EU to tackle ME. One target is to establish a Centre for ME Research, building on excellent biomedical research, to act as a hub for European research and treatment of ME. www.investinme.org Page 21 of 56

UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age Cathie Sudlow1,2, John Gallacher3, Naomi Allen2,4, Valerie Beral4, Paul Burton5, John Danesh6, Paul Downey7, Paul Elliott7, Jane Green4, Martin Landray4, Bette Liu8, Paul Matthews7, Giok Ong9, Jill Pell10, Alan Silman11, Alan Young4, Tim Sprosen4, Tim Peakman2, Rory Collins2,4* 1 University of Edinburgh, Edinburgh, United Kingdom, 2 UK Biobank, Stockport, United Kingdom, 3 University of Cardiff, Cardiff, United Kingdom, 4 University of Oxford, Oxford, United Kingdom, 5 University of Bristol, Bristol, United Kingdom, 6 University of Cambridge, Cambridge, United Kingdom, 7 Imperial College, London, United Kingdom, 8 University of New South Wales, Sydney, Australia, 9 University of Warwick, Warwick, United Kingdom, 10 University of Glasgow, Glasgow, United Kingdom, 11 University of Manchester, Manchester, United Kingdom * enquiries@ukbiobank.ac.uk Copyright: © 2015 Sudlow et al. The challenge of understanding the determinants of common life-threatening and disabling conditions is substantial. These conditions are typically caused by a combination of lifestyle, environmental, and genomic factors, with individually modest effects and complex interactions, the detection and quantification of which require studies with large numbers of disease cases. While retrospective case-control studies of particular diseases [1] or existing prospective studies of particular risk factors can help to address this challenge [2,3], a complementary approach is to establish large prospective cohorts designed to study a much wider range of known and novel risk factors for a wide range of diseases [4]. Prospective studies can assess exposures before the onset and treatment of disease, diseases that are not readily investigated by retrospective studies, and both the adverse and beneficial effects of a specific exposure on the lifetime risks of different diseases. UK (United Kingdom) Biobank is a very large, population-based prospective study, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases of middle and old age [5,6]. It aims to combine extensive and precise assessment of exposures with comprehensive follow-up and characterisation of many different health-related outcomes, as well as to promote innovative science by maximising access to the resource. Recruitment of Page 22 of 56 www.investinme.org Summary Points • UK Biobank is a very large and detailed prospective study with over 500,000 participants aged 40–69 years when recruited in 2006–2010. • The study has collected and continues to collect extensive phenotypic and genotypic detail about its participants, including data from questionnaires, physical measures, sample assays, accelerometry, multimodal imaging, genome-wide genotyping and longitudinal follow-up for a wide range of health-related outcomes. • Wide consultation; input from scientific, management, legal, and ethical partners; and industrial-scale, centralised processes have been essential to the development of this resource. • UK Biobank is available for open access, without the need for collaboration, to any bona fide researcher who wishes to use it to conduct healthrelated research for the benefit of the public. 500,000 participants and the collection of an unprecedented wealth of baseline data and samples were completed in 2010. Activity is now focused on further phenotyping of participants and their health outcomes and on providing access to researchers from around the world. Cohort Size The large size of the cohort was based on statistical power calculations for nested case-control studies [7], showing that 5,000–10,000 cases of any particular condition would be required for the reliable detection of odds ratios (ORs) for the main effects of different exposures of 1.3–1.5 (the upper end of the range reported from genomewide association studies of various conditions [8]), and around 20,000 cases for detection of interactions with ORs of at least 2.0. To observe such large numbers of cases of particular diseases within a reasonable follow-up period, prospective cohorts need very large numbers of participants. Projected numbers of cases of a range of common conditions expected to occur among 500,000 UK Biobank participants during 20 years of follow-up (Table 1) suggest that reliable assessment of the main determinants of most of these conditions (and others that are similarly common) should be possible during the current decade [6,9]. The age range for inclusion of 40–69 years represented a pragmatic compromise between participants being old enough for there to be sufficient incident health outcomes during the early Invest in ME research (Charity Nr. 1153730) years of follow-up and young enough for the initial assessment to occur before incipient disease had a material impact on exposures. Data Availability Data from the Baseline Assessment The 500,000 participants were assessed between 2006 and 2010 in 22 assessment centres throughout the UK, covering a variety of different settings to provide socioeconomic and ethnic heterogeneity and urban– rural mix. This ensured a broad distribution across all exposures to allow the reliable detection of generalisable associations between baseline characteristics and health outcomes. The assessment visit comprised electronic signed consent; a selfcompleted touch-screen questionnaire; brief computerassisted interview; physical and functional measures; and collection of blood, urine, and saliva (Table 2).Multiple aliquots of different sample fractions are stored in UK Biobank’s automated laboratory, allowing for a wide range of future assays [10]. Data from Additional Assessments to Enhance Phenotyping UK Biobank is conducting a range of additional phenotyping assessments in all (or large subsets) of the participants. Data are already available both from a detailed dietary web questionnaire [11], completed up to four times by over 200,000 participants, and from the first repeat of the entire baseline assessment in around 20,000 participants [12]. Over the comingmonths and years, further data will become available from: a range of biochemical assays and Invest in ME research (Charity Nr. 1153730) genome-wide genotyping of baseline samples from all participants;Web-based questionnaires to assess specific characteristics in more detail (e.g., cognitive function, occupational history); and, in subsets of 100,000 participants, collection of data from physical activity monitors and multi-modal imaging (Table 3). Data from Longitudinal Follow-Up for Health-Related Outcomes Follow-up is conducted chiefly through linkages to routinely available national datasets. Data are already available on over 8,500 deaths, over 75,000 prevalent and incident cancers, and over 600,000 hospital admissions, while linkages are planned to a range of other datasets, including primary care, cancer screening data, and disease-specific registers. In addition, to reduce misclassification and increase biological specificity of health outcomes, UK Biobank is developing methods for accurate identification and detailed phenotyping of outcomes in a range of disease areas. Initial ascertainment of outcomes with electronic and semi-automated sources will be supplemented by more intensive methods (e.g., retrieval of case records, imaging data, or banked tissue samples) for validation and subclassification (Table 3). Online Open Access to Researchers Many cohort studies have mechanisms for sharing data with external researchers on a collaborative basis, but relatively few have arrangements for open access to the data without any need for collaboration, and even fewer have been established from the outset with the intention of making the entire resource available to the www.investinme.org Page 23 of 56

global research community. The development of open access arrangements for data from cohort studies is an important step in maximising their impact with respect to scientific publications, policy making, and understanding of health and disease. Examples of resources whose impact has been enhanced in this way include the UK 1958 birth cohort study [13] and the Australian 45 and Up cohort study [14]. UK Biobank aims to encourage and provide as wide access as possible to its data and samples for healthrelated research in the public interest by all bona fide researchers from the academic, charity, public, and commercial sectors, both in the UK and internationally, without preferential or exclusive access for any user. UK Biobank’s publicly available Data Showcase (http://www.ukbiobank.ac.uk/) presents the univariate distributions and methods used for collection of all the contact are subject to a more rigorous process of scrutiny and scientific review. Following initial assessment by the executive team, all applications are assessed and either approved or rejected (with right of appeal) by an independent Access Subcommittee. Advice is sought on any applications raising potential ethical issues from both the University of Oxford’s Ethox Centre and the Ethics and Governance Council. Only de-identified data are provided to researchers, who must sign a material transfer agreement, undertaking not to attempt to identify any participant, to keep the data secure, and to use it only for the purposes of the approved research. Researchers must also undertake to publish their results and to return details of their methods, derived data, and/or sample assay results for incorporation into the UK Biobank dataset so that they can be made available to other approved researchers (see variables available for health-related research, enabling potential research users to explore what data are available and plan research applications. An online access process, launched in April 2012, aims to be fair, transparent, and streamlined. Applications for data only are approved so long as the proposed research is in the public interest and the data required are, or will become, available. Applications involving the use of depletable samples or requiring participant rePage 24 of 56 www.investinme.org www.ukbiobank.ac.uk/scientists/ for details). UK Biobank encourages, but does not mandate, publication of results of research based on the resource in open access journals. Ensuring that the resource and its access arrangements are widely communicated is Invest in ME research (Charity Nr. 1153730) an important task, requiring a dedicated communications team to manage UK Biobank’s website, scientific meetings, and other methods for communication with the scientific community, including emails, newsletters, and other social media. In the first two years after the launch of open access to UK Biobank, over 1,000 researchers successfully registered, and over 200 applications were submitted (see www.ukbiobank.ac.uk/approved-research/ for a summary of research that is currently underway). Over 80% of registered researchers were from the UK and over 95% from academic rather than commercial institutions. Approximately 85% of applications Invest in ME research (Charity Nr. 1153730) were for data only, with few as yet requesting use of samples or participant recontact. UK Biobank has now started to receive notifications of submitted abstracts and manuscripts based on the first few completed research projects. UK Biobank reviews its access procedures regularly, revising them in the light of experience and user feedback to make the process as streamlined as possible while remaining consistent with participant consent. Running UK Biobank Success so far in developing and enhancing the resource has relied on public willingness to participate www.investinme.org Page 25 of 56

in prospective research studies; close engagement with funders, government health departments, and the UK National Health Service; extensive consultation with the public, scientists, and a wide range of regulatory, legal, and ethics bodies; and the development of costeffective and efficient methodological approaches. The most significant challenges to be overcome are the implementation of scientifically rigorous processes on a very large scale, sustaining the funding required to ensure the benefits of the resource are fully realised, obtaining approvals from multiple regulatory bodies in a frequently changing political and healthcare environment, and ensuring as wide as possible communication of the non-preferential, open access nature of the resource. Interactions with Participants Participant recruitment, retention, and engagement with enhancement projects has benefited from the willingness of very large numbers of British people to take part in observational research without the prospect of direct personal gain [15]. Participants spent an average of about two and a half hours at the recruitment visit. All gave broad consent to use of their anonymised data and samples for any health-related research, to be re-contacted for further substudies, and for UK Biobank to access their health-related records. Large subsets have subsequently completed Web-based questionnaires, agreed to wear a physical activity monitor, and repeated the entire baseline assessment. Of those who attended the first repeat assessment visit and provided feedback, 92% reported that they would be willing to travel for up to two hours for an imaging assessment visit lasting half a day. UK Biobank keeps its participants involved through providing progress updates via its website, with annual newsletters, and through its dedicated Participant Resource Centre (PRC), enabling them to continue to support the project and participate in research over the years ahead. Interactions with Funding Bodies Having established UK Biobank as a charitable company over a decade ago, the UK Medical Research Council and Wellcome Trust have provided the vast majority of its funding so far. These major funders have had the long-term vision to continue to invest substantially in its ongoing development as a global research resource, coordinating both the scientific review of major proposals for developments to the resource and contributions from other funding bodies, including the Department of Health, Scottish and Welsh Governments, North West Development Agency, British Heart Foundation, and Diabetes UK. Long-term funding is not guaranteed, but depends on UK Biobank working Page 26 of 56 www.investinme.org in close partnership with its funders towards the common goal of facilitating high-quality, cost-effective research that will improve the public’s health. Crucial to this partnership is provision and joint discussion of regular updates on progress against challenging milestones, new strategic goals, scientific opportunities, financial plans, and use of the resource to generate new scientific knowledge. Interactions with the UK’s Publicly Funded National Health Service Participant recruitment relied on invitations being mailed to 9 million people whose contact details were obtained from National Health Service (NHS) central registers. Large-scale epidemiological studies in the UK benefit from the fact that 98% of the population is registered with the NHS, which keeps detailed records on all of them from birth to death. Linkages to NHS datasets provide the principal means of follow-up for health-related outcomes. Industrial Scale, Centralised Processes A key step i n achieving the cost-effective recruitment, characterisation, and follow-up of 500,000 participants was the creation of an executive and advisory team with complementary scientific and management skills and a coordinating centre dedicated to the generation of a resource for the scientific community. This facilitated the development of a centralised infrastructure, bespoke information technology (IT) systems, and industrial approaches to collection and processing of data and samples. For example, inviting potential participants via individual general-practice groupings (an approach used by smaller UK populationbased studies) would have been impractical for a study of UK Biobank’s scale, so appropriate approvals were obtained to allow direct mailing of invitations using contact details held centrally by the NHS. The recruitment process itself was coordinated centrally, with up to six assessment centres being active at any one time during the recruitment phase. Staffing and equipment needs were carefully configured to ensure the smooth flow of around 100 participants per day through each assessment centre for six days per week. Biological samples were also processed and handled centrally, requiring the development of bespoke laboratory information management and automated robotic systems to facilitate rapid, error-free sample storage in, and extraction from, the freezers (at rates of up to 1,500 samples per day) according to particular sample and participant characteristics [16]. Each step of the recruitment, assessment, and sample handling process was first piloted, modified as necessary and monitored centrally, using statistical methods to identify potential performance issues. Similar industrialInvest in ME research (Charity Nr. 1153730) scale, centralised processes have been or are being developed for the repeat assessment and imaging visits. Governance Structure UK Biobank’s Board of Directors has overall responsibility for its direction and management. An Executive Management Team, with epidemiology, clinical, management, laboratory, legal, and communications expertise, oversees the development and day-to-day management of the resource and is responsible for the staff working on the study, most of them based at its coordinating centre near Manchester, with others at the Universities of Oxford, Edinburgh, Cardiff, and London. The executive team receives guidance from a Steering Committee of leading UK scientists, supported by specialist working groups advising on baseline data collection, enhanced phenotyping, follow-up and outcomes adjudication, and an international perspective is provided by an International Scientific Advisory Board (see S1 Consent Form and www.ukbiobank.ac.uk/governance/). This governance structure has facilitated effective working between scientific and management disciplines, allowing UK Biobank to respond to advice from a wide network of scientists on the most scientifically valuable design and development of the PLOS Medicine | DOI:10.1371/journal.pmed.1001779 March 31, 2015 7 / 10 resource, with project management and implementation being the responsibility of UK Biobank’s Executive Management Team and dedicated staff. Robust Ethics and Governance Framework UK Biobank has consulted widely not only with the scientific community but also with the public, its participants, and other interested parties [17,18]. This has informed the development of its Ethics and Governance Framework, which lays out its principles and policies [19], as well as its access procedures [20]. UK Biobank’s research ethics committee and Human Tissue Authority research tissue bank approvals mean that researchers wishing to use the resource do not need separate ethics approval (unless re-contact with participants is required). An independent Ethics and Governance Council oversees adherence to the Ethics and Governance Framework and provides advice on the interests of research participants and the general public in relation to UK Biobank. In keeping with the informed consent given by its participants, UK Biobank does not generally provide feedback to individual participants about information derived from analyses of data or samples made following their assessment visits. Participants receive limited individual feedback in two areas. First, they Invest in ME research (Charity Nr. 1153730) receive a summary of standard measures (e.g., blood pressure, body mass index) at the end of each assessment visit and are encouraged to seek medical advice for results outside the normal range. Second, potentially serious incidental findings (i.e., those likely to threaten life span or have a major impact on quality of life) observed by study staff during these assessments (e.g., possible melanoma on exposed areas of skin) are brought to the attention of participants with encouragement to contact a relevant health professional. Similar feedback is occurring in the imaging substudy, with participants and their general practitioners informed of potentially serious incidental findings noticed by radiographers and confirmed by formal radiologist review. In addition, the overall findings and implications of results that derive from research using the UK Biobank resource are made available to researchers, participants, and the wider community so that they can influence public health strategies. Interactions with Regulatory Bodies The wide consultation, rigorous Ethics and Governance Framework, and Ethics and Governance Council oversight role have been essential in paving the way for UK Biobank to accomplish obtaining the multiple ethical and regulatory approvals required for participant recruitment, sample and data storage, linkages to routine health care data, enhancement studies, and the provision of access to data and samples for approved researchers. Substantial amounts of time, resources, patience, tenacity, and evidence of feasibility and/or acceptability from smaller scale pilot studies have also been required to provide regulatory bodies with the reassurance that they need of UK Biobank’s rigorous approach and commitment to protecting the interests of its participants within an acceptable legal and ethical framework. Conclusions The key lessons learned from establishing UK Biobank are that such large-scale studies require not only a clear scientific focus but also streamlined governance; effective working between academic and management disciplines; centralised infrastructure with industrial approaches to collection and processing of data and samples; close partnership with major funders; a wide network of scientific advisors; high-quality, pragmatic legal and ethical advice; and widespread public support [21]. The resource is now facilitating research by scientists from around the world who wish to investigate how different diseases are caused by the combination of lifestyle, environment, and genes, leading to improvements in prevention, diagnosis, and www.investinme.org Page 27 of 56

treatment. Perhaps unsurprisingly, early use has been mainly, but not exclusively, by UK-based scientists. A major aim for the immediate future is to encourage applications from outside the UK. To facilitate this, UK Biobank is further developing its communications strategy to increase awareness of the resource and its access procedures worldwide. Supporting Information S1 Consent Form. (PDF) S1 Text. UK Biobank Committees and Working Groups. (PDF) Author Contributions Wrote the first draft of the manuscript: CS JG NA GO RC. Contributed to the writing of the manuscript: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. ICMJE criteria for authorship read and met: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. Agree with manuscript results and conclusions: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. References 1. Clayton D, McKeigue PM (2001). Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 358: 1356–1360. PMID: 11684236 2. Willett WC, Blot WJ, Colditz GA, Folsom AR, Henderson BE, Stampfer MJ (2007). Merging and emerging cohorts: not worth the wait. Nature 445: 257– 258. PMID: 17230171 3. Collins FS, Manolio TA (2007). Merging and emerging cohorts: necessary but not sufficient. Nature 445: 259. PMID: 17230172 4. Doll R, Peto R (1981). The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute 66: 1191–1308. PMID: 7017215 5. Ollier W, Sprosen T, Peakman T (2005). UK Biobank: from concept to reality. Pharmacogenomics 6: 639–646. PMID: 16143003 6. UK Biobank (2006). Protocol for a large-scale prospective epidemiological resource. www.ukbiobank. ac.uk/resources/. 7. Burton PR, Hansell AL, Fortier I, Manolio TA, Khoury MJ, et al (2009). Size matters: just how big is BIG?: Quantifying realistic sample size requirements for human genome epidemiology. Int J Epidemiol 38: 263–273. doi: 10.1093/ije/dyn147 PMID: 18676414 8. Hattersley AT, McCarthy MI (2005). What makes a good genetic association study? Lancet 366: Page 28 of 56 www.investinme.org 1315–1323. PMID: 16214603 9. Collins R (2012). What makes UK Biobank special? Lancet 379:1173–1174. doi: 10.1016/S0140-6736 (12)60404-8 PMID: 22463865 10. Elliott P, Peakman TC (2008). The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. Int J Epidemiol 37: 234–244. doi: 10.1093/ije/dym276 PMID: 18381398 11. Liu B, Young H, Crowe FL, Benson VS, Spencer EA, et al (2011). Development and evaluation of the Oxford WebQ: a low cost web-based method for assessment of previous 24 hour dietary intake in large prospective studies. Public Health Nutrition June: 1–8. 12. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, et al (1999). Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 150: 341–353. PMID: 10453810 13. University of Leicester. About the 1958 Birth Cohort Study. http://www2.le.ac.uk/projects/birthcohort/ 1958bc/about. Accessed 12 October 2014 14. Sax Institute. 45 and up study. https://www.saxinstitute.org.au/our-work/45-upstudy/. Accessed 12 October 2014 PLOS Medicine | DOI:10.1371/journal.pmed.1001779 March 31, 2015 9 / 10 15. Pell J, Valentine J, Inskip H (2014). One in 30 people in the UK take part in cohort studies. Lancet 383: 1015–1016. doi: 10.1016/S0140-6736(14)60412-8 PMID: 24656186 16. Downey P, Peakman TC (2008). Design and implementation of a high-throughput biological sample processing facility using modern manufacturing principles. Int J Epidemiol 37 (Suppl 1): i46–i50. doi: 10.1093/ije/dyn031 PMID: 18381393 17. Manolio TA (2008). Biorepositories—at the bleeding edge. Int J Epidemiol 37: 231–233. doi: 10.1093/ije/dym282 PMID: 18381397 18. Barbour V (2003). UK Biobank: a project in search of a protocol? Lancet 361: 1734–1738. 19. UK Biobank (2007). Ethics and Governance Framework. www.ukbiobank.ac.uk/resources/. Accessed 12 October 2014. 20. UK Biobank (2011). Access Procedures: Application and review procedures for access to the UK Biobank Resource. www.ukbiobank.ac.uk/resources/. Accessed 12 October 2014. 21. Manolio TA, Collins R (2010). Enhancing the feasibility of large cohort studies. JAMA 304: 2290– 2291. doi: 10.1001/jama.2010.1686 PMID: 21098774 PLOS Medicine | DOI:10.1371/journal.pmed.1001779 March 31, 2015 10 / 10 Invest in ME research (Charity Nr. 1153730) In February we received the very sad news that Anne Örtegren from Sweden had passed away. We considered Anne a dear friend - although we had never met Anne in person, one of the sad things we carry with us. Yet we instinctively trusted and liked Anne from the very first time we communicated and counted her as a true friend. When we look at the correspondence with Anne we can see it had started in 2007 - a year after we were formed as a charity. In all the correspondence that we had with Anne one always admired the resilience, the articulate nature of her commenting, her strength of character, her dedication and her determination to continue to battle this disease, and her kindness in helping others and being there to make progress. She was a rock – somebody whose opinion we valued and whose help and support we greatly appreciated - and she was generous with her support. Anne’s determination to help us and to encourage Swedish researchers to participate was a shining light for us. Her help behind the scenes led to real collaborations between researchers who met at our Colloquiums. All of this despite the huge suffering that she endured for years. Yet she rarely referred to this. Anne was never one to promote herself or seek the limelight for the sake of it – a refreshing example in this age. She was irreplaceable. Her spirit was just an inspiration. Though we knew Anne was suffering, and had been for such a long time, we were still communicating with her until very recently and had no knowledge of what was to transpire. It is very difficult to read Anne’s last post (below). Not just because of the suffering and pain and hopelessness that she describes – but because Anne was so articulate in describing her situation – never with self-pity, always displaying the same courage that she showed in her life. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 29 of 56

Her story and her life should be seen as an inspiration and she shames those who pretend to be interested in getting change for ME but who do nothing of consequence. One loses a friend, one loses a part of oneself. Yet there are those who leave footprints in one's memory whom one will always remember. Anne Örtegren is such a person. Anne's facebook page is here https://www.facebook.com/anne.ortegren Extract from “Farewell – A Last Post from Anne Örtegren” Nobody can say that I didn’t put up enough of a fight. For 16 years I have battled increasingly severe ME/CFS. My condition has steadily deteriorated and new additional medical problems have regularly appeared, making it ever more difficult to endure and make it through the day (and night). Throughout this time, I have invested almost every bit of my tiny energy in the fight for treatment for us ME/CFS patients. Severely ill, I have advocated from my bedroom for research and establishment of biomedical ME/CFS clinics to get us proper health care. All the while, I have worked hard to find something which would improve my own health. I have researched all possible treatment options, got in contact with international experts and methodically tried out every medication, supplement and regimen suggested. Sadly, for all the work done, we still don’t have adequately sized specialized biomedical care for ME/CFS patients here in Stockholm, Sweden – or hardly anywhere on the planet. We still don’t have in-patient hospital units adapted to the needs of the severely ill ME/CFS patients. Funding levels for biomedical ME/CFS research remain ridiculously low in all countries and the erroneous psychosocial model which has caused me and others so much harm is still making headway. And sadly, for me personally things have gone from bad to worse to unbearable. I am now mostly bedbound and constantly tortured by ME/CFS symptoms. I also suffer greatly from a number of additional medical problems, the most severe being a systematic hyper-reactivity in the form of burning skin combined with an immunological/allergic reaction. This is triggered by so many things that it has become Page 30 of 56 www.investinme.org impossible to create an adapted environment. Some of you have followed my struggle to find clothes and bed linen I can tolerate. Lately, I am simply running out. I no longer have clothes I can wear without my skin “burning up” and my body going into an allergic state. This means I no longer see a way out from this solitary ME/CFS prison and its constant torture. I can no longer even do damage control, and my body is at the end of its rope. Therefore, I have gone through a long and thorough process involving several medical assessments to be able to choose a peaceful way out: I have received a preliminary green light for accompanied suicide through a clinic in Switzerland. When you read this I am at rest, free from suffering at last. I have written this post to explain why I had to take this drastic step. Many ME/CFS patients have found it necessary to make the same decision, and I want to speak up for us, as I think my reasons may be similar to those of many others with the same sad destiny. These reasons can be summed up in three headers: unbearable suffering; no realistic way out of the suffering; and the lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs. Important note Before I write more about these reasons, I want to stress something important. As for most other ME/CFS patients who have chosen suicide, depression is not the cause of my choice. Though I have been suffering massively for many years, I am not depressed. I still have all my will and my motivation. I still laugh and see the funny side of things, I still enjoy doing whatever small activities I can manage. I am still hugely interested in the world around me – my loved ones and all that goes on in their lives, the society, the world (what is happening in human rights issues? how can we solve the climate change crisis?) During these 16 years, I have never felt anylack of motivation. On the contrary, I have consistently fought for solutions with the goal to get myself better and help all ME/CFS patients get better. There are so many things I want to do, I have a lot to live for. If I could only regain some functioning, quieten down the torture a bit and be able to tolerate clothes and a normal environment, I have such a long list of things I would love to do with my life! Three main reasons So depression is not the reason for my decision to terminate my life. The reasons are the following: 1. Unbearable suffering Many of us severely ill ME/CFS patients are hovering at the border of unbearable suffering. We are constantly Invest in ME research (Charity Nr. 1153730) plagued by intense symptoms, we endure high-impact every-minute physical suffering 24 hours a day, year after year. I see it as a prison sentence with torture. I am homebound and mostly bedbound – there is the prison. I constantly suffer from excruciating symptoms: The worst flu you ever had. Sore throat, bronchi hurting with every breath. Complete exhaustion, almost zero energy, a body that weighs a tonne and sometimes won’t even move. Muscle weakness, dizziness, great difficulties standing up. Sensory overload causing severe suffering from the brain and nervous system. Massive pain in muscles, painful inflammations in muscle attachments. Intensely burning skin. A feeling of having been run over by a bus, twice, with every cell screaming. This has got to be called torture. It would be easier to handle if there were breaks, breathing spaces. But with severe ME/CFS there is no minute during the day when one is comfortable. My body is a war zone with constant firing attacks. There is no rest, no respite. Every move of every day is a mountain-climb. Every night is a challenge, since there is no easy sleep to rescue me from the torture. I always just have to try to get through the night. And then get through the next day. It would also be easier if there were distractions. Like many patients with severe ME/CFS I am unable to listen to music, radio, podcasts or audio books, or to watch TV. I can only read for short bouts of time, and use the computer for even shorter moments. I am too ill to manage more than rare visits or phone calls from my family and friends, and sadly unable to live with someone. This solitary confinement aspect of ME/CFS is devastating and it is understandable that ME/CFS has been described as the “living death disease”. For me personally, the situation has turned into an emergency not least due to my horrific symptom of burning skin linked to immunological/allergic reactions. This appeared six years into my ME/CFS, when I was struck by what seemed like a complete collapse of the bodily systems controlling immune system, allergic pathways, temperature control, skin and peripheral nerves. I had long had trouble with urticaria, Invest in ME research (Charity Nr. 1153730) hyperreactive skin and allergies, but at this point a violent reaction occurred and my skin completely lost tolerance. I started having massively burning skin, severe urticaria and constant cold sweats and shivers (these reactions reminded me of the first stages of the anaphylactic shock I once had, then due to heat allergy). Since then, for ten long years, my skin has been burning. It is an intense pain. I have been unable to tolerate almost all kinds of clothes and bed linen as well as heat, sun, chemicals and other everyday things. These all trigger the burning skin and the freezing/shivering reaction into a state of extreme pain and suffering. Imagine being badly sunburnt and then being forced to live under a constant scalding sun – no relief in sight. At first I managed to find a certain textile fabric which I could tolerate, but then this went out of production, and in spite of years of negotiations with the textile industry it has, strangely, proven impossible to recreate that specific weave. This has meant that as my clothes have been wearing out, I have been approaching the point where I will no longer have clothes and bed linen that are tolerable to my skin. It has also become increasingly difficult to adapt the rest of my living environment so as to not trigger the reaction and worsen the symptoms. Now that I am running out of clothes and sheets, ahead of me has lain a situation with constant burning skin and an allergic state of shivering/cold sweats and massive suffering. This would have been absolutely unbearable. For 16 years I have had to manage an ever-increasing load of suffering and problems. They now add up to a situation which is simply no longer sustainable. 2. No realistic way out of the suffering A very important factor is the lack of realistic hope for relief in the future. It is possible for a person to bear a lot of suffering, as long as it is time-limited. But the combination of massive suffering and a lack of rational hope for remission or recovery is devastating. Think about the temporary agony of a violent case of gastric flu. Picture how you are feeling those horrible days when you are lying on the bathroom floor between attacks of diarrhoea and vomiting. This is something we www.investinme.org Page 31 of 56

all have to live hrough at mes, but know it be over in days. If one told hat point: have to his for the r life”, I am would agree n’t feel o cope with the body in that insufferable state every day, year after year. The level of unbearableness in severe ME/CFS is the same. If we knew there were relief on the horizon, it would be possible to endure severe ME/CFS and all the additional medical problems, even for a long time, I think. The point is that there has to be a limit, the suffering must not feel endless. One vital aspect here is of course that patients need to feel that the ME/CFS field is being taken forward. Sadly, we haven’t been granted this feeling – see my previous blogs relating to this here and here. Another imperative issue is the drug intolerance that I and many others with ME/CFS suffer from. I have tried every possible treatment, but most of them have just given me side-effects, many of which have been irreversible. My stomach has become increasingly dysfunctional, so for the past few years any new drugs have caused immediate diarrhoea. One supplement triggered massive inflammation in my entire urinary tract, which has since persisted. The list of such occurrences of major deterioration caused by different drugs/treatments is long, and with time my reactions have become increasingly violent. I now have to conclude that my sensitivity to medication is so severe that realistically it is very hard for me to tolerate drugs or supplements. This has two crucial meanings for many of us severely ill ME/CFS patients: There is no way of relieving our symptoms. And even if treatments appear in the future, with our sensitivity of medication any drug will carry a great risk of irreversible side-effects producing even more suffering. This means that even in the case of a real effort finally being made to bring biomedical research into ME/CFS up to levels on par with that of other diseases, and possible treatments being made accessible, for some of us it is unlikely that we would be able to benefit. Considering our extreme sensitivity to medication, one could say it’s hard to have realistic hope of recovery or relief for us. In the past couple of years I, being desperate, have challenged the massive side-effect risk and tried one of the treatments being researched in regards to ME/CFS. But I received it late in the disease process, and it was a gamble. I needed it to have an almost miraculous effect: a quick positive response which eliminated many symptoms – most of all I needed it to stop my skin from burning and reacting, so I could tolerate the clothes and bed linen produced today. I have been quickly running out of clothes and sheets, so I was gambling with high odds for a quick and extensive response. Sadly, I wasn’t a responder. I have also tried medication for Mast Cell Activation Disorder and a low-histamine diet, but my burning skin hasn’t abated. Since I am now running out of clothes and sheets, all that was before me was constant burning hell. 3. The lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs The third factor is the insight that the risk for further deterioration and increased suffering is high. Many of us severely ill ME/CFS patients are already in a situation which is unbearable. On top of this, it is very likely that in the future things will get even worse. If we look at some of our symptoms in isolation, examples in my case could be my back and neck pain, we would need to strengthen muscles to prevent them from getting worse. But for all ME/CFS patients, the characteristic symptom of Post-Exertional Malaise (PEM) with flare-ups of our disease when we attempt even small activities, is hugely problematic. Whenever we try to ignore the PEM issue and push through, we immediately crash and become much sicker. We might go from being able to at least get up and eat, to being completely bedbound, until the PEM has subsided. Sometimes, it doesn’t subside, and we find ourselves irreversibly deteriorated, at a new, even lower baseline level, with no way of improving. PEM is not something that you can work around. For me, new medical complications also continue to arise, and I have no way of amending them. I already need surgery for one existing problem, and it is likely that it will be needed for other issues in the future, but surgery or hospital care is not feasible for several reasons: One is that my body seems to lack repairing mechanisms. Previous biopsies have not healed properly, so my doctor is doubtful about my ability to recover after surgery. Another, more general and hugely critical, is that with severe ME/CFS it is impossible to tolerate normal hospital care. For ME/CFS patients the sensory overload Page 32 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) problem and the extremely low energy levels mean that a normal hospital environment causes major deterioration. The sensory input that comes with shared rooms, people coming and going, bright lights, noise, tc, escalates our disease. We are already in such fragile states that a push in the wrong direction is catastrophic. For me, with my burning skin issue, there is also the issue of not tolerati ng the mattresses, pillows, textile fabrics, etc used in a hospital. Just imagine the effects of a hospital stay for me: It would trigger my already severe ME/CFS into new depths – likely I would become completely bedbound and unable to tolerate any light or noise. The skin hyperreactivity would, within a few hours, trigger my body into an insufferable state of burning skin and agonizing immuneallergic reactions, which would then be impossible to reverse. My family, my doctor and I agree: I must never be admitted to a hospital, since there is no end to how much worse that would make me. Many ME/CFS patients have experienced irreversible deterioration due to hospitalization. We also know that the understanding of ME/CFS is extremely low or nonexistent in most hospitals, and we hear about ME/CFS patients being forced into environments or activities which make them much worse. I am aware of only two places in the world with specially adjusted hospital units for severe ME/CFS, Oslo, Norway, and Gold Coast, Australia. We would need such units in every city around the globe. It is extreme to be this severely ill, have so many medical complications arise continually and know this: There is no feasible access to hospital care for me. There are no tolerable medications to use when things get worse or other medical problems set in. As a severely ill ME/CFS patient I have no safety net at all. There is simply no end to how bad things can get with severe ME/CFS. Coping skills – important but not enough I realize that when people hear about my decision to terminate my life, they will wonder about my coping skills. I have written about this before and I want to mention the issue here too: While it was extremely hard at the beginning to accept chronic illness, I have over the years developed a large degree of acceptance and pretty good coping skills. I have learnt to accept tight limits and appreciate small qualities of life. I have learnt to cope with massive amounts of pain and suffering and still find bright spots. With the level of acceptance I have come to now, I would have been content even with relatively small improvements and a very limited life. If, hypothetically, Invest in ME research (Charity Nr. 1153730) the physical suffering could be taken out of the equation, I would have been able to live contentedly even though my life continued to be restricted to my small apartment and include very little activity. Unlike most people I could find such a tiny life bearable and even happy. But I am not able to cope with these high levels of constant physical suffering. In short, to sum up my level of acceptance as well as my limit: I can take the prison and the extreme limitations – but I can no longer take the torture. And I cannot live with clothes that constantly trigger my burning skin. Not alone – and not a rash decision In spite of being unable to see friends or family for more than rare and brief visits, and in spite of having limited capacity for phone conversations, I still have a circle of loved ones. My friends and family all understand my current situation and they accept and support my choice. While they do not want me to leave, they also do not want me to suffer anymore. This is not a rash decision. It has been processed for many years, in my head, in conversations with family and friends, in discussion with one of my doctors, and a few years ago in the long procedure of requesting accompanied suicide. The clinic in Switzerland requires an extensive process to ensure that the patient is chronically ill, lives with unendurable pain or suffering, and has no realistic hope of relief. They require a number of medical records as well as consultations with specialized doctors. For me, and I believe for many other ME/CFS patients, this end is obviously not what we wanted, but it was the best solution to an extremely difficult situation and preferable to even more suffering. It was not hasty choice, but one that matured over a long period of time. A plea to decision makers – Give ME/CFS patients a future! As you understand, this blog post has taken me many months to put together. It is a long text to read too, I know. But I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide. And most importantly: to elucidate that this circumstance can be changed! But that will take devoted, resolute, real action from all of those responsible for the state of ME/CFS care, ME/CFS research and dissemination of information about the disease. Sadly, this responsibility has been mishandled for decades. To allow ME/CFS patients some hope on the horizon, key people in all countries must step up and act. www.investinme.org Page 33 of 56

If you are a decision maker, here is what you urgently need to do: You need to bring funding for biomedical ME/CFS research up so it’s on par with comparable diseases (as an example, in the US that would mean $188 million per year). You need to make sure there are dedicated hospital care units for ME/CFS inpatients in every city around the world. You need to establish specialist biomedical care available to all ME/CFS patients; it should be as natural as RA patients having access to a rheumatologist or cancer patients to an oncologist. You need to give ME/CFS patients a future. Anne ended her letter with – Take care of each other. Love, Anne Anne’s Swedish ME/CFS newsletters, distributed via email to 2700 physicians, researchers, CMOs, politicians and medical journalists https://mecfsnyheter.se/ To Prime Minister Erna Solberg and any other relevant recipients An Apeal for help to a seriously ill child My name is Nicoline and I will soon be 14 years old. The last half year I have been too ill to go to school. For 2 years before this I was often sick with many infections. I really like school and I am what one would probably call a concientious pupil. For me it has been awful not to be able to go to school. This is my first year in secondary school and I had really looked forward to beginning to get marks. My plan is to study law in the future. Luckily I have had extremely good help from PPT (Norwegian educational psychology service) and the school. I have received a robot that makes it possible for me to take part in lessons at school when I am able to. I also have home tuition up to two hours a week. This has meant that I have managed to keep up with the most important subjects and this means a lot to me. The reason I am writing is that, unfortunately, I have met with a part of the system designed to help which does not function at all. I suffer from exhaustion and many other awful symptoms which mean that I am bed bound and isolated at home. I am mostly too ill to meet Page 34 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) any friends and rarely manage to talk on the phone. My mother and many close family members have ME and we are afraid that I have inherited the disease. A little over a week ago I met my doctor at the paediatric clinic. It was an ugly experience for me. The doctor we met would not allow me or my parents to explain my situation and my symptoms. They only talked about psychiatry and how I should be «forced back to life». It was clear that they did not believe in me being physically ill. They did not want to hear about my symptoms because they did not want to «encourage me to be sick». They were totally against the school robot and home tuition because there are local children sick with cancer who do not receive such help. I think that is very wrong because I think it is equally bad for me to be too sick to go to school as it is for other sick children independent of the diagnosis. I am very confident in that I do not have a psychological problem. The PPT have also tested me quite thouroughly since last October and they confirm that there is nothing pointing to school refusal or my having something psychologically wrong. Despite this the doctor had decided even before seeing me that I was mentally sick. So I think that it is very hurtful and bad when a doctor «makes it sound like» I am missing shool for the rest of my life because I myself want to, and things will sort themselves out if only I push myself a bit. If the doctors had listened to me they would have known that I had pushed myself for two years until I collapsed. Just a month ago I was so sick that I just slept for many weeks. My mother had to wake me up regularly to get me to eat and drink. Luckily my mother has a lot of knowledge about exhaustion and I am a little bit better now even though I am still bed bound. I am fearful of going back to see this doctor. My next appointment is in a month’s time. My mother has explored possibilities of getting a referral elsewhere but it looks like children with exhaustion are treated in the same manner in most hospitals in the country. I think this is dreadful. When one gets sick as I did then it should be obvious to be met in a positive manner whilst in hospital. At least it should clearly be so that one is not disbelieved the moment one meets the doctor. I choose to give the doctor the benefit of the doubt and I think they would have treated me in a different manner had they had more knowledge. There is after all no doubt any longer that ME is a physical illness. Nevertheless, children with exhaustion, when there is a reason to suspect ME, are being treated as mentally ill. It is like rubbing salt in the wounds of children and their families who have it bad enough as it is. In my case the doctor has already, after the first appointment, gone as far as phoning my case officer at PPT and asked them to force me back to school. That will most probably make me even sicker. To become sicker does not only mean that I will be more exhausted. It also makes all of the other symptoms worse, such as extreme pain all over the body, nose bleeds, nausea, head ache, flu like feeling, sore throat, dizziness and much more. If it turns out that the symptoms were due to ME, as we suspect, then the chances of getting better will be reduced. It means that if I get pushed into using too much energy now then it may lead to my chances of never getting better or healthy - this is frightening when one is only 13 years old and has numerous plans for one’s life. I therefore think it is strange that the doctor will do this, long before I have a diagnosis – as the doctor is taking a huge risk on my behalf. I have been frightened ever since I came home from the hospital. I am worried that I shall miss all lessons at school now as I am not allowed to receive home tuition or use the school robot. I am also terribly scared of getting sicker than I am already, especially now that I have finally had some improvement. I know that you have previously engaged with ME patients. I think that is wonderful. Unfortunately, the situation for us children being investigated for ME and children who already have the diagnosis is critical – there is no expertise and no help available. It is urgent to improve our situation. I therefore ask you to address this so that we can get help soon. I am happy to contribute if there are any questions. With kind regards, Nicoline Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 35 of 56

Ola Didrik Saugstad A harsh debate about ME in Norway – A personal view from one of the participants orwegian debate on S has for many years been ed between those who E is a psychosomatic claiming Cognitive al therapy (CBT) and Process (LP) are therapies on this condition. ice supporting this view ller, a paediatrican who concluding ME is a stress herefore performed a E patients clonidine, a soenergic agonist which is a to treat high blood g theoretically could esponse and Wyller was e would cure ME patients. did not show any positive s. g his hypothesis might be o preach ME could be ol and he was a firm udy. Welfare workers believed in oung ME patients were d other activities, and the ases requested court orders ad to appear as a witness on several occasions. sease caused by stress and ress control, has therefore orwegian community, in E organisations and a few rt was published in 2015 nd and its defenders have argue against results esearch. Page 36 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) In September 2017 a new public ME debate was kicked off in Norway’s largest newspaper, Aftenposten. During the years there have been many discussions and articles about ME in Norwegian media. However, this time it was different. The debate became intense, lasted for several weeks and was flavoured with the most hatred personal attacks on those who referred to recent biomedical research and were advocating the view that ME is a somatic disease. It all started when a new group of 71 persons called “Recovery Norway” wrote an article with the message: “we know how to be cured of ME. Listen to our message”. The network consisted of previous patients or relatives, and some health personnel who recommend CBT and LP to cure ME. By mind control ME patients are able to control their disease the Norwegian public was told by this group. Not only ME could be cured by such mental exercise, a number of other diffuse conditions as fatigue, pain and tinnitus should be treated with these alternative methods. Why doesn’t anyone listen to us and why do so many doubt we previously have had ME and are now cured? the group asked rhetorically. Four days later September 22nd I wrote as a response with the title: Listen to the ME patients: “In Aftenposten September 18th there is an interesting article by a group of former ME patients who are now recovered. Why not take advantage of their experience using untraditional and alternative therapies such as LP and CBT? It is unfortunate that the group feel they are disbelieved both regarding their previous ME diagnosis and that they today are cured. We are grateful for every patient who have been healed and obliged to try to learn from their experience and what made their improvement.” I continued: “When we discuss ME it is, however, important to know that ME follows phases. Persons who previously were very active and healthy may quickly deteriorate. I have myself the last 10 years or so visited many of the sickest ME patients in Norway in their homes and probably seen more than most. Many have a condition compatible with encephalitis, and this is exactly what modern research seems to reveal. ME is an inflammatory condition affecting several organs, also the brain. The immune system is activated. Some patients improve spontaneously while others are bedridden through years with great pain. This is where those who claim to have improved from ME may contribute with valuable information. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 37 of 56 H s n cu si wi b I P

techniques to master challenging life conditions and diseases without curing these. The authors (Recovery Norway) are wrong and not up to date when they write: ”The debate regarding these problems is often about whether the disease is physical or psychosomatic. Lack of knowledge dominates this field.” After the report about ME from Institute of Medicine (IOM) in USA was published in 2015, there has been a paradigmatic change in the view regarding ME. It was concluded that ME is a serious physical, chronic and complex multisystem disease which is strongly debilitating and the misconception that the disease is psychogenic or a form of somatization must stop.” I then referred to a recent study (2016) from the USA with Maureen Hanson as senior author: “In one study from the Cornell University in the USA the researchers were able to identify biochemical and biological deviations in ME patients, which resulted in the following statement: “Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin." (quote by Maureen Hanson in Medical News Today, Tuesday 28 June 2016). I continued: “It is the supporters of the concept that ME is psychogenic who maintain to underline the lack of knowledge regarding ME. I agree with the Norwegian Research Council which supports biomedical ME research in line with the US effort to find treatment for the disease. Psychosomatic research has not brought us closer to understanding of ME and may have contributed to a prevention of development through years.” I did not, however want to disregard the Recovery Norway group and therefore added: “I belong to those who welcome the initiative of the group. It is useful to obtain information on why some were cured and others not. At the same time the group’s credibility is weakened by lumping together several poorly explained conditions such as fatigue, pain and tinnitus. One problem for ME patients has been that the health care system has not listened to the sickest, nor even cared to examine them. We must listen to the advice both from those who have improved and from those who still have not”. This article from me resulted in an outcry from those who supported the concept of ME as a psychogenic disease. Two neurologists from the University Hospital Page 38 of 56 www.investinme.org in Bergen, one even a professor, wrote that I was misusing my professor title.” Saugstad is exploiting his medical authority to oppress patients who have been cured and want to share their experience.” These two neurologists told us they had treated ME patients for years and never or at least only very rarely, seen any trace of inflammation in the central nervous system. I replied by referring to Mady Hornig and co-worker’s recent article (2017) showing ME patients have an immune signature in Cerebrospinal fluid reflecting the central nervous system and the study of Nakatomi Y et al (2014) indicating ME patients have activated immunecells in the brain. I also quoted Harvard Professor Komaroff who commented that if these findings were reproduced it indicates that ME patients have a low graded inflammation in the brain. A Norwegian professor of immunology confirmed that my comments were relevant. The two neurologists never replied. Wyller wrote a commentary: “Saugstad’s claims are misleading. That the immune-system is activated in ME does not mean ME is an inflammatory process. The immune-system is also activated in depressions, social stress and loneliness. Does Saugstad mean these are inflammatory conditions as well?”. Wyller is a firm supporter of the PACE study and wrote: “The PACE study showed that CBT has positive effect on ME. The study has been criticized but the main conclusion has not been disproven. Another recent study shows equivalent good effect of LP. That mental conditions may contribute to ME is documented well for instance by MRI pictures of the brain. This does not mean that the disease is psychogenic, but that the mechanisms are complex and both mental and somatic factors may play a role.” And Wyller continued: “Professor Saugstad introduces himself as an ME expert but has never carried out ME research himself. He is stuck in an old fashioned distinction between “body and mind” and is followed by a small but vocal group of ME patients who are fighting frantically against the concept that “the mind” has anything to do with this matter.” Wyller concluded his article: “I beg new patients, relatives, health workers – don’t listen to this pessimistic outdated message! Instead listen to the majority of patients - many have been completely cured – who make use of modern and documented therapies.” At this stage of the debate a number of doctors, ME patients and relatives had contributed to the debate with their own opinions and experiences. Wyller did not receive much support. In my reply I underlined I have never pretended to be an ME expert. But I wondered why some people became so emotional because I mentioned recent publications in Invest in ME research (Charity Nr. 1153730) the field. Nobody dared to attack the IOM report, instead they attacked me, a “messenger” informing the public about this ground breaking report. I was worried of the fact that those who went against me seemed to be frightened of new data and not willing to discuss recent international research results. I argued that the PACE study had not shown significant improvement for CBT and the recent Smile study concerning LP had profound weaknesses, only 30% of the eligible patients were enrolled in the study and the sickest ME patients had not been included. I also wrote I was surprised that Wyller characterized ME patients as a small and vocal group. After all, the Norwegian ME association has 4000 members and few of these support Wyller. “Fortunately it is rare for such disrespect from a doctor for the patients he is supposed to care for is uttered so clearly”, I wrote. Further, I wondered how Wyller could characterize international research in the field as old-fashioned and outdated. “Perhaps these new findings are threatening to his psychosomatic position Wyller is basing his academic career, a paradigm which is quickly losing ground? However, for the ME patients this development gives hope for the future” was my conclusion. Wyller’s next move came a few days later: “False information about ME may scare patients from documented treatment”. His article illustrated his views. I therefore refer extensively to parts of it: “Saugstad is a highly recognized researcher in neonatal medicine. It is therefore surprising that he, in the ME debate, breaks several rules for scientific reasoning and dissemination. That inflammation detected in the central nervous system of ME patients does not prove that inflammation is the cause of fatigue. To illustrate this point from another area: That patients with lung cancer often have yellow fingers does not implicate that yellow fingers are causing cancer (both yellow fingers and cancer may be caused by smoking). Saugstad has not published his research findings. Saugstad writes that he has in the last years built up a strong research group on ME. Why have the findings not yet been published? Wyller then continued to inform that he had published 25 research articles in the field with a holistic approach to the complex disease that ME is. He then indicated I am biased due to having a close relative with ME. Two Norwegian professors of medicine gave me their support against his emotional attack. In his next reply he continued to attack these two. As mentioned Wyller is a firm defender of the PACE study and when the results from the SMILE study came he embraced these results – he had for years supported LP and CBT for ME. Why not try them - they do not have any adverse effects, he suggested. I replied this is wrong. “Several ME patients report adverse effects of these two regimes. The major distinction in the understanding of ME is perhaps between those who understand this and those who do not”. Recovery Norway also attacked me claiming that I told ME patients they have an inflammation in the brain. This is definitely wrong I replied, I never diagnose ME patients I only refer to the scientific literature when I am asked. In my final statement I informed that unfortunately Recovery Norway had “forgotten” to disclose that several of their members were heavily involved financially in LP as LP instructors. This debate probably represents a watershed in the Norwegian ME debate and understanding. The psychosomatic ME wing had previously given the impression that they often are harassed by aggressive patients and relatives. They have also spread the information that those who support biomedical findings are afraid of new results. The debate demonstrated that the opposite is the case. The psychosomatic lobby’s reaction to new biomedical information was by resorting to personal and emotional attacks on us who had a different view. Their disrespect for the patients they are supposed to serve shocked many of the neutral bystanders. The debate was probably initiated due to the psychosomatic wing rapidly losing ground after the publication of the IOM report, the new emphasis on biomedical ME research by NIH and also the Norwegian Research Council, the CDC’s change in attitude to CBT, and the reanalysis of the PACE study showing minimal if any effect of CBT. Several of the psychosomatic supporters had invested their prestige and based their whole career on findings that supported their view. I understand it must be painful to see how the basis of their theory quickly eroded. This also explains their uncritical embrace of the Smile study. During the debate which lasted many weeks I received overwhelming support from more than 1000 persons in the newspaper and on social media. Ola Didrik Saugstad, MD, PhD, FRCPE Proferssor (em) of Pediatrics University of Oslo Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 39 of 56

Trial By Error: A Q-and-A with Leonard Jason, on Case Definition http://www.virology.ws/2018/05/02/trial-by-error-a-qand-a-with-leonard-jason-on-case-definition/ MAY 2018 By David Tuller, DrPH A Brief Update: Berkeley’s crowdfunding period closed on April 30th–Monday night. I ended the campaign with $87,580. After Berkeley’s 7.5% in fees, the funds will cover my salary/benefit from July 1, 2018 to June 30, 2019, and some travel costs. I really, really appreciate the fantastic support. Thanks to everyone! I’ve taken a few days to regroup from my Australia trip and catch up on my time zones. ********** Leonard Jason is a professor of psychology at DePaul University in Chicago. He has served as vice president of the International American Association of CFS/ME and as chairperson of the Research Subcommittee of the U.S. Chronic Fatigue Syndrome Advisory Committee. Professor Jason began investigating chronic fatigue syndrome almost 30 years ago. Much of his work has focused on the epidemiology and prevalence of the illness and on the impact of using various case definitions. He has long been concerned that the lack of a uniform set of criteria for identifying study participants has hindered progress in the science. Dr. Jason recently shared his thoughts about these issues. (This Q-and-A has been edited for clarity and length.) How common is fatigue? If you were to ask people right now if they are “fatigued,” which means feeling weak, tired, or lacking energy, about 25% of the population would say yes, so this symptom is very common. In contrast, “chronic fatigue” means that a person has had fatigue for 6 or more months. Only about 4-5% of the population has chronic fatigue. There are multiple reasons for people to be fatigued–for example depression, anxiety, over-exertion, people working three jobs, medications, sleep deprivation, weight problems, poor diet, inactivity, and deconditioning. These are just a few of the many causes of fatigue and chronic fatigue. Physicians see lots of people coming into their practices, where the patients are seeking help for their fatigue, and in fact it is one of the most common reasons for seeing a doctor. But it’s very hard for many physicians to differentiate complaints of general or chronic fatigue versus the illness known as ME [myalgic encephalomyelitis]. Yet it is of critical importance to make a differential diagnosis between those with purely chronic fatigue versus those who have ME. In fact, it is this failure to differentiate these two conditions that has caused so many problems, and the culprit is a flawed and imprecise case definitions as well as failures to gain an international consensus for one research case definition. So what is a case definition, and why are there different research and clinical definitions? A case definition is a set of rules that helps a researcher or a clinician make a decision about whether someone has a particular illness or does not have the illness. It’s that simple. A good case definition is critical for the assessment process, to identify those people who actually have an illness or disease. It is the cornerstone of medicine. A research case definition tries to identify a homogeneous group of people who have the illness and can be recruited for research purposes. In contrast, a clinical case definition is used to identify or diagnose a broader group of patients for treatment purposes, and many of these wouldn’t qualify for research studies. For Page 40 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) example, if someone is very obese, a research case definition might exclude that person because the weight issue could be causing the person’s problems. In other words, for research purposes, we want to select only patients who do not have other psychological or medical conditions that could be causing the illness we are studying. For science to progress, the research case definition is critical, as it can standardize the selection of patient samples so that research groups around the world are all studying the patients with the same disease. So gaining consensus among international scientists for a research case definition is a most critical task, and one that unfortunately has still not been accomplished for our field. One of the parameters that’s important for a research case definition for this illness, in your view, is that psychiatric co-morbidities should be excluded. Can you explain the reason for that? Yes, and let me give an example that illustrates this issue. A patient with a major depressive disorder with melancholic features would probably have fatigue, aches and pains, as well as sleep and cognitive problems. Yet these are also symptoms of ME, so some clinicians and researchers could easily confuse these two conditions. But they are very different illnesses, as people with a major depressive disorder feel selfreproach, whereas those with ME do not. If you ask people with a major depressive disorder what they would do tomorrow if they were well, they would not be sure. In contrast, if you asked people with ME what they would do if they were well, they’d give you a long list of all the things they have wanted to do but been unable due to their illness. If you are studying ME, you need to exclude people who have a primary psychiatric disorder from your study. If researchers misclassify people with a major depressive disorder as having ME, this will have serious negative consequences for identifying biomarkers, estimating prevalence rates, and determining outcomes of treatment trials. The issue of selecting patients who really have ME is the most important issue facing our field. In a sense, the lack of a consensus on a ME research case definition is like building a pyramid of playing cards with a very shaky bottom, and then everything built on top of this foundation is vulnerable to collapsing. Let’s start with what is the broadest case definition that has been used, the so-called Oxford criteria for Invest in ME research (Charity Nr. 1153730) CFS. Can you describe that and explain why it presents a problem? If you have six or more months of fatigue, then you meet this case definition, so it’s a very broad category. Clearly, as I mentioned earlier, a lot of people who meet this criteria have medical or lifestyle reasons causing their fatigue. One of my students, Madison Sunnquist, just published her master’s thesis that indicated how the CBT theoretical model only works if you identify people with a very wide case definition, but when you have a better and more restricted case definition that requires core symptoms of ME, then the CBT model no longer works. In contrast to the CBT approach, my research group for the past 20 years has been doing research on what we call the energy envelope. But this pacing approach is not a cure, just a strategy to help better cope with ME. Our approach involves helping patients to better monitor their energy levels, learn how to stay within their energy envelope, and sustain lifestyle changes that involve reprioritizing activities. So how did the CDC come up with the Holmes and then the Fukuda case definitions? The Holmes case definition came out in 1988. The CDC investigators had gone to Incline Village and ultimately named this illness CFS. Their first case definition included too many symptoms. In fact, to meet their case definition, a patient would have needed to have eight or more symptoms out of a list of 11. But here is the problem that soon emerged–if you develop a case definition that requires so many unexplained somatic symptoms, you have a very high probability of unwittingly selecting people who have a somatoform disorder. And you don’t want to select people who have a purely psychiatric condition. So in 1994, the Fukuda case definition was developed to replace the Holmes definition. For the 1994 case definition, the authors selected eight of the symptoms that had been listed in the Holmes criteria, and a patient needed to have any four of those eight symptoms to meet the new Fukuda case definition. But here is the problem with the Fukuda CFS case definition–patients are not required to have postexertional malaise, cognitive problems and unrefreshing sleep, and as we know, these are core symptoms of ME. So, a person could have four of the eight Fukuda symptoms and be diagnosed with CFS, and not have any of the three critical symptoms. In that case, you would be including in your sample a person who does not have the core elements of the illness. www.investinme.org Page 41 of 56

From 1994 and on, I have been doing research that shows some of the diagnostic problems with the Fukuda case definition. And remember, the Fukuda case definition is the research case definition that has been used throughout the world for the past 25 years. But this Fukuda case definition identifies a heterogenous group of patients, because core symptoms are not required of all patients. So, as a consequence, samples of patients with CFS based on Fukuda case definition vary widely in different research groups and labs. What is the impact of the case definitions on prevalence rates? In the late 1980s and early 1990s, the CDC conducted a prevalence study where they started by asking physicians in four cities to identify patients they thought had CFS. At that time, a lot of physicians didn’t believe CFS existed, so putting physicians as gatekeepers in the selection of patients for this study resulted in a prevalence rate that was very low. Also, many people in the US do not have the financial resources to have a physician, so relying on primary care doctors to identify patients was another reason for low prevalence rates. The study suggested that CFS was a rare disease that affected fewer than 20,000 people in the US. At that point, a group of researchers in Chicago began working on a study that involved finding patients from a random community sample, rather than a sample referred from physicians. In 1995, with NIH funding, our Chicago research team conducted a community-based prevalence study, which found that about a million people in the US had CFS. We also found that CFS affected all ethnic and socioeconomic groups, and thus we helped shatter the myth that CFS was a “Yuppie Flu” disease. What did William Reeves [then-head of the CDC division in charge of the illness] do with the so-called “empiric” criteria? And why did this increase the CDC’s estimate of disease prevalence by a factor of 10? In the early 2000s, Bill Reeves felt there was a need to operationalize the Fukuda case definition. For example, he tried to standardize the way we measure a patient’s disability or a substantial reduction in functioning. He used one instrument that has been referred to as the SF-36. According to Reeves, if a patient met criteria for one of several sub-scales within the SF-36, the patient would meet the disability criteria for having CFS. But one of these domains was “role emotional” functioning. It turns out that every person with a major depressive disorder meets the criteria for “role Page 42 of 56 www.investinme.org emotional” functioning. So you can’t just specify instruments such as the SF-36; you have to specify which sub-scales of the instruments you are going to use, and what are the cut-off points. And if any of these choices are wrong, you will identify people who have another illness. My team gathered data on this point, and we conducted a study that assessed people with major depressive disorder, and found that over onethird of them could be inappropriately classified as having CFS under the so-called Reeves empiric criteria. So, I think in the attempt to operationalize the Fukuda criteria, Reeves made mistakes, and I believe that is one of the reasons the estimated CDC prevalence estimates increased ten-fold, from .24% in a 2003 sample to 2.54% in 2007. They operationalized the Fukuda criteria in a way that classified many people as having CFS when they really had other illnesses. At that time, many thought this increase in prevalence figures that Reeves proposed was constructive as it suggested that far more people had the illness, and thus these findings could be used to argue for more attention and funding due to this illness being so widespread. But if you use a very broad criteria, and bring into the illness case definition people who don’t have the disease, then the entire research effort is seriously compromised. Fortunately, over the past decade, few researchers have used the Reeves way of operationalizing CFS. What about the CCC and ICC criteria? The CCC case definition for ME/CFS in 2003 was better because it specified key symptoms such as PEM. It was developed as a clinical case definition, and now it’s being used by several teams as a research case definition. With the 2011 ME-ICC, I have noticed problems, and in part this is due to them once again requiring too many symptoms that could, as with the Holmes criteria of 1988, bring into the ME category some individuals who have a primary psychiatric disorder. In addition, the ME-ICC criteria is complicated to use, and many clinicians and scientists will have a difficult time reliably using it with patients. What is the problem you see with the IOM case definition, apart from the name? Well, it is true that Systemic Exertion Intolerance Disease (SEID) is a name most patients dislike. However, the IOM report was correct in requiring several core symptoms, such as PEM. But I believe these authors made a mistake in indicating that a patient could have either cognitive impairment or orthostatic intolerance— Invest in ME research (Charity Nr. 1153730) one or the other. Cognitive impairment should have been required for all patients to have. But a more serious problem is that they inadvertently expanded the case definition by having just about no exclusionary illnesses, such as primary psychiatric disorders. My team recently conducted a study where about half the people with a variety of medical and psychiatric illnesses met the IOM criteria. Now the IOM criteria was developed as a clinical case definition, but there was no federal effort to develop a research criteria that selects a more homogenous group of patients. The failure to develop an international consensus on a research case definition means that many researchers will continue to use the problematic Fukuda case definition, or they might use the IOM clinical criteria to select patients for research purposes, and this process has already begun. To summarize, for research purposes, if a person has the core symptoms of the IOM definition, it would be important to exclude those with a primary medical or psychiatric condition, but this is not what the IOM authors recommended. So, the clinical IOM case definition once again over-identifies people as having the illness. That means what occurred with the Reeves criteria of a decade ago has once again occurred with the IOM, as these criteria broaden the types of patients identified as having the illness. What is at stake in this debate? The stakes are high, for if you have an inappropriately wide case definition for research purposes, you will bring into your studies many fatigued people with a variety of conditions. In other words, if you identify the wrong patients, then your study will make conclusions about people who do not have ME, and you will have significant barriers to engaging in critical scientific activities such as estimating accurate prevalence rates or identifying biological markers. Also, if you bring in lots of people who don’t have this illness but lifestyle issues and/or a solely depressive disorder, a good percentage of them will respond favorably to psychogenically oriented treatments. As I have been writing about for many years, this will ultimately lead to some researchers making conclusions about CBT and GET that are not true for patients with ME. My case is simple. You need to have one research case definition that is used by scientists throughout the world. The clinical case definition can be broader, but the research case definition has to be tightly focused on those with the illness so that results can be replicated in different laboratories. This scientific achievement has been accomplished with every illness or disease except for ME. We can do better. After working in this area for almost three decades, I am confident that we have the tools and methods to use psychometrically sound procedures to develop a consensus on one research case definition. I am optimistic that one day this will occur, and for me, there is literally nothing as important for our scientific field. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 43 of 56

Some may not have noticed but Invest in ME Research has its very own film star supporting the cause. Jon Campling is an actor, known to many Harry Potter fans as the 'Trainstopping Deatheater'. He wrote the introduction to the book about ME - Science, Politics …….and ME - written by Dr Ian Gibson and Elaine Sherriffs. Jon is married to Ali, also an actor – an actor-singer-dancer. Ali was diagnosed with ME after 2 years of increasingly debilitating symptoms. Like many, Ali was prescribed 18 months of CBT and advised to use PACING techniques – but realised that there was little real understanding of this illness and no ongoing care. So Jon and Ali have found themselves dealing with the same problems as all people with ME have to deal w ith. Jon has been a staunch support of Invest in ME Research and constantly uses his fame to raise awareness and valuable funds for research. Jon could have just hidden this away and not raised the issue. He didn’t. He uses immense time for fundraising for ME earning the admiration and thanks from so many families where ME has struck. Jon’s fundraising page is here - Page 44 of 56 Invest in ME Research (Charity Nr. https://www.justgiving.com/fundraising/walktall4me Invest in ME research (Charity Nr. 1153730) www.investinme.org Conference Abstracts Conference Chair Dr Ian Gibson Former Dean of Biological Sciences, UEA Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, ecame Dean of the hool of biological ences in 1991 and was d of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA Dr Elizabeth R. Unger Chief of Chronic Viral Diseases Branch, National Center for Emerging and Zoonotic Infectious Diseases, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention Elizabeth (Beth) Unger, PhD, MD, received an undergraduate degree in Chemistry at Lebanon Valley College, Annville, PA. She hen earned her PhD and MD in the Division of Biologic iences at the University of icago where she also began a dency in pathology. Her residency and fellowship was completed at Pennsylvania State University Medical Center. During this time, Dr. Unger developed a practical method of colorimetic in situ hybridization. This work led to interest in tissue localization of HPV and ultimately to her initial appointment to CDC in 1997 to pursue molecular pathology of HPV and CFS. Dr. Unger has served as the Acting Chief of CVDB since January 2010 and has 13 years of experience in CVDB, where she has participated in the design and implementation of CFS research and HPV laboratory diagnostics. During this time, she was co-author on 25 peer-reviewed manuscripts related to CFS, including the often-cited descriptions of the Wichita and Georgia population-based studies. In addition, Dr. Unger has been instrumental in efforts by WHO to establish an HPV LabNet and serves as lead of a WHO HPV Global Invest in ME research (Charity Nr. 1153730) Reference Laboratory. She is co-author of 142 peerreviewed publications and 24 book chapters and serves on the editorial board of six scientific journals. In 2008, for her HPV research accomplishments, she received the Health and Human Services (HHS) Career Achievement Award. Dr Unger has been selected to serve as the Chief of the Chronic Viral Diseases Branch (CVDB) in the Division of High-Consequence Pathogens and Pathology (DHCPP), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for Disease Control and Prevention (CDC). Abstract: Abstract not available at time of printing. Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States. Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. www.investinme.org Page 45 of 56

She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Abstract: Abstract not available at time of printing. Dr Avindra Nath NIH National Institute of Neurological Disorders, Bethesda, Maryland, USA Dr. Nath received his MD degree from Christian Medical College in India in 1981 and completed a residency in Neurology from University of Texas Health Science Center in Houston, followed by a fellowship in Multiple Sclerosis and Neurovirology at the same institution and then a fellowship in Neuro-AIDS at NINDS. He held faculty positions at the University of Manitoba (1990-97) and the University of Kentucky (1997-02). In 2002, he joined Johns Hopkins University as Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections. He joined NIH in 2011 as the Clinical Director of NINDS, the Director of the Translational Neuroscience Center and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases. Abstract: Abstract not available at time of printing. Professor Simon Carding Research Leader, Quadram Institute Bioscience Upon completing postgraduate work at the Medical Research Council’s Clinical Research Centre in Harrow, Page 46 of 56 www.investinme.org Simon Carding took up a postdoctoral position at New York University School of Medicine, USA,and then at Yale University as a Howard Hughes Fellow in the Immunobiology Group at Yale University with Profs Kim Bottomly and Charlie Janeway Jr. While at Yale an interest in gamma-delta (γδ) T cells was acquired working closely with Adrian Hayday on molecular genetics and then with Prof. Peter Doherty to establish their role in (viral) infectious disease. He left Yale after five years to take up a faculty position at the University of Pennsylvania in Philadelphia where he developed a research interest in mucosal and GI-tract immunology, performing studies in germfree mice with Prof John Cebra that helped establish the role of gut microbes in the aetiology of inflammatory bowel disease (IBD). After 15 years in the USA, he returned to the UK to take up the Chair in Molecular Immunology at the University of Leeds where he established a new research programme on commensal gut bacteria and Bacteroides genetics leading to the development of a Bacteroides drug delivery platform that is being used for developing new interventions for IBD and for mucosal vaccination. In 2008 he was recruited by UEA and IFR to develop a gut research programme, taking up the Chair of Mucosal Immunology at UEA-MED and the position of head of the Gut Biology Research Programme at IFR, which later became part of the Gut Health and Food Safety (GHFS) Programme. GHFS research covers a broad area of gut biology including epithelial cell physiology, mucus and glycobiology, mucosal immunology, commensal microbiology, foodborne bacterial pathogens, and mathematical modelling and bioinformatics. The success of this programme has led to the establishment of the Gut Microbes and Health research programme that is integral to the research agenda of The Quadram Institute. Within these programmes, much of the work undertaken in his research group builds upon that carried out in the USA and latterly in the UK with a major focus on understanding the mechanisms of intestinal microbial (bacterial and viral) tolerance. In particular, identifying the pathways and mediators of microbe-host cross talk and the role they play in establishing and maintaining gut health and in diseases that not only affect the gut but other organ systems. Invest in ME research (Charity Nr. 1153730) This has led to the development of new research projects relating to the gut-microbiome-brain axis and understanding how the intestinal microbiome impacts on mental health and the development of neurodegenerative diseases, and the intestinal virome and the role that prokaryotic and eukaryotic viruses play in microbial homeostasis and dysbiosis. Abstract: Abstract not available at time of printing. Dr Peter Johnsen University Hospital of North Norway, Harstad, Norway - Internal Medicine Dr Johnsen works in the medical department at the University of Northern Norway in Harstad. He is currently involved in the clinical trial of FMT which is being funded by the Norwegian Health Council. Five million Norwegian kroner has been awarded for the trial. Together, it will include 80 participants who either receive treatment with FMT from a healthy donor or placebo. The study is double blinded, which means that neither participants nor scientists will know who received the treatment from donor or placebo before the study ends. Startup with the inclusion of participants begins during Summer 2018. Abstract: The Comeback study – a double blinded randomized placebo-controlled trial testing the efficacy of faecal microbiota transplantation (FMT) in CFS/ME Earlier published data suggests that a dysbiotic gut flora may be an important factor in the pathophysiology of CFS/ME. Differences in host metabolism and immune activation pointing to a leaky gut are found in the context of at gut flora that is less diverse with an altered composition when CFS/ME is compared to healthy controls. In addition, an open label study has shown persistent relief in CFS/ME after transplantation of enteric bacteria. To test the gut dysbiosis hypothesis in CFS/ME we will launch a double blind randomized, placebo-controlled, parallel-group, single-centre trial to test FMT as treatment for CFS/ME. Eighty CFS/ME participants will receive either donor transplant or placebo FMT, with 12 months follow up period. Primary endpoint is the efficacy of FMT at three months. We will use a patient reported outcome by the Chalder Fatigue Scale to determine efficacy. Recently we performed a trial with the same study design testing the effect of FMT in irritable bowel syndrome (IBS). In the primary endpoint three months after treatment there was significant improvement on gastrointestinal complaints. Preliminary results also show a significant effect on fatigue, which is a common complaint in irritable bowel syndrome. Conversely, gastrointestinal complaints are common in CFS/ME. Because of our previous experience with FMT for functional disease, the symptom overlap between IBS and CFS/ME, and the evidence for an involvement of the gut microbiome in both, we are eager to lunch our trial in August 2018. We expect to have the final results ready by August 2020. UK charity Invest in ME Research has provided us with a network of great collaborators that may help us to establish a true cause and effect relationship by performing analysis of immunological markers and the gut metagenome. Biobanking of feces, blood and urine is an important asset to this study and will allow for tandem characterization of the immune response, metabolome and metagenome in CFS/ME. In outlining the study protocol we found the lack of consensus on symptom severity assessment challenging. We are hoping for input on how we can optimize the use of our biobank for insights in CFS/ME pathophysiology and discussions on what are the most relevant endpoints in efficacy studies for CFS/ME. We are thankful for the possibility the Invest in ME Research Foundation has given us to meet and network with the world leading expertise on CFS/ME. There is great interest in and a commercialisation of FMT treatment, including FMT for CFS/ME. However, this enthusiasm needs to be balanced with a need for caution with the use of FMT. The screening regime for FMT donors is just as extensive as the regime for donors of blood, cells and live tissue. Our main aim is to provide physicians and other caregivers to CFS/ME patients’ evidence-based advice regarding the efficacy of FMT. Thereby, this study will fulfil its intention regardless of the conclusion. However, there is a greater potential in this trial. Participants may serve as their own control pinpointing which mechanisms change if they transcend from sick to healthy or improved. In conjunction with the intervention any hypothesis can be tested in silico against the clinical outcomes to identify new therapeutic targets and biomarkers for improving diagnosis or personalizing FMT treatment. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 47 of 56

Professor Karl Johan Tronstad Professor Institute for Biomedicine , Tronstad Lab, Bergen, Norway Prof. Tronstad completed his graduate studies in biochemistry at the University of Bergen (UiB) in 2002. As postdoc at the Haukeland University Hospital, he studied bioactive compounds with the potential to modulate mitochondrial functions in cancer cells. In 2005 he was recruited to the Department of Biomedicine, UiB, where he started his research group to investigate metabolism and mitochondrial physiology. His laboratory seeks to better our understanding of how defective mitochondrial homeostasis may disturb cell physiology, and how this may be involved in mechanisms of cancer and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Karl was involved with the recent paper to come from Bergen - Journal of Clinical Investigation Insight. The Tronstad Lab investigates cell metabolism and mitochondrial biology and we are very fortunate that he can spare time to participate in the Colloquium. Abstract: Cellular energetics in ME/CFS Irregularities in cellular energy metabolism have been linked to many human diseases, including metabolic disorders, mitochondrial diseases, cancer, neurodegeneration and ME/CFS. The possible consequences of cellular energy failure caused by a metabolic defect are context-dependent, and may range from mild cellular stress to cell death. An energydepleted cellular state may theoretically be counteracted by metabolic rewiring, but if this is not sufficient to re-establish the energy level, additional (patho)physiological responses are activated. The consequences may include elements of cellular fatigue, but the mechanisms involved under such conditions are often poorly understood. Recently we found changes in amino acid levels and gene regulation consistent with altered regulation of the central enzyme pyruvate dehydrogenase (PDH) in patients with ME/CFS compared with healthy individuals. Further, the presence of serum from ME/CFS patients changed energy metabolism in healthy human muscle cells in culture. These findings combined with the anticipated role of dysimmunity in ME/CFS, suggest the presence of an immuno-metabolic Page 48 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) pathomechanism. We are now investigating potential mechanisms involved, and characterizing contextual consequences of cellular energy failure, with particular focus on the mitochondrial oxidation machinery. Defects in this machinery are likely to cause energy deficiency and excessive lactate production, which are hallmarks of fatigue and post-exertional malaise (PEM). By using a translational research approach, we investigate whether impaired energy metabolism may be linked to ME/CFS symptoms, which could provide support for the development of new biomarkers and treatments. Our research strategy is to build on existing knowledge that has recently emerged concerning metabolic changes in ME/CFS, and to adopt new methods and strategies for studying the mechanisms at the cellular level. This presentation will discuss our current approaches and recent data. Professor Don Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Professor Staines has been a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as cross-disciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. He is now Co-Director at The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University in Australia Abstract not available at time of printing. Professor Theoharis Theoharides Professor of Pharmacology and Internal Medicine, Tufts University, Boston, USA Theoharis Theoharides is Professor of Pharmacology and Internal Medicine, as well as Director of Molecular Immunopharmacology and Drug Discovery, in the Department of Immunology at Tufts University School of Medicine, Boston, MA. He was born in Thessaloniki, Greece, and graduated with Honors from Anatolia College. He received all his degrees with Honors from Yale University, and was awarded the Dean’s Research Award and the Winternitz Prize in Pathology. He trained in internal medicine at New England Medical Center, which awarded him the Oliver Smith Award “recognizing excellence, compassion and service.” He also received a Certificate in Global Leadership from the Tufts Fletcher School of Law and Diplomacy and a Fellowship at the Harvard Kennedy School of Government. He has been serving as the Clinical Pharmacologist of the Massachusetts Drug Formulary Commission continuously since 1986. In Greece, he has served on the Supreme Advisory Health Councils of the Ministries of Health and of Social Welfare, as well as on the Board of Directors of the Institute of Pharmaceutical Research and Technology, and he is a member of the International Advisory Committee for the University of Cyprus School of Medicine. He first showed that mast cells, known for causing allergic reactions, are critical for inflammation, especially in the brain, and are involved in a number of inflammatory conditions that worsen by stress such as allergies, asthma, chronic fatigue syndrome, eczema, fibromyalgia, migraines, mastocytosis, multiple sclerosis, psoriasis, and most recently autism spectrum disorder. He has also shown that corticotropin-releasing hormone (CRH), neurotensin and substance P, peptides secreted under stress, act together, and with the cytokine IL-33, to trigger mast cells and microglia to secrete inflammatory molecules. These processes are inhibited Invest in ME research (Charity Nr. 1153730) by the novel flavonoids, luteolin and tetramethoxyluteolin that he has helped formulate in unique dietary supplements and a skin lotion. He has published over 400 scientific papers (JBC, JACI, JPET, NEJM, Nature, PNAS, Science) and 3 textbooks with 29,887 citations (h-factor 84) and he is in the top 5% of authors most cited in pharmacological and immunological journals. He has received 37 patents and trademarks, including three patents covering the use of luteolin in brain inflammation and autism: US 8,268,365 (09/18/12); US 9,050,275 (06/09/15); US 9,176,146 (11/03/15). Acting as Advisor, he was instrumental in the development of ibuprofen (Upjohn), Cetirizine (UCB) and Niaspan (Kos). He is also the Scientific Director of Algonot, LLC, as well as President of Theta Biomedical Consulting and Development Co., Inc., of BiomedAdvice, LLC, and of the nonprofit Brain-Gain.org. He is a member of 15 academies and scientific societies. He was inducted into the Alpha Omega Alpha National Medical Honor Society and the Rare Diseases Hall of Fame. At Tufts, he served on the Curriculum, Students Promotion, Grievance, Faculty Promotion and Tenure, as well as Strategic Planning Committees. He received the Tufts Excellence in Teaching ten times, the Tufts Distinguished Faculty Recognition Award twice, the Tufts Alumni Award for Faculty Excellence, Boston Mayor’s Community Award, and the Dr. George Papanicolau Award, as well as Honorary Doctor of Medicine from Athens University and Honorary Doctor of Sciences from Hellenic-American University. He is “Archon” of the Ecumenical Patriarchate of Constantinople. Abstract: Brain mast cell involvement in Myalgic Encephalopathy/Chronic Fatigue Syndrome Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) affects about 1-2% of the US population and is characterized by debilitating fatigue of six months in the absence of systemic diseases. Many ME/CFS patients also have fibromyalgia and skin hypersensitivity, which worsen with stress. We hypothesize that stimulation of mast cells (MC) in the hypotahalamus activate microglia leading to secretion of pro-inflammaotry mediators that disrupt normal homeostasis and advesrsely affect mitochondrial function. Corticotropin-releasing www.investinme.org Page 49 of 56

hormone (CRH), neurotensin (NT) and substance P (SP) are secreted under stress and can stimulate MC, necessary for allergic reactions, to release inflammatory mediators that could contribute to ME/ CFS symptoms directly or via activation of microglia. We showed that CRH and NT act synergistically to stimulate MC to secrete VEGF, which increases permeability of the blood-brainbarrier (BBB) and would allow entry of toxins in the brtain. We also showed that NT can activate microglia to secrete IL-1beta. Moreover, we showed that the combined action of SP and the alarmin IL-33 lead to impressive amounts of TNF secretion from human MC. We further investigated the effect of combining ip injection of polyinosinic:polycytidylic acid [poly(I:C)], to mimic a viral infection, with 15 min forced cold swim stress, to mimic exercise and stress, on female C57BL/6 mice locomotor activity, as well as brain gene expression and serum levels of inflammatory mediators. Treated mice showed decreased locomotor activity over 72 hrs, while serum levels of TNF, IL-6 and KC (IL-8/CXCL8 murine homologue), as well as their gene expression in the brain, were increased increased. When other mice were provided with chow high in isoflavones for 2 weeks prior to treatment, this intervention reversed the reduced locomotor activity and minimized the increased serum levels and gene expression of the proinflammatory mediators. Moreover, the unique natural flavonoid, tetramethoxyluteolin potently inhibited both human cultured MC and microglia activation. We are presently seeking funding to measure these neuropeptides and cytokines in the blood of ME/CFS patients before and after exercise, as well as develop an intranasal tetramethoxyluteolin formulation for direct delivery to the hypotalamus through the cribriform plexus (Funded by an Anonymus grant). References from this article will be in the online version of the journal. Associate Professor Mady Hornig Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, Page 50 of 56 www.investinme.org and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Abstract: Abstract not available at time of printing. Professor Maureen Hanson Director, Center for Enervating Neuroimmune Disease Liberty Hyde Bailey Professor, Department of Molecular Biology and Genetics, Cornell University, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. Invest in ME research (Charity Nr. 1153730) degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Abstract: Research at the Cornell Center for Enervating Neuroimmune Disease The Center for Enervating Neuroimmune Disease (ENID Center) encompasses a number of projects, including research carried out by the Cornell NIH ME/CFS Collaborative Research Center (CRC). The CRC has undertaken 3 projects, all unified by performance of an exertion challenge by subjects, who will perform twoday cardiopulmonary exercise tests (CPETs) using the protocol developed by the Workwell Foundation and Prof. Betsy Keller (Ithaca College). To ensure that all subjects meet the criteria for ME/CFS or for healthy sedentary controls, Drs. Susan Levine, Geoffrey Moore, and John Chia will diagnose and screen volunteers. In a project led by Professor Dikoma Shungu at Weill Cornell Medicine in New York City, subjects will undergo Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) of their brains in order to evaluate oxidative stress and neuroinflammation. The neuroimaging will occur before performing an initial CPET and before performing a second one the next day, in order to determine the effect of exertion. Blood will be collected before and after each CPET at Weill Cornell Medicine, and before and after CPETs supervised by Dr. Keller at Ithaca College and supervised by the Workwell Foundation at Dr. John Chia’s clinic in Los Angeles. Blood will be fractionated and sent to Cornell University in Ithaca. There, my lab group will analyze extracellular vesicle number, size, and content in plasma, and Dr. Andrew Grimson’s lab will isolate individual white blood cells to sequence and identify genes that are expressed. The molecular data, neuroimaging, and subject survey data will be examined by a Data Analysis Core headed by Dr. Fabien Campagne (Weill Cornell Medicine) for correlations to identify relationships specific to diseased or healthy status, or pre- or post-exertion state. By examining patients when at baseline and after postexertional malaise has been induced, we hope to gain insights into the factors that cause this disabling symptom, which also should shed light on the biological basis of the disease. The Center also has an active outreach program, facilitated by Executive Director Susi Varvayanis and our Patient Advocate Committee. More information about Invest in ME research (Charity Nr. 1153730) activities can be found here: http://neuroimmune.cornell.edu/news/ or by following us on twitter: @DrMaureenHanson or @CornellMECFS . The Center also has several other ongoing studies, including comparisons of gene expression, oxidative phosphorylation, and glycolysis in B, T, and NK cells from patients vs. controls. We have begun pilot studies to examine plasma metabolites and extracellular vesicles using an existing set of samples collected from patients at baseline. Information from these studies will be presented. Professor Markku Partinen University of Helsinki, Finland Prof Markku Partinen is a neurologist and an internationally wellknown opinion leader and expert in sleep research and sleep medicine. Professor Partinen is currently Director of the Helsinki Sleep Clinic, Vitalmed Research Centre, and Principal Investigator of Sleep Research at Institute of Clinical Medicine, Clinicum, University of Helsinki, Finland. He has been the coordinator of the NARPANord Narcolepsy Consortium. He became interested in sleep research while studying medicine at the University of Montpellier, France. He obtained his medical degree (DrMed) from Montpellier in 1976 (Supervisor Prof Pierre Passouant). He received his PhD in 1982 (epidemiology of sleep disorders), and degree of a specialist in neurology in 1982, in Helsinki, Finland. He has worked as a postdoc researcher at Stanford University, USA in 1985-86 and in Bologna, Italy in 1987. In addition, he has had several shorter visits as visiting researcher or visiting Professor at different Universities in Europe. His main interests in sleep medicine have been narcolepsy, excessive daytime sleepiness and fatigue (including ME), sleep apnea, and parasomnias. He has published more than 330 original articles in peer reviewed Journals in addition to writing many book Chapters and editing several books. His Hirsch factor (H-factor) is 59 in ISI Web of Sciences and 64 in Scopus. www.investinme.org Page 51 of 56

He has served in the Editorial Boards and as Assistant Editor in Sleep, Journal of Sleep Research and Sleep Medicine. He has had many International positions in different research societies including Member of the Scientific Board and Vice-President of the European Sleep Research Society (ESRS), President of the Scandinavian Sleep Research Society, President Elect and President of the World Association of Sleep Medicine (WASM), Coordinating Secretary of the World Federation of Sleep Research Societies (WFSRS) and President and Member of the Board of the Scandinavian Sleep Research Society. He has been President of the ESRS congress in 1992 (Helsinki), the World Congress of Sleep Apnea in 2003 (Helsinki), and the WASM congress in 2007 (Bangkok). In addition, he has organized several smaller meetings and symposia in the field of narcolepsy, RBD and different sleep disorders. Currently he is a Member of the Board in the ESRS EUNarcolepsy Network (EU-NN) and Chair of Scientific Board of the EU-NN, President of the Finnish Parkinson Association and President of the Finnish Sleep Research Society. Abstract: Abstract not available at time of printing. Professor James Baraniuk Professor of Medicine at Georgetown University Medical Centre, Washington, USA James N. Baraniuk was born in Alberta, Canada, south of Banff. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his long-standing collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk Page 52 of 56 www.investinme.org returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. Abstract: Abstract not available at time of printing. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical genomics. The genomic revolution has been spurred by technological advances that made nucleotide sequencing inexpensive, high-throughput, and accessible. The next phase in this revolution to pave the way for personalized health entails similar breakthroughs in biosensor technologies for personal molecular monitoring. Just as with DNA sequencing, the key features to optimize are accuracy, sensitivity, cost, and accessibility. Through close collaboration between engineers, biochemists, geneticists, and clinicians, our team has developed several such technologies and devices. The technologies target the biophysical properties of the cells and molecules, and therefore do not rely on introducing labels or other complex sample preparation techniques. We have successfully applied these technologies to detecting drug resistance, resolving cells and molecules in bodily fluids and Invest in ME research (Charity Nr. 1153730) tissues, and engineering advanced, multiparametric, wearable biosensors. We have begun applying these methods to understand chronic fatigue syndrome, one of the last major diseases about which almost nothing is known. We anticipate that these technological breakthroughs coupled with data integration of personal molecular profiles will play an instrumental role in the realization of personalized health regimens and disease prevention strategies. Abstract: Revolutionizing biomedical research through technology development The genomic revolution has been spurred by technological advances that made nucleotide sequencing inexpensive, high-throughput, and accessible. The next phase in this revolution to pave the way for personalized health entails similar breakthroughs in biosensor technologies for personal molecular monitoring. Just as with DNA sequencing, the key features to optimize are accuracy, sensitivity, cost, and accessibility. Through close collaboration between engineers, biochemists, geneticists, and clinicians, our team has developed several such technologies and devices. The technologies target the biophysical properties of the cells and molecules, and therefore do not rely on introducing labels or other complex sample preparation techniques. We have successfully applied these technologies to detecting drug resistance, resolving cells and molecules in bodily fluids and tissues, and engineering advanced, multiparametric, wearable biosensors. We have begun applying these methods to understand chronic fatigue syndrome, one of the last major diseases about which almost nothing is known. We anticipate that these technological breakthroughs coupled with data integration of personal molecular profiles will play an instrumental role in the realization of personalized health regimens and disease prevention strategies. Patient groups and charities from fourteen European countries working together for ME Campaigning in Europe for people with ME and engaging with health agencies, governments, professionals, the media, patients and public Working closely with researchers and organisations and researchers interested in finding treatments and cures for ME Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 53 of 56

Page 54 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) IiMER Advocacy Conferences Colloquiums Educational DVDs Campaigning Young/ECR Researchers Research European ME Research Group www.investinme.org/research Funding www.investinme.org/donate Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 55 of 56

Journal of IiMER I N V E S T in M E R E S E A R C H Journal Of IiMER MAY 2017 VOLUME 11 ISSUE 1 UK Char i ty Invest in ME Research (Char i ty Nr . 1153730)

RESEARCH into ME? Journal of IiMER WE NEEDED A RETHINK Small charity BIG Cause With no major investment into correct research into myalgic encephalomyelitis during the last decades Invest in ME Research has, with a determined band of supporters, taken action for change in the absence of any coherent or scientific establishment policies. Funding has to be given to biomedical research and new knowledge from other disciplines such as virology, immunology, endocrinology etc. has to be brought in to help research into ME. Invest in ME Research has initiated and funded high-quality biomedical research at UCL and UEA and Quadram Institute Biosciences - and brought in collaborations with other researchers in Bergen, Uppsala, Berlin and within the UK in Oxford. Vision with action can change the world Journal of IiMER Journal of IiMER M A Y 2 0 1 7 C O NTE NT 03 Vision of Excellence for Research into ME 08 Biomedical Research Colloquium 10 UK CENTRE of EXCELLENCE for ME 16 Finding, Facilitating, Funding Research into ME DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME Research. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. www.investinme.org 18 RESEARCH COLLABORATION 20 Science, Politics, …….and ME 23 PHILANTHROPY and ME 25 The Gut Microbiome in ME 32 No Isolation 34 Letter from America 36 IiMER Visit to CMO 42 The PACE Trial 45 Open Letter to Psychological Medicine 50 Margaret Williams Repository 51 EMEA News 66 Conference Abstracts All content in the Journal of IiMER is copyright to Invest in ME Research and the authors. Permission is required and requested from Invest in ME Research before republishing anything from this Journal. Page 3 of 82

Journal of IiMER I I M E C 1 2: Marking TWELVE Years in Creating a Vision of Excellence for Research into ME Conference welcome from Chairman Kathleen McCall A nother year and a new conference. Invest in ME Research is an independent UK charity whose objectives are to initiate, maintain and augment a strategy of high-quality biomedical research into Myalgic Encephalomyelitis (ME), to provide and promote better education about ME, and to raise awareness of the effects of the disease on patients and families. Finding, facilitating and funding a strategy of biomedical research into ME is, we believe, the only way to make any real and lasting impact on the lives of those affected by this disease. We are a small charity but with a growing number of supporters who have big hearts - and a determination to get the best possible research to be carried out to find the cause of myalgic encephalomyelitis and develop treatments. The charity is run by volunteers - patients or parents of children with ME and supported by patients, family, friends, and others who are determined to change the prospects for people with this disease. We do not receive and have never received funding from government or government organisations and our research Colloquiums and public Conferences are funded by the charity itself. The charity decided early on that biomedical research into ME was crucial in order to make progress in treating this disease. We also decided that education of healthcare staff, the media, www.investinme.org government departments, patient groups and patients was to be a priority. The charity commits itself to a strong stance against deceptive practices, corrupt or flawed policies toward ME and to disingenuous posturing from those seeking to influence governments, the media or even patients. The charity has always spoken out strongly against the flawed and null PACE Trial. However, we have also engaged with the government, Department of Health, Medical Research Council, Chief Medical Officers and, as part of the European ME Alliance (EMEA) have been working closely with European colleagues to make progress in Europe. We have also participated in recent NINDS discussions organised by the NIH. Almost twelve years on from when Kathleen McCall formed the organisation that became Invest in ME Research the charity has an optimism about the future and a continuing determination to force change and create a foundation of biomedical research in Europe that will finally Page 4 of 82 Journal of IiMER provide answers and treatments for this disease. Our efforts are focused on setting up a UK Centre of Excellence for ME that will provide proper examinations and diagnosis for ME patients and a coordinated strategy of translational biomedical research into this disease. Now our twelfth conference is taking place in 2017, as always in Westminster, London, and as the charity has embarked on a new decade of finding, funding and facilitating biomedical research into ME, and research into ME in order to find treatment(s) and cure(s). Our supporters have achieved an incredible feat in making something out of nothing and creating an opportunity for real progress to be attained for ME research. Now, with solid progress made in establishing the UK Centre we can look for more rapid progress in the coming years as CDC and NIH demonstrate more acceptance of this disease and new initiatives continue to realise the charity’s goal of international collaboration in research into ME. These initiatives will eventually drag and force complacent and ineffectual organisations into taking action rather than false posturing. Good collaborations have been built between UK, European, and US organisations that can only strengthen the level and quality of biomedical www.investinme.org increasing knowledge and awareness of the disease. Our conferences and, later, our closed research colloquiums were organised from the beginning in order to provide a platform for research and a means of facilitating education about ME. For Invest in ME Research, education and research are the key to progress, and hence change. The IiMER conferences have formed a crucial part of this education and our research colloquia form a crucial and productive part of the research. The conferences now regularly attract delegates (researchers, clinicians, nurses, patient groups and patients, advocates and, we always hope, a sprinkling of as many politicians, journalists and others whom Invest in ME self-fund to allow people to be exposed to real science) from twenty countries in a unique international event that is friendly and conducive for learning and Page 5 of 82

Journal of IiMER networking. Our choice of venue reflects our commitment to patients, families, carers, researchers and healthcare staff in providing the best venue for conducting this annual event - now #IIMEC12. Our Colloquium banner used the quote attributed to Henry Ford to describe the progress made – "Coming together is a beginning; keeping together is progress; working together is success" Our invited delegates (researchers from 14 countries around the world) embraced this theme. The BRMEC6 Colloquium was a pivotal point in the history of Invest in ME Research as it celebrated its 10th year as a charity. Because, coming from the meeting, one detected a palpable sense of research into ME really having become an international concern – endorsing Invest in ME Research’s strategy of international collaboration in research into ME. For 2017, IIMEC12 brings the best from the world’s Centres of Excellence for ME – now up and running as in the UK at Norwich Research Park or Australia, where the NCNED has been operating for some years, and in Norway and those being developed such as in USA. The charity’s commitment over 12 years to bringing the best research to the public and professionals has given biomedical research into ME a platform that allows researchers to overcome the bias and prejudice built up over the years by false views held by governments, research councils and establishment collaboratives that are more self-serving rather than interested in making progress. The Invest in ME Research conferences bring together this optimism and determination in a happy mixture of wanting, needing to learn, optimism and hope that things will improve. In June 2016, Invest in ME Research held its sixth Biomedical Research into ME Colloquium in London - BRMEC6. The Colloquium had as its theme international collaboration. Collaboration and working together can easily become just buzzwords – meaningless terms given out in press releases and handouts, attempting to make an impression that something is happening. Yet BRMEC6, and the following public IIMEC11 conference, really did validate our long held belief that international collaboration in biomedical research can lead to patients being given back their lives. We are hoping that BRMEC7 this year will produce a similar result. Last year was the first time that the Invest in ME Research conferences had a speaker from a government organisation. It was wonderful to have Dr Vicky Whittemore representing the National Institute of Health, opening both our BRMEC7 Colloquium and IIMEC12 Conference and showing NIH visibility for this disease, and endorsing this international collaboration as a critical means to an end. This year we are honoured also to welcome Dr Elizabeth R. Unger from the USA Centres for Disease Control. Dr Unger will be opening the Biomedical Research into ME 7 Colloquium 7. Also attending will be the Norwegian Health Council – appearing at both Colloquium and www.investinme.org Page 6 of 82 Journal of IiMER Conference – symbolising the huge potential and hope coming from the efforts of dedicated Norwegian biomedical researchers. Both the Colloquium and Conference are high quality, forward-looking events that serve to improve knowledge of this disease, generate, and improve international collaboration into ME. A high quality, professionally produced DVD of the conference proceedings will be produced as always – not a small task for a small charity – but it continues to serve not just as a historical record but also a means to educate doctors and clinicians about the seriousness of this disease. The DVDs have been distributed to twenty countries proving the increasing interest in research into this disease. We were pleased to see that the US NIH listed as its goals for ME research the following -  Advance research on the cause, prevention, diagnosis, pathophysiology and treatment of ME/CFS  Encourage biomedical research investigators and organizations to study ME/CFS  Communicate ME/CFS research information among and between NIH Institutes and Centres, and the NIH Office of the Director The first two goals are similar to those that Invest in ME Research have been promoting and implementing for the past eleven years and have mentioned in our letters to the UK MRC, Department of Health and others in the position of influence. The third has elements that epitomise the IiMER strategy as our proposal for a Centre of Excellence for ME – something we have been aiming for since 2010 – now develops. Progress has inevitably been too slow from the patients’ perspective but as we pass into our twelfth year as a charity, more and more signs and developments are indicating that things are changing. Research into ME has needed a strategy – it was www.investinme.org Page 7 of 82 surely missing when IiMER was formed and has continued to elude the major UK funding organisations. Yet the Invest in ME Research strategy of bringing in researchers from other fields to help and improve biomedical research into ME was a necessity. It has been successful and well worth the effort and cost and we can witness this approach becoming more popular. Our conferences bring together patients, researchers, clinicians and healthcare staff and allow knowledge and experiences to be shared – and IIMEC11 and BRMEC7 will see us entering our twelfth year in doing this. We will see many new faces in London as well as old friends. Back to the theme of collaboration and highquality research with a purpose. Let us remember again these words that illustrate the Invest in ME Research approach to research into ME and the raising of awareness - "Vision without action is merely a dream. Action without vision just passes the time. Vision with action can change the world." Precisely the ethos of the Invest in ME Research Biomedical Research Colloquiums and Conferences! Welcome to London - Welcome to IIMEC12 and BRMEC7 Kathleen McCall CHAIRMAN INVEST IN ME RESEARCH

In 2011, Invest in ME Research initiated a different type of meeting that was appended to our annual public conference. We gave that meeting the term “Corridor Conference” – as most of the productive discussions at seminars often took place in corridors or places away from the presentations. And so the idea of the Biomedical Research into ME Colloquium was born. A meeting that would not compromise our research ethos with false views of ME but would instead concentrate on high-quality biomedical research and international collaboration. Journal of IiMER BIOMEDICAL RESEARCH into ME Building a Future for Research into ME The Corridor Conference organised in London by IiMER was flowed with the impressive and forward-thinking collaboration with the Alison Hunter Memorial Foundation of Australia to form BRMEC2 – the two-day Clinical Autoimmunity Working Group CAWG) research group which met in London the next year and before the IIMEC7 conference. This became our way of making rapid progress in biomedical research into ME. We attract experts from other disciplines to bring their expertise and skills to bear on this disease. By doing this we can bypass the negativity and misinformation that has pervaded the perception of ME for a generation and influenced the establishment research bodies – and instead focus on proper science. The Invest in ME Research Biomedical Research into ME Colloquiums are research meetings organised by the charity to encourage biomedical research into ME and international collaboration amongst researchers. This is one of the main objectives of the charity. Invest in ME Research began arranging biomedical research conferences in our first year and have continued them ever since - mostly funded by the charity but with help from some wonderful supporters and some good friends. The Invest in ME Research International Biomedical Research into ME Colloquiums began as a way of bringing together researchers from around the world in a roundtable discussion of ME research and ideas. They are designed to encourage collaboration and sharing of experience and to bring in new ideas and knowledge from outside the field of ME. A small charity with a BIG cause can www.investinme.org achieve this. Over the years this has broadened into sharing of experiences, data and plans for future research. A culmination of much of this effort was the initiative to bring European researchers together to form The European ME Research Group (EMERG) which had an inaugural meeting in October 2015 in London to set up a strategy of European collaboration in ME research. There is a basis now for creating a strategy of high-quality international biomedical research - something that has been lacking in the past. This will hold great promise of finding funding opportunities and raising awareness of biomedical research into ME. As stated, our aim with the annual CPDaccredited research colloquiums has also been to introduce new researchers into the field of ME research, to gain new insights into the disease and enhance the strategy of research we are building. The Invest in ME Research colloquiums have spawned a number of positive initiatives over the years and are the most successful research meetings for forming new research initiatives for ME with multiple collaborative initiatives being formed across continents. We have proven that high-quality biomedical research can be initiated in an international, collaborative environment and we salute all those researchers who continue to participate and work with us for the benefit of all people with ME and their families. We will continue to work together to facilitate the best hopes to make progress in finding the cause(s) of and treatments for this disease. Page 9 of 82 COLLOQUIUM

Journal of IiMER UK CENTRE of EXCELLENCE for ME To create a base of research into ME has been the ambition of Invest in ME Research since 2007 – with more specific focus from 2010. With the objective of improving and promoting education about ME amongst healthcare staff and raising awareness of the disease, the charity feels that the best way to make progress is to establish a national centre of excellence for ME. To this end we have focused on facilitating research and resources to build the foundations of a UK Centre of Excellence for Biomedical Research into ME. www.investinme.org Page 10 of 82 Journal of IiMER The charity believed that a change needed to be made in the way service provision for ME patients was carried out and proposed a simple but effective structure for providing services and instituting major biomedical research into this disease. This would have profound effects on the way ME is treated in the UK and establish a hub of scientific and clinical excellence for ME within Europe. In the last years real progress has been made in achieving this and the charity has created and facilitated opportunities that can now boast five PhDs involved in research, with another planned to join in 2017 and a post-doc/research assistant being employed to facilitate a UK clinical trial of rituximab. All of this is combined with national and international collaboration that is ongoing. This substantial effort is, even if we say it ourselves, a tremendous achievement by our supporters and a validation of their commitment and support for this new way forward. With our planned research ongoing and developing then we hope this will soon be possible. Diagnostic tests and medical treatments can only be developed from sound scientific biomedical research. This is why the charity has concentrated much effort on establishing the research centre. A clinical lead consultant would assess and plan the development of future services in conjunction with commissioning CCGs It would provide access to specialist assessment, diagnosis and advice on www.investinme.org Page 11 of 82 the clinical management, including symptom control and specific interventions, for both patients and health professionals. The charity has held discussions with the Norfolk and Norwich University Hospital CEO and UEA Medical School to create a position for a consultant who can oversee proper examinations of ME patients which include diagnosis according to correct criteria and possibilities for acceptance into clinical trials being performed at the Centre, or in associated spokes of collaborative research. There are also a number of new ideas being developed. Establishing a Centre of Excellence allows new ideas to be generated and more synergy to be obtained between different research disciplines. The research proposal would build a strategy of research that would involve patients, clinicians and researchers working together. This will take a substantial effort to achieve but we feel it can be done and the rewards for people with ME would be huge. The Centre of Excellence for ME would be welcome news for patients, and their families and doctors, across Europe and would facilitate and initiate new international collaborations, consolidate and improve existing ones, and develop new research ideas. Funding bids would enable cooperation and sharing with joint projects being undertaken.

Journal of IiMER The Centre of Excellence will also provide a highquality partner for those Centres of Excellence being set up or existing in USA and Australia. The Centre of Excellence for ME is not just one building or one lab – it is a model that has fundamental components of collaboration, data sharing and cooperation – sharing facilities, data and ideas. With the help of leading researchers, the charity is proposing a number of initial projects that would help establish a research base and lead to further projects being initiated based on findings. gratitude for the specialised knowledge and input that has been provided. The UCL team are in the regular multi-centre status meetings in Bergen - such is the respect in which they are held, as well as continuing the good collaboration. As we prepare for the UK rituximab trial this is good news indeed. It has now developed into closer collaboration with Dr Fluge and his team visiting Norwich Research Park in January of this year to discuss the UK rituximab trial and collaboration with the UK researchers on developing the best options for the UK rituximab clinical trial. The Norwegian team will visit again in the autumn as the Phase III trial in Norway begins to establish results. The research is the key component for change. Based on a strategy of biomedical research the Centre would create projects that dovetail and would collaborate with other centres where biomedical research into ME was taking place. Apart from those researchers in the Norwich Research Park, the charity has also funded the Bcell research underway at UCL in London where Fane Mensah has been working under supervision of Dr Jo Cambridge. The good relationship that has been established with the researchers at Haukeland University Hospital in Bergen continued and Dr Cambridge and Dr Fluge met in Stockholm at a conference organised by our European ME Alliance colleagues at RME Sweden. This collaboration between high quality biomedical researchers - one of the major themes behind Invest in ME Research's research strategy - has been a great success with the Norwegians expressing to us, and Dr Cambridge, their www.investinme.org Having shown great vision and determination in looking at other areas of research linked to their phase III trial experiences and developing an incremental, evolutionary method of research then we feel the Norwegian Haukeland researchers have exactly the model of how good research should proceed. Establishing such a Centre represents a very progressive step in looking for cause(s) of ME and the possibilities will be further increased as the research team moves into the new Quadram Institute, which will open next year. More information is on our microsite at http://www.cofeforme.eu where there are ways to help us raise funds and awareness of this venture - see http://www.investinm.org/ceSupport-cofeforme.shtml Our hashtags for the Centre are #CofEforME and #LetsCresearch. The Centre of Excellence will also provide a highquality partner for those Centres of Excellence being set up or existing in USA and Australia. The Centre of Excellence harnesses the benefits of Page 12 of 82 Journal of IiMER collaborative biomedical research in modern facilities with world-class researchers. Our aim is to establish a sustainable examination and research centre that would form the hub of European research and treatment for this disease and produce a pathway to produce huge benefits for the nation, and further across the world. We invite all to support us as we move forward with research. Let us make this vision a reality. http://investinme.org/ce-thecentreforme.shtml As a first step to realising the ambition of the Quadram Institute, on April 28 2017, the Institute of Food Research (IFR) transformed into Quadram Institute Bioscience. The lead of the Quadram Institute is Professor Ian Charles – who is again giving the keynote speech at the Invest in ME Research IIMEC12 international Conference. Quadram Institute Bioscience The Institute of Food Research (IFR) and Norwich Medical School will relocate to the new Quadram Institute building that is set for completion in 2018. One can follow the QI progress at this link in Norwich Research Park here - https://quadram.ac.uk/ Professor Charles opened IIMEC10 - the 10th Invest in ME Research International Conference in London in 2015. He has over 30 years’ experience in academic and commercial research and was a founding member of The Wolfson Institute for Biomedical Research at University College London, one the UK’s first institutes of translational medicine. More from Quadram - https://quadram.ac.uk/research_areas/gutmicrobes-health/ Norwich to be Home to the Quadram Institute The Quadram Institute is located on the Norwich Research Park and will integrate under one roof research teams from the current Institute of Food Research (IFR) and University of East Anglia’s (UEA) Faculty of Science and Norwich Medical School with the Norfolk and Norwich University Hospital’s (NNUH) gastrointestinal endoscopy facility.

Journal of IiMER OUR CURRENT FUNDING STREAMS The UK Centre of Excellence for ME Support for the UK Centre of Excellence for ME will provide a solid foundation for high-quality biomedical research into ME. This approach to research will change the landscape for research into ME and make this an area of research that will encourage innovation and novel research. Rituximab Trial/B-Cell Research The B-cell/Rituximab research. The charity is keen to replicate the recent Norwegian findings using Rituximab. We initiated B-cell research at UCL leading to a UK rituximab clinical trial. A specific web site has been set up to document this project – see www.ukrituximabtrial.org. Gut Microbiota Related Projects Beginning with our foundation project at Norwich Research Park. It is not often realised that 60-70% of the immune system is located in the gut as a vast network of lymph tissue referred to as GALT (gut associated lymphatic tissue). The research highlighted in the proposal involves looking at gut microbiota, which is some of the latest thinking in how to go about research. A foundation project at the University of East Anglia began in 2013 - funded by the charity. Medical Students Part of the charity's strategy for improving education has been to involve medical students in research into ME. By participating in the research projects funded by the charity then students are able to learn far more about ME and patients as well as passing on the reality of this disease to their peers. www.investinme.org Page 14 of 82 Journal of IiMER THE Big Give for the BIG Cause Project We welcome investment in developing the UK Centre of Excellence for ME and support from all who wish to see research into ME based on high-quality science and an urgency in all efforts to tackle this disease. Invest in ME Research have a Big Give page describing the basics of establishing a Centre of Excellence for ME and a donate option for supporting this work. The link is here https://secure.thebiggive.org.uk/projects/view/9169 Join our C Selfie Campaign to Raise Awareness To support the UK Centre of Excellence for ME we are asking people to send in photographs - or ask your MP, GP, any celebrities, sportspersons, etc. to support the campaign. To show support please take a photo of the person supporting us by using the right hand and make the C sign for supporting the charity's proposal for a Centre of Excellence for ME. Just send the photos to Invest in ME Research (our e-mail address is cofeforme@investinme.org) and include some short information or story behind the photograph #COFEFORME #LETSCRESEARCH www.investinme.org Page 15 of 82

Journal of IiMER Finding, Facilitating, Funding Research into ME Part of the development of the UK Centre of Excellence for ME consists of involving medical students in the research by intercalating in their fourth year of medical studies, and facilitating and encouraging students to look for a career in researching ME. An example recently demonstrate the benefits in our strategy of having medical students involved in research into ME. Navena Navaneetharaja and Verity Griffiths have been involved in the gut microbiota research in Norwich Research Park. Navena also spent several months with Professor Maureen Hanson at Cornell University in New York, USA. They produced a paper together with Professors Wileman and Carding from the Centre that provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS. This led the authors to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious “trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics. The paper is - A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)? Abstract from the Paper Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus www.investinme.org infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest. This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious” trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing muchneeded approaches in preventing and managing a disease desperately in need of confronting. http://www.mdpi.com/2077-0383/5/6/55 Another paper produced from IiMER funded research at UCL was released recently. Fane Mensah produced a paper with Dr Amolak Bansal, Brian Ford and Dr Jo Cambridge Chronic fatigue syndrome and the immune system: Where are we now? Abstract from the Paper Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by multiple symptoms including fatigue, headaches and cognitive impairment, which have a significantly adverse effect on the normal functioning and wellbeing of the individual. These symptoms are often triggered or worsened following physical or mental exertion. ME/CFS has long been thought of as having a significant immunological component, but reports describing changes in immune function are often inconsistent between study groups. Although the wide range of physical, neurocognitive and autonomic symptoms reported have seriously hampered attempts to understand pathophysiological pathways, investment in Page 16 of 82 Journal of IiMER biomedical research in ME/CFS is finally increasing with a number of novel and promising investigations being published. The onset of ME/CFS may often be linked to (viral) infections which would be consistent with a variety of alterations in natural killer (NK) cell function as described by a number of different groups. Consistency in cytokine data has been lacking so far, although recently more sophisticated approaches have led to more robust data from large patient cohorts. New hope has also been given to sufferers with the possibility that therapies that deplete B cells can result in clinical improvement. To understand the pathogenic mechanism in this complex condition, it is important to consider repeated analysis in different cohorts. In this review, we will discuss the potential of different components of the immune system to be involved in the pathogenesis of ME/CFS. https://www.ncbi.nlm.nih.gov/pubmed/28410877 “My beautiful daughter is totally bedbound. She has a diversity of symptoms that seem endless. (Most of the very severely affected have between 60+ and 100+ symptoms). The worst thing of all is the relentless, agonising pain. Widespread pain in every muscle, joint, and organ possible. She has not had one day free from pain since the illness began. Her whole life now is lived from her bed. Not her choice for she is a talented artist and photographer and she dreams of being in summer meadows photographing the dancing bees and butterflies and painting the colourful flowers. ….. “Her dreams have been snatched from her by this awful disease that others misunderstand by thinking it's just about feeling tired or attention-seeking”…. “Her days are spent in a darkened room and in as much silence as the outside environment will allow. She is hypersensitive to light, noise, odour, vibration, touch, movement, chemicals, some foodstuffs, and medicinal drugs. …..” “She is unable to sit or stand due to being moribund with pain, orthostatic intolerance, paralysis, blackouts and much more and so her bed is her companion twenty-four hours a day. …... She cannot tolerate touch as her skin is always 'on fire' like it's been grated with a cheese grater. Her description. I have to cut her pyjama tops off (when she can tolerate a change of tops) because any movement causes her indescribable pain. She has difficulty speaking sometimes and so asks me to be her voice…... “ " My amazing daughter has such a positive view of life. I'm stunned that she's not depressed or angry. Although she sometimes has her low days, her courage and inner strength are immeasurable. Not a day passes without seeing one of her magical smiles which sometimes just breaks my heart.” - from Lili http://investinme.org/mestory1010.shtml www.investinme.org Page 17 of 82

Journal of IiMER RESEARCH – COLLABORATION Research News from Fane Mensah Fane Mensah is funded by Invest in ME Research for B-cell research [The potential role of B cells and their products in ME/CFS Patients] Collaboration with Christopher Armstrong As part of our Solve ME/CFS Initiative Ramsay award winning collaboration, Christopher Armstrong from the Bio21 Institute (Melbourne University, Australia) came over to work with us at UCL for one month. A quick flashback to June 2016, at the 6th Invest in ME Research International Biomedical Research into ME Colloquium (#BRMEC6) meeting in London where Chris and I met. We were the two youngest scientists at the meeting to give a presentation about our research. It would not have been the first thing we would have in common! Straight after our presentations we started to talk about each other’s experiments and found out that the two completely different fields we were working in (Immunology and Metabolomics) could be complementary. It is well known that immune issues have often been associated with ME/CFS (B cells, NK cells T cells etc.). More recently, different groups, including Christopher and his colleagues have studied changes in the metabolic profile in ME/CFS patients. Their data is very promising and consistent which supports a possible role in this condition. Following some bonding drinks after the conference, Christopher visited us (myself and Dr. Cambridge) the next week at UCL where we laid the base for our collaboration. After Christopher returned to Australia, and several (late and early) Skype meetings we put together a grant application for the Solve ME/CFS www.investinme.org Initiative Ramsay award which is an award that supports (young) scientists from different fields committed to ME/CFS research. This award gives them the opportunity to lay the basis for more substantial collaborative research projects. The next generation scientists: BSc student internship at UCL With the support of the Invest in ME Research charity, we were very fortunate to have Isabelle de Rooij visiting our laboratory for a 5-month internship. Isabelle is a BSc student from Hoge school Rotterdam in the Netherlands (my old University) undertaking the Bachelor of Science course in biology and medical laboratory sciences. As tipped for the best student in her year, we had big expectations from here and she did not disappoint us! During her internship, she not only learned Page 18 of 82 Journal of IiMER different laboratory skills and techniques but also got an insight into the biomedical research applied to ME/CFS. This was just as important as the technical part of the internship. Isabelle really enjoyed her time her and was very The article by Fane shows the importance of Invest in ME Research's strategy of international collaboration in research into ME. The meeting between Fane and Chris (and Zaher Nahle from Solve ME/CFS) came about because the charity invited all of them to the #BRMEC6 Colloquium. The article also demonstrates the importance of our strategy of funding students in research into ME - a strategy proven to be successful and making a real difference. Subscribe to our Newsletter ME QUOTES passionate about her project. She significantly contributed to the development of new protocols for our future experiments, and assisted me with ongoing projects related to the joint project with Christopher Armstrong. We were very proud of Isabelle when she finished her internship, which was examined based on her technical lab skills and final report, with 9.5/10. A great achievement from a great student! Her university was so impressed and satisfied with her achievements and progress in our group that they have asked us if we would be interested in future collaborations. From Invest in ME Research www.investinme.org "It is of the greatest importance to keep in mind the goal toward which one works in science, but it is also of equal importance to simply explore and define the 'new' while keeping that mind well prepared for finding new treasures. It is only through such efforts that we believe the etiology of CFS will be finally illuminated." Steven Tracy and Nora Chapman, University of Nebraska Medical Center: http://www.investinme.org/ArticleJ31Human Enteroviruses and Chronic Infectious Disease.shtml Page 19 of 82

At the 10th Invest in ME Research International ME Conference in 2015 Dr Ian Gibson announced that he was planning on writing a book about ME - and the politics and prejudice which has affected the way that ME is perceived, treated, researched and funded - as well as the resultant effects on patients and their families. Journal of IiMER Dr Ian Gibson led an inquiry into ME in 2006 [2]. Without official funding, and at a time when unbiased and independent analysis on the way ME was being treated and reported on by the establishment organisations and media was lacking, Dr Gibson provided a checkpoint which attempted to get publicity and force change which would help ME patients. The Inquiry's report made several recommendations [3]. That the then Labour government ignored the report, and its recommendations, will forever cast a shadow on the health minister at the time and on the government itself. Since that time Dr Gibson has been influential in assisting IiMER get high-quality biomedical research established in Europe. He has also chaired the IiMEC* conferences. After 12 years of IIMEC* conferences, and following the tenth anniversary of the Gibson Inquiry, and when change was slowly managing to creep into establishment organisations, Dr continues to be the subject of misrepresentation, inappropriate media reporting, ineffective research funding and a pervading prejudice that needs to be exposed. Dr Gibson is familiar with the political events in the UK, how they affect healthcare and patients and how some organisations and individuals are unduly influencing these policies. It is important to understand the politics of ME and how the ‘establishment’ in most countries reacts. Dr Gibson, and co-author Elaine Sherriffs, started interviews with knowledgeable individuals following the IiMER London conference and established new contacts. Dr Gibson and Elaine visited or interviewed researchers, clinicians, advocates, patients, carers and others to produce this an analysis of ME - the Science and Politics behind the way ME is treated. Gibson felt it was necessary to look at the way that politics and the actions of some have influenced the way ME has been, and www.investinme.org Although heavily constrained by the limited funds that the charity was able to raise interviews were carried out by Elaine and Dr Gibson – and included a visit to Stockholm, Sweden, where they spoke with patients, clinicians, researchers and politicians from Sweden and other countries. The project was aided by a generous donation Page 21 of 82

Journal of IiMER toward the production of the book from the Irish ME Trust. We also had donations from some individuals for which we were extremely grateful. The book was published earlier this year and is available via Amazon. Few diseases can have been so maligned by false information, so manipulated by an insidious establishment-controlled ideology, or so poorly dealt with by those holding the purse strings for research into the disease, than Myalgic Encephalomyelitis (ME). This book examines a scandal in our generation - a scandal still being played out by corrupt, apathetic, inept or ignorant attitudes in governments and Medical Research Councils and health services. We welcome all support for raising awareness of the book – a book able to reach more people in society in a way that should make them want to know more and question why a section of the population are being so abused by crass, self-serving and Please help in raising awareness of this book. Thank you for your support. Buy from Amazon www.investinme.org References: 1 IIMEC10 10th International ME Conference 2 Gibson Inquiry Report 2006 3 Gibson Inquiry Recommendations 4 Gibson Book - JustGiving Donations 5 Gibson Book - The BIG Give Project Page 22 of 82 Journal of IiMER Philanthropy and ME Philanthropy – “the desire to promote the welfare of others, expressed especially by the generous donation of money to good causes” Philanthropists may be thought of as wealthy, individuals or organisations contributing to causes, for reasons either personal or financial or from expediency. But philanthropy comes in all flavours and different guises and not always from obvious quarters, and not always by means of donating money. The philanthropy given and displayed by supporters of Invest in ME Research is of the highest level. Many of the charity’s supporters are very ill and have little means of financially contributing – left with little financial possibilities due to the ravages of the disease on them or their family, exacerbated by punitive and immoral government policies on welfare benefits to disabled people. Yet their efforts made to support the charity and its research has changed the landscape of UK research into this disease – forcing biomedical research into the mainstream when, for years, little was done to make progress by existing establishment organisations. Jo Best and helped on by Jan Laverick and Paul Kayes – all ME patients. Instead of continually reacting to what others were doing or saying they decided to take a proactive approach. A campaign was started to support the Invest in ME Research proposal for the Centre of Excellence for ME. The difference with this campaign? To use the skills and ideas of patients who want more than anything else does to regain their health. By harnessing these ideas and enabling people to feel positive about doing something LDIFME The Let’s Do It for ME (LDIFME) campaign and our core group of supporters are helping to fashion a change in ME research and this determination and enthusiasm will influence researchers – both within the ME research area and those from outside. themselves to effect change then the campaign could be turned into something which was fun. Positive campaigning – with an objective to fund sorely needed translational biomedical research into ME and to harness patient power to influence ME research – something which had been missing from the equation. As the charity initiated a plan to develop a Centre of Excellence for ME an idea was born by www.investinme.org The Let's Do It For ME campaign is a positive and proactive campaign. The aim is to raise funds for Page 23 of 82

Journal of IiMER biomedical research but everyone's input is welcomed - be it just ideas or moral support for other people's fundraising. Whilst raising funds for biomedical research the campaign has also raised much needed awareness and this has allowed more correct information about ME to be disseminated. Let's do it for ME! is a patient-driven campaign to raise awareness and vital funds for the UK Centre of Excellence for ME performing translational biomedical ME research, clinical assessment, diagnosis and treatment for patients, and training and information for healthcare staff based at the Norwich Research Park in the UK but working collaboratively with international biomedical researchers. The Let’s Do It For ME campaign has been running now for 7 years. http://ldifme.org “We constantly receive letters from the Department of Health stating that very little is known about ME and yet without doctors like Dr (Nigel) Speight, who are willing to believe in and listen to children with ME and learn in the process, many patients would have little hope for a better and safe future. Paediatricians and doctors in the UK generally demonstrate an overwhelming degree of ignorance toward ME– either disbelieving it exists, misdiagnosing other diseases in its place, failing to identify the potential consequences of severe ME and failing to spend any time in improving their education about the disease. Sometimes they just continue to hold their pet theories on this disease. The Institutes of Medicine concluded in their report of 2015 [9] that ME is an organic disease. The IOM report looked at the effects on children from this disease [10]. “There is clear evidence of the impact of ME/CFS on the education and social development of these young people. The stigma and social effects of paediatric ME/CFS include the loss of normal childhood activities and in some extreme instances, inappropriate forcible separation of children from their parents” As part of the research review carried out the IOM reported on an Australian study of 189 adolescents by Rowe and Rowe concluded that evidence for somatization disorder among young people with ME/CFS was negligible. “They all note that ME/CFS symptoms often make it more difficult to do schoolwork, so children and adolescents with ME/CFS may be misclassified as having “school phobia.” Invest in ME Research deplore the concocted term school phobia, or pervasive refusal syndrome, and those promoting these terms in relation to ME/CFS, as they have never applied to children with this disease.” Invest in ME Research - Ignoring the Elephant in the Room http://www.investinme.org/IIME-Newslet-1604-NS999.shtml www.investinme.org Page 24 of 82 Journal of IiMER The gut microbiome in Myalgic Encephalomyelitis Maureen R. Hanson and Ludovic Giloteaux (Cornell University, USA) April 2017 © Biochemical Society O ver the last dozen years, increasingly powerful DNA sequencing methods have allowed characterization of the microbes residing on and in humans in much greater detail than ever possible before. Abnormalities present in the gut microbiome—those microbial communities residing in our intestines—have now been observed in a number of diseases. One such illness is Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS). CFS was a name coined by the US Centers for Disease Control (CDC) in 1988, and reviled by patients for the resultant trivializing of this serious illness. Recently, the US National Academy of Medicine (NAM) recommended a new name: Systemic Exertion Intolerance Disease, though this name is not yet widely used. In ME, as in other diseases, the diversity of the bacterial species in the gut microbiome is lower than in healthy individuals. Furthermore, the abundances of different bacterial residents of the gut, which influence health both favourably and negatively, differ between ME patients and healthy controls. Bacteria translocate into the blood in greater amount in ME, leading to inflammation. Dysbiosis in the gut likely contributes to symptoms in this life-limiting disease . Three to four times more women than men have ME. Children and adolescents as well as adults are susceptible to the disease. Prevalence is difficult to determine because of the lack of a simple, objective diagnostic test. While physicians experienced with the disease are readily able to make correct diagnoses, the clinical criteria often vary between studies, making enumeration of patients difficult. An investigation of ME in three regions of England found that about 0.2% fit a widely used 1994 CDC definition. A meta-analysis of 14 studies www.investinme.org found the prevalence by clinical assessment to be 0.76%. These numbers translate into 128,000 to 486,000 ME patients in the UK. Thus, even if the lower figure is used, ME does not fit the definition of a rare disease (see www.raredisease.org.uk). An example of a rare but serious disorder that affects intestinal function is Clostridium difficile infection which is at least 10 times less common than ME. The severity of the disease varies, though most affected individuals are unable to work or attend Page 25 of 82

Journal of IiMER school full time. For example, a small survey of 25 children with ME in the UK found that only one could attend a full day. Indeed, another study found that ME was responsible for 42% of the medically certified, extended school absences in the UK over a five-year period. While the ‘fatigue’ element in the name emphasizes a major symptom of ME, most patients report that the fatigue is not the same as that experienced by healthy individuals after vigorous physical exercise or inadequate sleep. Instead, the fatigue is described as a profound lack of energy, more akin to the sensation of exhaustion that occurs during a severe case of influenza or mononucleosis. Two additional symptoms were identified by the National Academies of Medicine committee in a 2015 report (http://www. nationalacademies.org/hmd/Reports/2015/MEME. aspx) as hallmarks of the disease: postexertional malaise and unrefreshing sleep. The new diagnostic criteria also require either cognitive impairment or orthostatic intolerance. The latter refers to a surge of symptoms when upright that improves when the patient reclines, likely due to a disturbance in the autonomic nervous system. With regard to cognitive impairment, patients often report ‘brain fog,’ like the impaired mental capacity, poor memory and concentration that healthy individuals experience when they have been awake all night. Most people with ME reach a steady-state level of physical and/or mental activity they can sustain without inducing an ensuing increase in symptoms known as post-exertional malaise. Many are homebound – simple acts such as shopping for groceries can result in worsening of their symptoms. For those who are bedbound, any sort of stimulation, even the mental and physical effort to carry on a conversation, can intensify their symptoms. Many ME patients, whether bedbound or not, are unusually sensitive to light and sound. Bedbound patients often require eyeshades and sound-protecting headphones to cope with those stimuli. Among the most severely ill ME patients (Figure 1), some must be supported at the level of those who are comatose. Some are too impaired to speak and cannot eat nor digest food normally and must be tube fed. Possible roles of the gut microbiome in ME Gastrointestinal disturbance is a symptom often reported by ME patients. This fact has encouraged several investigators to compare the gut microbiome in patients versus controls. Our research group undertook a study of the bacterial gut microbiome by comparing 16S rRNA from faecal samples of 48 ME patients and 39 controls. The 16S rRNA sequence is commonly used to identify bacterial species, as the presence of very variable regions in www.investinme.org Page 26 of 82 Journal of IiMER the 16S rRNA gene provides species-specific signature sequences. We obtained an average of 98,000 sequence reads per sample, more than ample to identify almost all of the bacterial diversity. To determine how many reads are needed, the number of species detected per number of sequences can be graphed to produce a ‘rarefaction curve’ (Figure 2). As more sequences are obtained, the number of species detected increases until a plateau is reached, where few additional species will be found despite a large number of additional sequence reads. For our samples, it is evident that 30,000 reads would be more than sufficient. For the example shown of a theoretical sample with low diversity, 5000 reads would have been adequate, while the high-diversity example indicates that even 30,000 reads would not suffice. A conclusion that can be drawn from Figure 2 is that ME cases have reduced bacterial diversity in comparison to healthy controls. Such reduced diversity has been observed in other diseases such www.investinme.org Page 27 of 82

Journal of IiMER as Clostridium difficile infection, inflammatory bowel disease and necrotizing enterocolitis. The sequence data can also be analyzed for differences in the abundance of various species between cases and controls. Some species that we found to be differentially abundant represented a very small fraction of the bacteria present and thus may not have a large effect on gut ecology and function. In Figure 3, we show those genera that a) represent more than 1% of the gut microbiome and 2) varied significantly among faecal samples between ME and healthy controls. The reduced abundances of Bifidobacterium and Faecalibacterium species in patients have also been reported in inflammatory bowel disease and other conditions. Faecalibacterium species produce butyrate, a short-chain fatty acid that has antiinflammatory properties, and thus its reduction would predict lower levels of butyrate. While we did not measure butyrate in our samples, when faecal samples of 34 female cases and 25 controls were examined by Armstrong et al. in another study, surprisingly, butyrate was higher in the ME patient samples. Determining which metabolites are actually present in the gut can be difficult to predict merely from a list of species that reside there, given the complex interactions among different microbial communities and with the cells in the intestine. Several studies in which bacteria were cultured also demonstrated differences between ME patients and controls. However, many gut microbial residents cannot be cultured and are known only by their DNA sequences, so that high-throughput sequencing of 16S ribosomal DNA for identifying bacterial taxonomic groups is beginning to supplant culture methods. Nevertheless, there are also limitations to knowledge from DNA sequences of intestinal contents. For example, while ribosomal DNA sequencing can detect that Escherichia coli is present, it doesn’t reveal whether one of the highly virulent E. coli strains is present in addition to benign or beneficial E. coli strains that reside in www.investinme.org most individuals. To find pathogenic E. coli, bacteria are grown on specific culture media and then tested with an antibody that reacts with proteins present in disease-causing E. coli strains. Thus, a harmful bacterium could be present in ME patients and go undetected by ribosomal DNA sequencing. Leaky gut problems When the intestinal lining is inflamed, bacteria can translocate into the bloodstream through loosened intestinal tight junctions leading to a ‘leaky gut’ (Figure 4). The immune system then detects the presence of bacteria or bacterial components in the blood and mounts an immune response to counter this apparent invasion. There can be collateral damage from the immune system’s attack on perceived threats. ME patients often have symptoms of chronic inflammation such as muscle and joint pain and swollen lymph nodes. In order to find out whether ME patients might have more bacterial products in their blood than healthy people and could be responding to them, we tested whether the levels of certain molecules were different in the blood of the same ME patients and healthy controls whose faecal samples were sequenced. We found that patients had higher levels of lipopolysaccharides (LPS), a large molecule comprised of both lipid and sugar components. LPS are present on the outer membrane of some bacteria and cause a strong immune response. We found that levels of LPS, LPS-binding proteins and a receptor for LPSbinding protein (soluble CD14), which signals the presence of LPS to the immune system, are increased in ME patients. Thus, the abnormal gut microbiome in ME patients likely contributes to their chronic inflammation and ensuing symptoms. While digestion most often comes to mind when considering intestinal bacterial species, there is increasing evidence that the gut microbiome affects the risk of colorectal cancer, obesity and abnormal mental function. Metabolites and proteins from the gut enter the bloodstream in healthy as well as diseased individuals, and some can affect the central Page 28 of 82 Journal of IiMER nervous system and brain. Prospects for treatment Oral prebiotics and probiotics are being investigated for restoration of bacterial diversity and resolution of gastrointestinal diseases. Prebiotics are substances thought to improve growth of beneficial species, while probiotic supplements contain microbes known to be present in healthy guts. In order to be incorporated into a probiotic pill, bacteria must be grown in culture, but culture conditions for growing many of the bacterial species present in the human gut are not known. Thus, only a selection of certain species can be incorporated into commercially available probiotics. How these different species affect people with different types of gut microbiomes, and whether gastrointestinal illnesses can be improved with their aid is an important topic that is currently being explored in the research community being explored in the research community. www.investinme.org Because pure cultures of many gut microbes cannot be obtained, researchers have turned to faecal transplants, i.e. introduction of faecal material from healthy human donors into recipients. This treatment has cured some individuals with severe gastrointestinal dysfunction from Clostridium difficile infection. Whether this process can also help patients with other types of intestinal diseases and ME is less clear. Promising reports have appeared about improvements in ulcerative colitis, Crohn’s disease and autism. With regard to ME, anecdotal reports from patients who have tried faecal transplantation indicate some reduction in symptoms, but not complete recovery nor persistent improvement in their conditions. One study of faecal transplantation indicated that 42/60 ME patients had a favourable response. The results are sufficiently promising to suggest that a clinical trial of faecal transplants in ME would be worthwhile. Page 29 of 82

Journal of IiMER Future directions Multiple studies now show that the gut bacterial composition is abnormal in patients with ME, a lifelimiting disease. These findings are now among many discoveries of biological differences between ME patients and healthy individuals, all of which should dispel any remaining notions that the illness is psychological in nature. Future studies on the eukaryotic microbiome and virome may reveal additional disturbances in the microbial communities of people with the disease. While these gut abnormalities may be a response to some other inciting factor, rather than the basal cause of disease, learning how to ameliorate them could have clinical benefits for patients and help promote recovery, perhaps in conjunction with other treatments. ■ Ludovic Giloteaux Ludovic Giloteaux, PhD, is a Research Associate in Dr Hanson’s lab group. His research addresses the molecular mechanisms of biological processes, ranging from environmental concerns such as the bioremediation of arsenic- and uraniumcontaminated environments to human disease, namely the biological basis of ME. His research uses integrated approaches combining molecular biology and microbiology to study the microbiome in ME, and the effect of the disease on gene expression and proteins from immune cells. Email: lg349@cornell.edu. Further reading 1. Committee on the Diagnostic Criteria for CFS. (2015) Beyond Myalgic Encaphlomyelitis/Chronic Fatigue Syndrome. The National Academies Press, Washington, D.C. ISBN 978-0-309-31689-7. http://www. nationalacademies.org/hmd/Reports/2015/MECFS.aspx 2. Navaneetharaja, N., Griffiths, V., Wileman, T. and Carding, S.R. (2016) A role for the intestinal microbiota and virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS)? J. Clin. Med. 5(6). pii: E55, http://dx.doi.org/0.3390/jcm5060055 www.investinme.org Maureen Hanson Maureen Hanson, PhD, is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, New York. Her research projects concern gene expression and genetic engineering in plants and the molecular basis of ME/CFS, funded at various times by NSF, USDA, DOE, NIH and several non-profit organizations. Her lab has produced over 180 peer-reviewed articles. She is currently Director of the Cornell Center for Enervating Neuroimmune Disease. Email: mrh5@cornell.edu 3. Nacul, L.C., Lacerda, E.M., Pheby, D. et al. (2011) Prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Med. 9, 91, http://dx.doi.org/10.1186/1741-7015-9-91 4. Johnston, S., Brenu, E.W., Staines, D. and Marshall-Gradisnik, S. (2013) The prevalence of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: a meta-analysis. Clin. Epidemiology 5, 105–110, http://dx.doi.org/10.2147/CLEP.S39876 5. Kennedy, G., Underwood, C. and Belch, J.J. (2010) Page 30 of 82 Journal of IiMER Physical and functional impact of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis in childhood. Pediatrics 125, e1324–1330, http:// dx.doi.org/10.1542/peds.2009-2644 6. Dowsett, E. and Colby, J. (1997) Long-term sickness absence due to CFS in UK schools: an epidemiological study with medical and educational implications. J. Chronic Fatigue Syndrome 3, 29–42, http://dx.doi. org/10.1300/J092v03n02_04 7. Stewart, J.M. (2013) Common syndromes of orthostatic intolerance. Pediatrics 131, 968–980, http://dx.doi.org/10.1542/peds.2012-2610 8. Aaron, L.A., Burke, M.M. and Buchwald, D. (2000) Overlapping conditions among patients with Chronic Fatigue Ayndrome, fibromyalgia, and temporomandibular disorder. Arch. Int. Med. 160, 221–227, PMID: 10647761 9. Giloteaux, L., Goodrich, J.K., Walters, W.A., Levine, S.M., Ley, R.E. and Hanson, M.R. (2016) Reduced diversity and altered composition of the gut microbiome in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microbiome 4, 30, http://dx.doi.org/10.1186/ s40168-016-0171-4 10. Armstrong, C.W., McGregor, N.R., Lewis, D.P., Butt, H.I. and Gooley, P.R. (2017) The association of faecal microbita and faecal, blood serum and urine metabolites in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Metabolomics 13, 8, http://dx.doi.org/10.1007/ s11306-016-1145-z 11. Grimm, V. and Riedel, C.U. (2016) Manipulation of the microbiota using probiotics. Adv. Exp. Med. Biol. 902, 109–117, http://dx.doi. org/10.1007/978-3-319-31248-4_8 12. Hudson, L.E., Anderson, S.E., Corbett, A.H. and Lamb, T.J. (2017) Gleaning insights from faecal microbiota transplantation and probiotic studies for the rational design of combination microbial therapies. Clin. Microbiol. Rev. 30, 191–231, http://dx.doi. org/10.1128/CMR.00049-16 13. Borody, T.J., Nowak, A. and Finlayson, S. (2012) The GI microbiome and its role in Chronic Fatigue Syndrome: a summary of bacteriotherapy. J. Australasian College Nutrition Env. Med. 31, 3–8. ISSN: 1328-8040 www.investinme.org Page 31 of 82

No Isolation E arlier this year Invest in ME Research were contacted by a Norwegian company who were interested in use this to publicise awareness of the effects of ME on children. promoting a product which aimed to reduce the isolation experienced by many younger people who were unable to attend school, or were cut-off from social contact due to illness. Obviously, the charity immediately saw the parallels with ME and the possibility of raising awareness of one of the least publicised side effects of this disease on patients, and their families. Our immediate reaction was how we can help We then invited the company – No Isolation – to take a table at the IIMEC12 conference and offered to work further to support this campaign. The charity does not normally advertise products, or businesses, but on this occasion we feel it is a worthwhile cause that could help alleviate some of the unnecessary suffering which careless or ignorant education systems inflict on sick children and their families. In this article from No Isolation researcher, Oda Opdal Zachrisen, the company’s product AV1 is described. The AV1 robot helps children and youths with ME In Norway, a small white robot has become a stand-in in the classroom for children and youths suffering from ME. The robot is now available in the UK. The Norwegian start up No Isolation has developed a robot that helps children and youths with long-term illness www.investinme.org Page 32 of 82 Journal of IiMER participate in the classroom on their own terms. The robot, called AV1, acts as the students’ eyes, ears and voice in the classroom on days where they cannot be physically present. The student is in control The student controls the robot with an app on a tablet. When the student raises their hand, a light flashes on AV1’s head. The robot can be turned 360 degrees, so the student can see the entire classroom and talk to other students. If the student does not feel like actively participating, they communicate it by turning on a blue light on AV1’s head. AV1 is designed to withstand Childs play, and can join classmates in the playground or on after school visits. AV1 is already helping ME-patients Today, more than 170 children and youths are using AV1 in Norway. Children and youths suffering from ME is the largest user group. Research fellow Jorun Børsting and senior lecturer Alma Leora Culén at the Institute for Informatics, University of Oslo, are researching the technology needs of ME-patients. They have studied the use of AV1 among nine children and youths suffering from ME. They see a big advantage in the fact that the robot is designed with ME-patients in mind. – The advantage in participating in class through a tablet is that they have full control over sound levels, light and movement. In a normal classroom they do not have the option to control sensory inputs in this way. Furthermore, they can participate exactly when they feel like it, taking into account that symptoms can fluctuate over the course of the illness, even from hour to hour, Børsting comments. Børsting stresses that the robot cannot fully replace normal attendance at school or home teaching, but act as a supplement. – Of the children I followed several had not attended school in a long time when they first received the robot. Some had been out of school for over six months. After they received AV1, all of them participated regularly, on their own terms. The robot, which has been in use in Norway since autumn 2016, is now available in the rest of Europe. This little helper, which is already underway to children in the UK, can be ordered from No Isolation, at www.noisolation.com www.investinme.org Page 33 of 82

Cuts Threaten Research for Terrible Disease Once Called Chronic Fatigue Syndrome by Llewellyn King Journalist, broadcaster, public speaker Llewellyn King is the creator, executive producer and host of “White House Chronicle,” a weekly news and public affairs program, airing nationwide on PBS and public, educational and government (PEG) access stations, the commercial AMGTV network, and SiriusXM Radio. King writes a weekly column for the InsideSources Syndicate. King was the founder and publisher of The Energy Daily. The newsletter was the flagship of his award-winning King Publishing Group, which he sold in 2006. The group’s other titles included Defense Week and New Technology Week. In 2011 he created a charity for Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome. The charity has a YouTube channel, ME/CFS Alert. When you are sick, very sick, you wait for medicine to work its magic. But if the disease is Myalgic Encephalomyelitis (ME), you have to wait for the medicine to be invented. The bad news is that so little funding is going into solving the ME problem, commonly known as Chronic Fatigue Syndrome, that those sick today may be sick for the rest of their lives. They are living a life that is a nearly intolerable to themselves and a massive burden to their loved ones, spouses, parents and caregivers. What is known is that ME is a disease of the immune system. It is vicious and debilitating, leaving the patient confined to a marginal life, a parallel and unequal existence. Most infections are of healthy people who are struck down often, but not always, after exercise. The first symptoms can be flu-like: The sufferers feel a few days in bed will do the trick. But having ME is a life sentence. There also have been group infections, known as “clusters,” where hundreds www.investinme.org have been stricken. If you have ME, the least exertion can force you to spend days in bed, exhausted, hurting in myriad ways from headaches to what one woman described as “feeling like your bones are exploding.” In severe cases, the patient cannot tolerate light or sound. A young man, newly married, and felled unaccountably, had to live in a closet for an extended period before he could handle light and sound. Symptoms vary but most of the time a victim feels, as one told me, “like you are a car that has run out of gas and your tank cannot be filled up again.” A teenager told me that if she is to go out with friends, she has to weigh that against days of bed rest, in a complete state of collapse. The National Institutes of Health (NIH) ― the principal researcher into ME and dozens of other perplexing diseases ― has historically given ME a pittance. In the last three years funding has been held to $5 million a year, although the Obama Page 34 of 82 Journal of IiMER administration had promised more. To put this in perspective, the trade association of the pharmaceutical industry calculates that it costs $1.2 billion dollars to bring a new drug to market. Sadly that industry has not shown interest in ME, so the research is mostly funded by NIH and private groups and individuals. The news that the Trump administration is thinking of cutting the total NIH budget by $5 billion has caused a palpable anxiety to grip the ME community. The disease is cruel enough, does it need to be compounded by the government? That is why those who could manage it and members of their families were enthusiastic supporters of the March for Science. They were out there with a sense of being at the barricades as the barbarians massed on the other side. The United States has led the world for years in scientific discovery and implementation. It is deeply disturbing to think that the country would draw back from it. But the administration’s ambivalence is clear. The Department of Energy with 17 national laboratories, every one the envy of the world, is headed by Rick Perry. When he ran for president, he did so on a plank that included closing the department. The Environmental Protection Agency, with a history of struggling to get the regulatory science right, is headed by Scott Pruitt. As attorney general of Oklahoma, he sought to hobble the agency with lawsuits. So across science, from the National Aeronautics and Space Administration to the research service of the Department of Agriculture, there is fear among scientists; fear for their jobs, fear for science and fear for America. In the sick rooms of the 1 million or so ME sufferers, despondency has reached new depths. You will not be cured if no one cares enough to look for a cure. Can you double down on despair? www.investinme.org Page 35 of 82

Journal of IiMER Invest in ME Research Visit The CMO of England clinicians in other countries. Therefore, in this discussion we also used the knowledge and collaborative activities from discussions the charity has had with all of our international contacts. Recently Invest in ME Research again invited the Chief Medical Officer of England to our 12th International ME Conference in London [1]. Regrettably, this invitation was declined. However, after the continued orchestrated and misleading headlines relating to the PACE Trial II on children then we felt a new approach was required. In England, the CMO is a member of the board of the National Health Service (NHS), a civil servant in the Department of Health, and head of the medical civil service. So this presents us with an opportunity to cover failings in these areas. We must change the false view of ME constantly being represented by some organisations responsible for funding research and the media. The CMO has a duty to be informed - and support good research and clinical practice. Invest in ME Research therefore arranged a meeting with the CMO in London which will include our advisors and cover areas such as policy around ME since the last CMO report [3], epidemiology of ME, current/future international research, education regarding ME etc. Invest in ME Research is already approaching the issues around ME with an international context. We have already engaged with researchers and www.investinme.org Along with our colleagues in the European ME Alliance (EMEA) we are looking at ME in Europe and EMEA has been working very hard within the European Federation of Neurological Alliances (EFNA). We are also in continuing discussions with NIH on ways to improve diagnosis, research and treatments for ME. Regarding the CMO meeting - this is a UK problem -and therefore requires a UK strategy. Invest in ME Research therefore also invited the CMOs of Scotland, Northern Ireland and Wales to this meeting. But a Summit of CMOs for ME - sounded like something that could be useful. All of the UK's CMOs were invited to our 12th International ME Conference 2017 in London Invest in ME Research had requested a meeting with all four CMOs (England, Wales, Scotland and Northern Ireland) and on Wednesday 11 January 2017 a meeting took place with the Deputy CMO of England Dr Gina Radford at Whitehall Court, London. Invest in ME Research previously wrote about our intention to engage with the Chief Medical Officers of the UK and appraise them of the research into ME that the charity is facilitating and the current issues which continue to exist and which we believe the CMOs have a duty to confront - A Summit of CMOs ATTENDEES:  Dr Gina Radford, Deputy Chief Medical Officer, England  Professor Jonathan Edwards (UCL)  Dr Ian Gibson Page 36 of 82 Journal of IiMER  Countess Mar  Fane Mensah (PhD student, UCL)  Representatives from Invest in ME Research Apologies:  Dr Nigel Speight  CMO Scotland  CMO Northern Ireland  CMO Wales Prior to the meeting the charity had submitted two documents to the CMOs and participants. One concerning children and the deplorable state that exists as well as case studies of children badly affected by the way that the existing mentality toward ME is allowed to distort proper healthcare. In this document evidence was presented to the CMO of the way many families of children with ME are being harassed and subject to child Protection proceedings. Though the establishment organisations have totally failed children with ME the harassment is not, however, confined to vulnerable patients or their families either - as witnessed by this story - (http://investinme.org/IIME-Newslet-1604NS999.shtml). The following document had also been sent prior to the meeting to all attendees - Summary of developments following CMO’s report of 2002 It was agreed that the meeting would take an informal format to allow free discussion and the available agenda would be used as guidance. It was mentioned that Invest in ME Research had sent in information beforehand to allow the CMOs time to familiarise with the issues on the agenda. Dr Radford said she had read the information given and stated that the CMO could not resolve most of the problems mentioned as the CMO’s remit had changed and many of the issues mentioned would be the responsibility of NHS England. She would, however share the notes with other www.investinme.org CMOs in Wales, Scotland and Northern Ireland. The charity pointed out that the CMO’s remit includes influencing policy and that from experience it seems that ME is not on the CMO’s radar. The charity mentioned that the previous and current CMOs had never accepted the charity’s invitations to attend or speak at the international conferences that the charity had organised in the past 11 years. The invitation was always either too early or too late. There never seemed to be a right time and this sent a message to patients, carers, researchers and doctors interested in ME that ME was not on the CMO’s agenda. The charity explained that the meeting was taking place and as far as we were concerned, we were talking directly to the CMOs of the UK. The charity asked directly whether the CMO was happy with the current status of ME research and what was their official opinion on ME? Dr Radford stated that she could not speak for the CMO and she made the point once again that the CMOs of England, Wales, Scotland and Northern Ireland do not run the NHS. It is the NHS England that runs the services and we would need to discuss these matters with them. The CMO’s relationship with the NHS and remit has changed since 2002 when the 2002 CMO report on CFS/ME was published. Parameters have changed and now the CMO’s remit is to give broadly advice to the government. The charity read out the publicly stated remit of the CMO such as protect the public, tackle inequality, review policy (mentioned no policy for ME), influence by statements and discussions. CMO Remit Countess of Mar said Dr Martin McShane makes nice noises but nothing happens. The charity described cases provided in the accompanying document where severely ill children with ME who failed to recover with Page 37 of 82

Journal of IiMER CBT/GET programmes were then re-diagnosed and given labels such as pervasive refusal syndrome and parents/carers accused of Munchausen Syndrome by Proxy. The PACE trial was mentioned and Dr Radford had not read PACE. So Countess of Mar described the well-known shortcomings of the PACE trial including the Information Commissioner’s Office being involved leading to a court case to get raw data released and reviewed according to the original protocol and the damage it has caused to the worldwide patient community. Professor Edwards explained the reasons why the PACE trial and CBT/GET studies were poor science and the system is failing as it allows authors of these papers take on roles as reviewers of the same papers. The Cochrane review was an example of this. Dr Gibson described the annual IiMER Colloquium/Conference and how the science is getting interesting. There seems to be lack of duty for biomedical research into ME, neglect in taking an all- around approach and ME is not getting its fair share. Dualism was a waste of time and research should open up and the government has failed to take it up. Fane Mensah described the situation for a young researcher. He said there needs to be support for young researchers. Students who are thinking about their career choices need to know there is a future in this exciting and complex field. He described how the patients he sees as part of the research funded by Invest in ME Research are so grateful that someone is taking them seriously and listens to them. The charity asked Dr Radford how the CMO made decisions when taking up issues such as antibiotic resistance, Ebola, Zika virus etc.? Dr Radford said it was because they were major worldwide issues. www.investinme.org The charity said that ME is a major worldwide issue - yet no one knows numbers affected (only rough estimates) and the diagnosis is inaccurate and variable. Sally Davies should at least make a brief visit to the conference or send a representative to learn about the latest developments. Dr Clare Gerada as the chair of the Royal College of GPs gave a talk at the IIMEC8 conference in 2013 and admitted GPs knew very little of ME. Professor Edwards said ME was a bigger problem than rheumatoid arthritis. Epidemiology in general was lacking and current service provision was poor. The direction of ME research has not been founded in good science and the Norwegian phase III rituximab trial results will guide the future. The psychiatrists do not understand the problem and that is a BIG problem. The PACE trial is a text book case how not to do a trial. In Practical terms: we need physician led services (very few of which currently exist) which provide help and continued surveillance. ME is an identifiable problem due to the characteristic of post exertional malaise (PEM). Surveillance is needed as other diseases such as lymphoma can be hidden in that cohort. Major change has happened in USA, but not in the UK. Dr Radford asked what we wanted to ask the CMO. The following points were stated -  Genuinely appreciate the size of the ME problem  Maintain consultant led services  Appreciate new research  Appreciate current services have been hijacked by bogus science and patients find that dispiriting and dangerous NICE was briefly discussed and a decision whether the guideline will be reviewed should be made by the summer of 2017. Dr Radford said that it is important there is new Page 38 of 82 Journal of IiMER research that they can look at otherwise the guideline remains in a vacuum. The current recommendation of GET was brought up as harmful and putting children in danger. The severely ill need information and support. Professor Edwards mentioned MS patients get 6 monthly neurology appointments but ME patients get nothing. Problems with FITNET were mentioned and Dr Radford was aware of this and stated that FITNET was being reviewed. Dr Gibson said research is moving toward finding biomarkers. Metabolomics was proving promising as presented at the Invest in ME Research international conference. The approach has been too simplistic in the past. Dr Radford mentioned she is involved in an alliance of rare diseases and that there are hundreds of diseases in the same situation as ME. The charity said these rare diseases are recognised and patients are not dismissed and stigmatised by the establishment the way ME patients are. ME patients’ healthcare complaints, unrelated to ME, are often ignored and dismissed due to the patient’s ME label. The importance of accurate diagnosis with careful history taking was mentioned as endocrine disorders are often misdiagnosed as ME. Actions Dr Radford finished the meeting by summing up action points Highlight emerging research (relevant for NICE guidelines) Mention IiMER colloquium/conference to people of influence Agree that a new meeting arranged by the charity will take place later in the year when the Norwegian rituximab trial results would be known by the team involved. IiMER Summary Did we expect more from the visit with the CMO? Of course! Our aim is not to have just a cosy chat and keep the status quo. Action is required. As we stated before ME is a UK/worldwide problem - we did expect (and request) that all UK CMOs attend. But we have the CMO's attention now, to some extent. We will not leave it alone. We have a follow-up meeting planned and we will ensure that the CMOs of UK do not remain in the dark about the seriousness or severity of the issues with this disease. PostScript: At the CMO’s suggestion the charity contacted Simon Stevens of NHS England and Sir Bruce Keogh. At the current point in time we have to state that the treatment of our request for a meeting by Sir Bruce has been not just disappointing but appallingly apathetic to the plight of people with ME and their families. References ► Articles on PACE Trial ► Articles on ME/CFS by Margaret Williams and Professor Malcolm Hooper www.investinme.org Page 39 of 82

Journal of IiMER Summary of developments following CMO’s report of 2002 The ME community were by and large delighted at the contents of this Chief Medical Officer’s Report in 2002, with its strong implicit acceptance of ME/CFS as a primarily organic/biological illness. The members of the psychiatric viewpoint were sufficiently disheartened by this to refuse to sign up to the report’s conclusions. In 2004 the RCPCH (Royal College of Paediatrics and Child Health) published paediatric guidelines which were very much in line with the CMO’s report. In 2007 NICE guidelines came out, and for all the criticism of these guidelines, regarding their overemphasis of suggested merits of CBT and GET, these also cemented the concept of ME/CFS as an organic illness and made it “official”. What went wrong post 2002? First and foremost, there was an abdication on the part of adult medicine of responsibility for this condition. This must have been partly due to the tendency to specialisation on the part of even DGH physicians. No specialty would accept responsibility. In particular, the neurologists were very reluctant to be involved despite the WHO’s having designated ME as a neurological disease. The main problem was that there was no “ology” for ME, neither was one created. This failure on the part of general medicine had a knock on effect on general practice. GP’s sensed the reluctance of physicians to accept referrals, thus making ME less of an official disease and more of a “controversial” condition. These factors mitigated against the positive recommendations of the above three reports/guidelines. www.investinme.org Secondly, and as a result of this abdication by adult medicine, when specialist ME centres were set up very few medical specialists came forward, and the only people eager to step into the vacuum were the psychiatrists. (Two exceptions to this rule were in Newcastle and Epsom and St Helier, where immunologists took the lead). There has been widespread patient dissatisfaction with most of these centres. Firstly, the patients seldom saw an actual doctor to at least receive an official medical diagnosis. Secondly, the only support on offer consisted of different forms of CBT and GET which patients found either ineffective or harmful depending on the variety of therapy offered. The very existence of these specialist centres, of course, removed the obligation of DGH physicians and paediatricians to actually see, diagnose, help and support ME patients. Thirdly and most importantly, the psychiatric lobby made a concerted counterattack to recover their lost ground. This was all the more effective for being indirect. Their strategy consisted of the following 1) Ensuring that they were well positioned to influence medical education, both undergraduate and postgraduate. Again, they were filling a vacuum left by organic medicine. The two major medical textbooks (The Oxford textbook of Medicine and Kumar and Clark) have chapters on ME/CFS written by psychiatrists and buried in the section on “Functional illness” or “Medically unexplained symptoms”) Of course, the term “ME” is gradually airbrushed out of the narrative and does not occur in the indexes. Likewise, the major paediatric text Forfar and Arneil had a section on CFS placed in the section Page 40 of 82 Journal of IiMER on Child Psychiatry where it is stated baldly “CFS is the commonest psychosomatic illness in adolescence” 2) Use of the term “Biopsychosocial approach” as a further means of muddying the waters. (No one can object to the concept of a “biopsychosocial approach” in theory, as it is just another word for an holistic approach to any patient. However, the psychiatric lobby tend to use it excessively in their approach to ME/CFS, and then seem to forget the “bio” component! 3) Monopolising research and funding for ME/CFS for their own psychiatric agenda. Enormous sums have been involved and large research empires have been created. This all centres round CBT and GET, which have recently been called into question with major criticisms of the PACE trial. Again this has all happened because of the dearth of alternative proposals from those wishing to do research aimed at biological factors. (we should note that this, in turn, has been caused by the total lack of funding given to those biomedical research proposals which have been made – thus influencing attitudes in academia) 4) As already mentioned, the specialist centres are largely run by psychiatrists and psychologists. All this activity is carried on as if the CMO’s Final anecdote A GP phones an ME helpline for advice. He says “ I’m really worried I have developed ME”. Adviser clucks sympathetically. GP “That’s not the main problem – it’s just that I don’t know what to say to my colleagues” Further sympathetic cluck.. “You see, it has always been a policy of our practice to treat patients with ME with unremitting hostility, ridicule and rejection....So I can’t face telling my colleagues. I think I will just tell them I am suffering with depression ....”! report and NICE Guidelines did not exist, and as if there was not a growing body of evidence for biological causation of ME/CFS. Regarding the patient community, the psychiatric group steadfastly avert their gaze from the large number of severely affected patients, none of whom have responded to CBT or GET The current state of affairs -  One still hears GPs saying “we don’t believe in ME in this practice”  Adult patients have difficulty obtaining an official diagnosis of ME/CFS, and this can lead to them being deprived of benefits  ME/CFS has effectively been downgraded from being an official medical condition to one that is unofficial and “controversial”  There are a large number of severely affected adult patients and young people who are being neglected by the profession. Both GPs and consultants frequently refuse to do home visits on patients who are too unwell to attend surgery/outpatients.  Most distressingly, a significant number of families of children with ME/CFS are being subjected to “Abuse by professionals” (see attached paper)  Virtually no doctors are coming forward to establish an “ology” for ME www.investinme.org Page 41 of 82

THE PACE TRIAL THE PACE Trial has been frequently discussed in articles on the Invest in ME Research website and on the charity’s social media since the first paper was published by Lancet in 2011. [1] The PACE Trial has been shown to be flawed and a colossal waste of scarce public funding which should have gone to funding biomedical research which, by now, may well have been leading to a breakthrough in treating this disease. Recently the results from this trial have been thoroughly analysed and destroyed by a series of articles published in Professor Vincent Racaniello’s (Columbia University, USA) Virology blog by US journalist David Tuller. [2] Once these reviews began to create huge interest over the internet then the usual typical orchestrated media reaction appeared. As always happens the establishment media trot out their normal array of buffoons and denialists – spreading more oil on the fire by linking ME patients with militants and those who see stigma in mental health – with no real evidence to support either accusation and demonstrating a profound ignorance of the disease and of ME patients [3]. But then the establishment view is to see any valid criticism against false science as a threat - and their only method of response is to denigrate those who are suffering the most. Despite an orchestrated attempt to maintain the pretence that anything valid was produced by this research it must surely be plain for all to see, including a great many more academics and unbiased opinion, that the PACE Trial is now synonymous with farce, bias and null field research. www.investinme.org On October 27th the Information Commisioner’s Office (ICO) ruled in favour of a complainant that had requested raw data from the PACE trial to be made publicly available by the QMUL. [4]. In attempting to thwart attempts via FOI to get PACE Trial data released QMUL spent, in one month, over twice as much money as patients raised in three years of fundraising for IiMER’s biomedical research foundation project. As our advisor Emeritus Professor Jonathan Edwards from UCL has written - "If scientific interpretation is poor it deserves no protection. If it is good it needs none." The MRC policy is unequivocal on this – as pointed out by James Coyne PhD [Why the scientific community needs the PACE trial data to be released Posted November 11, 2015] [5] The UK Medical Research Council (MRC) 2011 policy on data sharing and preservation has endorsed principles laid out by the Research Councils UK including "Publicly funded research data are a public good, produced in the public interest, which should be made openly available with as few restrictions as possible in a timely and responsible manner. To enable research data to be discoverable and effectively re-used by others, sufficient metadata should be recorded and made openly available to enable other researchers to understand the research and re-use potential of the data. Published results should always include information on how to access the supporting data." -UK Medical Research Council (MRC) 2011 policy on Page 42 of 82 data sharing and preservation ber%202015.pdf So it is even more incongruous that, in all of the recent discussions, the MRC and other funders of this trial were so silent regarding this clear breach of guidance, this utter waste of money, this total waste of years of opportunity for good research into ME? Although it does not surprise us the silence is, nevertheless, indicative of an establishment organisation whose policy toward ME research is being led by those who do not best serve the interests of patients. Retraction of the PACE trial paper and release of the raw data for other scientists to review would no doubt mean that the whole mess around the PACE trial would have consequence elsewhere - as it is not just about one paper but the influence that it has had on health policies across the world. It would, however, send a strong message that misleading research is not tolerated nor should it be used as a means to bolster a universities’ Research Excellence Framework (REF) as has been the case now. The seriousness of the way in which this whole research has been conducted, and the consequences still remaining as referenced research, requires that the PACE Trial paper itself has to be retracted. Retracting the whole paper will send a message that poor quality research, especially when it is designed to influence healthcare policy, cannot be allowed. The Lancet, which fast-tracked the first of the PACE trial papers in 2011, really ought to have favoured patients. The editor of the Lancet failed even to respond to Invest in ME Research’s letters regarding the PACE trial http://www.investinme.org/Documents/Lancet/Lette r%20to%20Editor%20of%20the%20Lancet%20Novem www.investinme.org In this day and age it is unacceptable that research performed with public funding can be allowed to be controlled by anyone who is not transparent and open in their treatment of data related to the research. If raw data from the trial shows that the public has been misled even more than so far identified then there should be a public inquiry The MRC invests in research on behalf of the UK tax payer. The taxpayer has been ill-served by the PACE Trial. The MRC should therefore examine the possibility of having the funds for the PACE Trial returned in part or in full to the public – and from there to be allocated to biomedical research into ME. It must be considered whether the Principal Investigators of the PACE Trial be barred from receiving any further public funding for future research into ME. The MRC need to review the management of this trial and procedures for deciding how funding for research into ME is decided to be allocated. The refereeing system for reviewing research applications for ME needs to be overhauled and made transparent. Those in the MRC who have been responsible for research into ME over the last eleven years must, if still in positions of influence with regard to ME research, be replaced. The MRC policies have been a shambles and valuable years of research possibilities have been wasted - along with a monumental loss of scarce public funding. Conflicts of interest of those in the MRC who have any influence on ME research need to be declared and examined. Page 43 of 82

Journal of IiMER Consideration ought to be made for a government inquiry, or parliamentary committee to scrutinise the conduct of the MRC with regards to its policies, research grant applications and grants for ME made over the last 13 years since the CMO’s report was made. We are sure none of this will happen. The establishment looks after its own. But it seems impossible to see how, after the way the MRC has operated over the last ten years, ME patients or carers or ME patient groups or ME charities could possibly have any faith in an organisation such as this unless it is reformed. We fail to see how any healthcare professional or researcher can have faith in the Lancet until the PACE Trial is recognised for the farce that it has become. Professor Jonathan Edwards wrote the following “The PACE trial of cognitive behavioural therapy and graded exercise therapy for chronic fatigue syndrome/myalgic encephalomyelitis has raised serious questions about research methodology. An editorial article by Geraghty gives a fair account of the problems involved, if anything understating the case. The response by White et al. fails to address the key design flaw, of an unblinded study with subjective outcome measures, apparently demonstrating a lack of understanding of basic trial design requirements. The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed.” http://journals.sagepub.com/doi/full/10.1177/1 359105317700886 References White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, et al. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 377: 823–836. doi: 10.1016/s01406736(11)60096-2 http://www.virology.ws/2015/10/21/trial-by-error-i/ http://www.virology.ws/2015/10/22/trial-by-error-ii/ http://www.virology.ws/2015/10/23/trial-by-error-iii/ http://www.virology.ws/2015/10/30/pace-trialinvestigators-respond-to-david-tuller/ http://www.virology.ws/2015/10/30/david-tullerresponds-to-the-pace-investigators/ http://www.virology.ws/2015/11/09/trial-by-errorcontinued-why-has-the-pace-studys-sister-trial-beendisappeared-and-forgotten/ http://www.telegraph.co.uk/news/health/11959193/C hronic-Fatigue-Syndrome-sufferers-can-overcomesymptoms-of-ME-with-positive-thinking-andexercise.html https://ico.org.uk/media/action-weve-taken/decisionnotices/2015/1560081/fs_50565190.pdf Professor James Coyne http://blogs.plos.org/mindthebrain/2015/10/29/unint erpretable-fatalflaws-in-pace-chronic-fatiguesyndrome-follow-up-study/http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/18135 http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/41185 http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/17492 http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/23887 “An open letter to Dr. Richard Horton and The Lancet"http://www.virology.ws/2015/11/13/an-openletter-to-dr-richard-horton-and-the-lancet www.investinme.org Page 44 of 82 Journal of IiMER An open letter to Psychological Medicine about “recovery” and the PACE trial A letter, for which Invest in ME Research helped in obtaining signatures from some of the top scientists, was recently published and sent to Psychological Medicine . The letter included signatures from eminent scientists and researchers from institutions including the following - HHV-6 Foundation University of California DePaul University Cornell University National Cancer Institute USA Georgetown University Bateman Horne Center EVMED Research University of Medicine and Dentistry of New Jersey University of Manchester George Mason University University of Sunderland Columbia University University of Utah University of British Columbia Stanford University Tulane University School of Medicine University of East London Harvard Medical School Ithaca College New York Nova Southeastern University Hunter-Hopkins Center University of Kent Stichting Cardiozorg Northwestern University Pritzker School of Law Linköping University University of Oslo University of Minnesota National Centre for Neuroimmunology and Emerging Diseases George Mason University Solve ME/CFS Initiative Tufts University WorkWell Foundation University of Calgary University of Cumbria Catholic University of Valencia School of Medicine Rutgers Robert Wood Johnson Medical School Soerabaja Research Center London School of Hygiene & Tropical Medicine University of Birmingham Victoria University of Wellington Also signing were organisations from around the world such as Invest in ME Research and our partners in the European ME Alliance, Open Medicine Institute. Also from UK individuals such as - Simon Duffy (Director Centre for Welfare Reform), Jonathan C.W. Edwards, MD (Emeritus Professor of Medicine University College London) and Ian Gibson, PhD (Former Member of Parliament for Norwich North Former Dean, School of Biological Sciences University of East Anglia). The letter (shown on the following page) demonstrates the gathering weight of scientific opinion exposing the PACE Trial. Stanford University School of Medicine Rutgers New Jersey Medical School Duke University School of Medicine Nevada Center for Biomedical Research from “MEDICINE and ME” http://www.investinme.org/IIME-Cartoons-2013-01.shtml www.investinme.org Page 45 of 82

Journal of IiMER 13 MARCH 2017 Sir Robin Murray and Dr. Kenneth Kendler Psychological Medicine Cambridge University Press University Printing House Shaftesbury Road Cambridge CB2 8BS UK Dear Sir Robin Murray and Dr. Kendler: In 2013, Psychological Medicine published an article called “Recovery from chronic fatigue syndrome after treatments given in the PACE trial.” [1] In the paper, White et al. reported that graded exercise therapy (GET) and cognitive behavioural therapy (CBT) each led to recovery in 22% of patients, compared with only 7% in a comparison group. The two treatments, they concluded, offered patients “the best chance of recovery.” PACE was the largest clinical trial ever conducted for chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME/CFS), with the first results published in The Lancet in 2011. [2] It was an open-label study with subjective primary outcomes, a design that requires strict vigilance to prevent the possibility of bias. Yet PACE suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings. [3] Despite these flaws, White et al.’s claims of recovery in Psychological Medicine have greatly impacted treatment, research, and public attitudes towards ME/CFS. According to the protocol for the PACE trial, participants needed to meet specific benchmarks on four different measures in order to be defined as having achieved “recovery.”[4] But in Psychological Medicine, White et al. significantly relaxed each of the four required outcomes, making “recovery” far easier to achieve. No PACE oversight committees appear to have approved the redefinition of recovery; at least, no such approvals were mentioned. White et al. did not publish the results they would have gotten using the original protocol approach, nor did they include sensitivity analyses, the standard statistical method for assessing the impact of such changes. Patients, advocates and some scientists quickly pointed out these and other problems. In October of 2015, Virology Blog published an investigation of PACE, by David Tuller of the University of California, Berkeley, that confirmed the trial’s methodological lapses.[5] Since then, more than 12,000 patients and supporters have signed a petition calling for Psychological Medicine to retract the questionable recovery claims. Yet the journal has taken no steps to address the issues. Last summer, Queen Mary University of London released anonymized PACE trial data under a tribunal order arising from a patient’s freedom-of-information request. In December, an www.investinme.org Page 46 of 82 Journal of IiMER independent research group used that newly released data to calculate the recovery results per the original methodology outlined in the protocol.[6] This reanalysis documented what was already clear: that the claims of recovery could not be taken at face value. In the reanalysis, which appeared in the journal Fatigue: Biomedicine, Health & Behavior, Wilshire et al. reported that the PACE protocol’s definition of “recovery” yielded recovery rates of 7 % or less for all arms of the trial. Moreover, in contrast to the findings reported in Psychological Medicine, the PACE interventions offered no statistically significant benefits. In conclusion, noted Wilshire et al., “the claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.” In short, the PACE trial had null results for recovery, according to the protocol definition selected by the authors themselves. Besides the inflated recovery results reported in Psychological Medicine, the study suffered from a host of other problems, including the following: *In a paradox, the revised recovery thresholds for physical function and fatigue–two of the four recovery measures–were so lax that patients could deteriorate during the trial and yet be counted as “recovered” on these outcomes. In fact, 13 % of participants met one or both of these recovery thresholds at baseline. White et al. did not disclose these salient facts in Psychological Medicine. We know of no other studies in the clinical trial literature in which recovery thresholds for an indicator actually represented worse health status than the entry thresholds for serious disability on the same indicator. *During the trial, the authors published a newsletter for participants that included glowing testimonials from earlier participants about their positive outcomes in the trial.[7] An article in the same newsletter reported that a national clinical guidelines committee had already recommended CBT and GET as effective; the newsletter article did not mention adaptive pacing therapy, an intervention developed specifically for the PACE trial. The participant testimonials and the newsletter article could have biased the responses of an unknown number of the two hundred or more people still undergoing assessments—about a third of the total sample. *The PACE protocol included a promise that the investigators would inform prospective participants of “any possible conflicts of interest.” Key PACE investigators have had longstanding relationships with major insurance companies, advising them on how to handle disability claims related to ME/CFS. However, the trial’s consent forms did not mention these self-evident conflicts of interest. It is irrelevant that insurance companies were not directly involved in the trial and insufficient that the investigators disclosed these links in their published research. Given this serious omission, the consent obtained from the 641 trial participants is of questionable legitimacy. Such flaws are unacceptable in published research; they cannot be defended or explained away. The PACE investigators have repeatedly tried to address these concerns. Yet www.investinme.org Page 47 of 82

Journal of IiMER their efforts to date—in journal correspondence, news articles, blog posts, and most recently in their response to Wilshire et al. in Fatigue[8]—have been incomplete and unconvincing. The PACE trial compounded these errors by using a case definition for the illness that required only one symptom–six months of disabling, unexplained fatigue. A 2015 report from the U.S. National Institutes of Health recommended abandoning this single-symptom approach for identifying patients.[9] The NIH report concluded that this broad case definition generated heterogeneous samples of people with a variety of fatiguing illnesses, and that using it to study ME/CFS could “impair progress and cause harm.” PACE included sub-group analyses of two alternate and more specific case definitions, but these case definitions were modified in ways that could have impacted the results. Moreover, an unknown number of prospective participants might have met these alternate criteria but been excluded from the study by the initial screening. To protect patients from ineffective and possibly harmful treatments, White et al.’s recovery claims cannot stand in the literature. Therefore, we are asking Psychological Medicine to retract the paper immediately. Patients and clinicians deserve and expect accurate and unbiased information on which to base their treatment decisions. We urge you to take action without further delay. Sincerely, [1] White PD, Goldsmith K, Johnson AL, et al. 2013. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227-2235. [2] White PD, Goldsmith KA, Johnson AL, et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823–836 [3] Racaniello V. 2016. An open letter to The Lancet, again. Virology Blog, 10 Feb. Available at: http://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on 2/24/17). [4] White PD, Sharpe MC, Chalder T, et al. 2007. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 7: 6. [5] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. Virology Blog, 21-23 Oct. Available at: http://www.virology.ws/2015/10/21/trial-by-errori/ (accessed on 2/24/17) [6] Wilshire C, Kindlon T, Matthees A, McGrath S. 2016. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical www.investinme.org Page 48 of 82 Journal of IiMER commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior; published online 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on 2/24/17) [7] PACE Participants Newsletter. December 2008. Issue 3. Available at: http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter3.pdf (accessed on 2/24/17). [8] Sharpe M, Chalder T, Johnson AL, et al. 2017. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior; published online 15 Feb. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1288629 (accessed on 2/24/17). [9] Green CR, Cowan P, Elk R. 2015. National Institutes of Health Pathways to Prevention Workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine 162: 860-865. IiMER Conference DVDs The Invest in ME Research conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo. They contain all of the presentations from Invest in ME Research International ME/CFS Conferences (2006 – 2015). Also included in the DVD sets are interviews with ME presenters, news stories, round-table discussions or pre-conference dinner presentations. The Invest in ME Research conference DVDs have been sold in over 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.eu/IIMEC11.shtml#dvd or via emailing Invest in ME Research at mailto:info@investinme.org www.investinme.org Page 49 of 82

Journal of IiMER MARGARET WILLIAMS REPOSITORY www.margaretwilliams.me What we are witnessing now is the gradual destruction of the flawed and negligent perception of ME, which vested interests have created for the last decades in UK and elsewhere and which has so pervasively influenced government departments, academia, medical establishments, the media and, by eventual lemming-like acceptance, the public. The flagship of the those who have promoted (and benefited) from the biopsychosocial view of ME for so long has begun to sink, run aground on the rocks of reason, science and an intractable dedication from some patient organisations and patient advocates. The wreck that is PACE is now dragging down those pillars of the establishment that have supported it. For so many years when establishment organisations and individuals have been following a false path of research and treatments for ME, supported by fickle media editors and buffoon, journalist hacks, there was a constant source of information and analysis about ME - a voice of science, reason, and factual evidence that gave the lie to the biopsychosocialists. This came from Margaret Williams - a severely affected, but articulate patient who saw through the falsehood of the myths perpetrated by vested interests and produced countless articles exposing the corrupt environment maintained by the establishment toward ME. Invest in ME Research has featured many of Margaret Williams' articles during its 11 years as a charity. Now all of her articles have been indexed and made available online at this URL www.margaretwilliams.me Not only is this compendium of articles and information fully indexed but the website also contains a search button enabling one to search on any topic, organisation or individual very easily. This is a resource that will be of historical significance for academics - and a huge testament to one of the great ME advocates. You don’t have to be go crazy to raise funds for Invest in ME Research – simple things such as a North Pole marathon, Everest Base Camp, 28 EU marathons …… Look at current and past fundraising events http://www.investinme.org/fundraising.shtml http://www.investinme.org/prev-fundraising.shtml EUROPEAN ME ALLIANCE NEWS Summary Report Breakfast Colloquium European Parliament – Brussels March 7th 2017 The European ME Alliance recently organised a meeting in the European Parliament to discuss the situation with regard to ME in Europe. This event followed meetings for clinicians on the day before organised by EMEA-Belgium member [ME Association]. The intent with the meeting – labelled Breakfast in Brussels – was to make European MEPs aware of the lack of services for people with ME, the negligible amount of proper research being carried out into the disease across Europe, and the lack of funding given to biomedical research into the disease and the waste which is being given to flawed psychiatric theories which have caused harm to patients across the continent. With the help of MEP, Mrs. Helga Stevens and her staff the Belgian ME Association coordinated the event that consisted of a number of selected speakers addressing a gathering of MEPs. The speakers were Dr. Ian Gibson, Dr. Olli Polo, Dr. Nigel Speight, Dr. Louise Brinth and CRPD Expert Dr. László Lovászy – who shared their knowledge and expertise with the audience. The following are extemporaneous notes compiled by EMEA Belgium during the meeting. www.investinme.org Page 51 of 82

Journal of IiMER Welcome by host MEP Mrs. Helga Stevens MEP Mrs. Helga Stevens thanked everyone for attending, and thanked EMEA for letting her host this event and for organising this important Breakfast Colloquium at the European Parliament. She started by saying that Myalgic Encephalomyelitis (ME) is a very serious, disabling and chronic organic disorder classified by the World Health Organisation as a distinct neurological disorder since 1969 and that ME is often denigrated end denied by doctors, policymakers and the general public. This is why the classification as a neurological disease is an important step towards broader official recognition by the medical and scientific establishment! Personally, she found it very interesting not to look at the disease from a medical point of view but also in terms of it potentially being recognised and understood as a disability and from a social model of disability point of view whereby it is the environment that is disabling rather than victimising the individual him/herself. Mrs. Stevens looked forward to learning more about ME, in particular about children with ME and what good practice examples exist out there. She wished EMEA all the best for the event. Politicians have a predisposition to try and save money and in this area definitions are extremely important in determining whether patients get benefits or not. Putting money into biomedical research, Dr. Gibson said, is much more expensive - even though it might be more productive in the long run and save a lot of money. In the short term, it is about trying to get definitions. Going over to therapy Dr. Gibson touched upon a paper called “The PACE Trial” which is been looked at now by some very serious academics in the United Kingdom and has been discredited. When asking questions in the House of Commons they did not receive any credible answers. On the other hand there was huge support for the MP who asked these very pertinent questions about these decisions, why they were made and about disability and benefits. He became a hero in the ME community. The economic consequences of not being www.investinme.org Page 52 of 82 Dr. Ian Gibson – European Issues Dr. Ian Gibson talked about public disability problems and how those are supported, not just in the Member States but across the European Parliament as well. He referred to Professor Tom Shakespeare (at University of East Anglia) who shows that much of the determination of policy on illness depends on trying to stop people with illnesses getting benefits. Rather than judging whether a person has a practical chance of being able to find a job the new capability assessment investigates whether the person has the ability, in theory, to do any form of work at all. Most likely the eligibility criteria can substantially make it more difficult for people to access benefits. Journal of IiMER diagnosed at an early stage are increasing by the minute, but the research may bring about something in that field. We are not there yet, but we need to support the research that is going on. The Americans have calculated that across the world hundreds of billions of pounds/euro’s in benefits are not being given to people who are not being able to work. Dr Ian Gibson said there are two things for which the UN in developing countries could be supportive. Firstly, the WHO should be able to organise activities to support ME and its patients. Because there is money there and they have worked on diagnosis, treatment and care before e.g. in polio. Secondly, they have defined ME as a neurological problem but nothing is being done about it. So some of us are working very hard to change that. He also mentioned the WHO ICDclassification is still being looked at. The main issue for politicians to consider is the millions of people that have been classified with ME and remember that their lives are being ruined together with that of their families. However, to the question of how many people we are talking about, there is no answer because of lack of any registered data. So we do not really know how many patients have ME but the estimate is about 25 million patients around the world. ME is not recognised or being taken seriously. However, scientific research is finally going ahead and showing progress. It is mostly funded by private money, charities and other organisations and we have to find ways to increase this. The Americans are joining in, and are coming to the Invest in ME Research conference in London, which takes place for the 12th year now in June. At the conference patients and scientist are there together and it is amazing to see them talking to each other because doctors do not like talking to patients because of the difficult questions that are asked. It is also great to show people there is progress. The Norwegians are on the way to making a change for the patients. Conclusion www.investinme.org Many people out there need your support, and benefit from the exchange of different countries and that is something too to bear in mind when one thinks about ME. It is not just the illness itself but also the effect it has on millions of peoples’ lives and the realisation that nothing has changed over the last ten years. Nevertheless, it is starting to change now. Dr. Olli Polo – MD’s View of ME How patients with ME are seen by doctors without any particular knowledge of the disease? Myalgic Encephalomyelitis is a very particular condition and the normal concepts that one can apply to many other diseases cannot be applied here. This is clearly due to the misunderstanding about this disease. Last week one of his patients said: “Going to the doctor, is like going to the court. The doctor is the judge and the patient is guilty.” Dr. Olli Polo wondered if this was true, but there are stories that corroborate this based on the way doctors with a lack of knowledge of ME treat patients. The behaviour of doctors towards ME patients is characterised by loss of contact with reality, altered values and social interaction impairment. Doctors say that their patients are somaticizing their mental symptoms but now we actually know that the doctor is psychiatrizing the patient’s traumatic symptoms. Normally, doctors run the research but, in this case, the patients ask for research and recognition for ME as a real disease. Patients are Page 53 of 82

Journal of IiMER then confronted with the resistance of the medical society to get into this. Investment in medical research is decreasing overall and we are also producing more doctors with differing standard levels of knowledge because they no longer have a scientific background. We have a few written treatment guidelines that should set the minimum level of standard care in primary care and regional hospitals. If patients cannot be treated according to the guidelines then they are referred to the university hospitals. However, the reality today is that, after twenty years, public health care is only provided and available treatment at the university hospitals. In other words, one can only receive evidence based diagnostics and treatments, so if a treatment works but is not in the guidelines one is not entitled to receive this treatment. This makes doctors afraid of regulatory actions (e.g. we had an eleven year old, paralysed girl, who had to be taken to Holland – Rotterdam to get Immunoglobulin-IV treatment.). There is actually written evidence about the use of this therapy in ME but in Finland no one dares to give it or fear of regulatory actions. Doctors who are interested in studying or treating ME/CFS experience the same faith as patients. The doctors lose their credibility, their jobs and jeopardised by the medical establishment. The Finnish health professionals state that the purpose of a health professional is to maintain health, prolong health, heal sick patients and alleviate their suffering. Also in his professional activity he must apply commonly accepted, experience-based, medically acceptable procedures, before giving any medication to a patient which must be continuously updated. Therefore, a research-orientated doctor/scientist may arrive in a contradictory situation, where commonly accepted procedures are more about about promoting health than alleviating suffering of the patient. So what to do? For instance, if an ME patient is misdiagnosed with depression then, unfortunately, they have little expectation other than the increase of exercise, despite the www.investinme.org worsening of symptoms, just in order to get social benefits. Patients who are malnutritioned are proposed Graded Exercise Therapy to improve their fitness. If a doctor fails to alleviate suffering, or fails to use experience-based accepted procedures and medication then the doctor will be subject to regulatory actions. This is also applied by the Ethical Review Board (ERB). Evidence-based medicine has gone somehow too far. There is no evidence-based treatments when treatments are being used for the first time. So they are experimental treatments, and the possibility to carry out these treatments calls for innovations as they are advancing science very much. Nowadays we speak a lot about personal medicine versus quality medicine. In USA some doctors have been sued for their innovative and experimental treatments. This could happen in Europe. A physician and surgeon should not be subject to disciplinary action solely on the basis that the advice or the treatment he/she rendered to the patient is an alternative or complementary medicine, as long as that treatment or advice meets all the following requirements:  There is informed consent  The patient knows he/she is not getting evidence-based standard medical care  they have been fully informed of what the conventional treatments available are  they have been informed of any side effects that may still be allowed but not cause delay in traditional treatments or cause death or bodily injury Conclusion The medical community is getting more and more regulated which is understandable if the educational level of doctors is decreasing. However, at the same time, we should be careful not to throw out the baby with the bathwater for those who are innovative and practise medicine Page 54 of 82 Journal of IiMER with true ethical principles, which they have learned in medical school, in order to help the patients using all their means. If we are intelligent and innovative, why do we not use our qualities just to try to help the patient? was the abuse that families of children with ME suffer as a result of doctors not protecting them properly. Over 30 years he had been involved with 40 families who had been subject to child protection proceedings reaching case conference level, sometimes court proceedings, to remove children. Fortunately, he has been successful in 38 cases but lost one in England and one in Norway. Each case was a tragedy. Dr. Nigel Speight Children with ME Dr. Nigel Speight thanked the Parliamentarians for the opportunity to speak at the European Parliament. A lot has already been said on the basic issue about ME being an organic disease and for him one of the beauties of working with children is they highlight this fact. Dr. Speight once told an adult neurologist that he had an interest in paediatric ME. The neurologist replied: “Oh, I didn’t realise that it occurred in children, maybe I should think again.” In other words the neurologist had the common view that all adults with ME were just depressive losers but if children can get ME, that would make him think again. Dr. Speight says his experience with working with children and seeing happy, healthy, cheerful, sociable children struck down with ME for him is the biggest proof one can have of ME being fundamentally an organic process. He actually accumulated over 600 cases of ME over the last 30 years mainly within the United Kingdom but has also been to Ireland, Norway and Germany. Dr. Nigel Speight briefly shared some of his clinical experience but what he really wanted to talk about www.investinme.org Dr. Speight showed some slides of a follow up study showing progress over time of 49 patients, of which 15 recovered over two to five years. Seven of them who were unlucky and were getting worse, and a large number who were going up and down. ME is a very unpredictable condition, with wide fluctuations in severity. Overall, there is grounds for cautious optimism and the prognoses is probably slightly better in children than in adults. Apart from what we can learn from the fact that children can get ME, he thinks the severe cases of ME teach us something else. These are the severe cases that have not responded to Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) so those treatments cannot be that effective. Dr. Speight has seen about seven of these, they are bed-ridden, have very severe unpleasant symptoms, have severe sleep problems and five of them are tube fed because they are to tiered to chew and swallow. Dr. Polo mentioned immunoglobulin, he gave this to all the severe cases and they did remarkably well. According to him immunoglobulin as well as Rituximab deserve re-examination for severe cases. Many paediatricians can see ME and when they see their first case, they panic. Dr. Speight talked about a girl who had been handed to him by the court. The girl had been subjected to three months of vigorous physiotherapy and had severely worsened. The court eventually asked to rehabilitate her before going home. She was lying in a darkened room, catheterised and in severe pain. If any doctors are in charge of a severe case, he advises them not to panic. A doctor always has a Page 55 of 82

Journal of IiMER need to treat and investigate and actually trying too hard and over-investigating and treating with things that do not work, is the worst thing you can do for these patients. Immunoglobulins is one possibility, antibiotic therapy just in case there is an atypical infection such as Lyme disease, otherwise they just deserve tender love and care for their palliative symptoms. The last case was a German girl, the worst he had ever seen, treated the same way. She was in hospital, having severe pain, was tube fed and the mother was accused of arguing with the doctors about the treatment being provided. The girl was subjected to an activity regime, where she was put in a wheelchair every day. Dragged out of bed, put in the wheelchair - head strapped to the wheelchair because it kept falling. Shoved around the hospital, she was then exposed to a teacher, then exposed to a psychologist, and then exposed to a physiotherapist. She suffered this treatment month after month after month. Dr. Speight asked the doctor in charge: “Have you got her informed consent for this treatment?” and he said no! Dr Speight asked: “Do you have an assessment of her competence to give consent to this treatment?” Again the answer was no! It was not ethical, but they had a court order and the mother had no rights. Luckily, a nice female judge accepted my evidence and reversed the care order and released the girl from the hospital, restored the mother’s parental rights and allowed her to take her daughter home. Only two months after that ordeal you can see the girl returning, she is a smiling girl with glistening eyes, nothing like the girl from the hospital. She has been given no magical treatment, just the respect of her autonomy and human right and the company of people who believe in her. that usually includes subjective evaluations of both positive and negative aspects of life ”. For me something crucial was missing in this sentence namely that “Quality of life” also depends on the balance between these positive and negative aspects of your life. Starting from this perspective, I looked at how Myalgic Encephalomyelitis or ME affects my life. ME, completely changed my life. I went from an active working mother and wife, with two children - six and nine years old at the time- to a debilitated spouse and mum who could barely make it from her bed to the sofa and back. People around me had no idea what was happening to me and reacted with disbelieve and ignorance. My employer kept asking me to work from home, up to the point when I literally felt my brain sparking. My brother said: “If you were working for me, you would’ve been sacked a long time ago.” and my mother kept repeating I had to do more, she said I was lazy. I ended up losing all my friends, hardly saw any relatives and spend my days between four walls in the company of my husband and children. Nancy Van Hoylandt – Quality of life As an ME patient (and a patient representative) I asked myself what is ‘quality of life’? Looking for a definition I found this on the WHO website: “Quality of life is a broad multidimensional concept www.investinme.org After a few months my GP sent me to a psychiatrist. The seed of depression was planted. The psychiatrist recommended psychotherapy in a day care facility, so I went. This approach did not seem to work and after six months I was told they could not help me, blaming me for the failure of the therapy. By that time I was a complete wreck and needed more therapy to undo the damage from the first round of psychotherapy. My second psychiatrist would eventually apologise for asking too much, too soon, too fast, explaining to me there was more to my condition than meets the eye. I also followed months of hydrotherapy and Page 56 of 82 Journal of IiMER physiotherapy, the result being none other than getting worse. Falling asleep in the car after therapy was no exception; I was exhausted and needed rest. You do not need to worry, I was not the driver! Once I rode my bike and was not able to lift my legs from the pedals approaching a red light. I had fallen down with the bike before, for the same reason. The light turned green at the last minute. I do not want to know what would have happened otherwise. After the red light incident I stopped riding my bike because it became too dangerous. After eight years I was diagnosed. Unfortunately, this did not mean getting access to appropriate care, treatment, necessary benefits, etc. The lack of suitable care and available treatment leaves much room for a lot of question rather than answers. And the commonly used name, chronic fatigue syndrome, maintains the enormous burden of stigma attached Myalgic Encephalomyelitis and the psychiatric opinion of it. Having ME effects every part of my daily life. It starts in the morning when I have to get out of bed, when it feels like I have been run over by a truck, to going to bed when I am not able to fall asleep right away and lie awake for hours. I feel it when I take a shower and I can hardly lift my arms to wash my hair. Or when I am too tired to stand under the shower and need a small stool to sit on or on days when it is really difficult and I ask one of my daughters to help me. On days when I do not have to leave the house I save energy by just walking around in my pyjama, taking no shower and not combing my hair. However, this is something people do not see when they see me. While getting dressed I use a chair, always! Because I cannot stand for a long time. When I stand up straight for a long time I get dizzy, nauseous, weak, everything gets black before my eyes and it feels like I am going to faint. This is why I usually sit, hang or do something in between. During the day the pain varies according to the things I do. When I do too much physical or mental www.investinme.org ‘work’ the pain is worse and I may get a fever. When I go to sleep the following nights, it feels like I have a very sever flu and my whole body aches and shivers. Migraines are my constant companion as a result of stepping over my limits. But that limit can be a scent that is too strong, like my daughter’s perfume or a light that is too bright like the sun. I used to be better but after every severe migraine attack I never returned to my old level of functioning. My digestive problems get worse the more I get tired. The fact that my husband cooks is for two reasons. I cannot manage three pots and pans anymore, and when I do cook I am too tired to eat afterwards. The hardest symptom for me to deal with is the cognitive impairment. This makes me feel like I am losing my intellectual abilities. The work I do takes an enormous amount of time, I have trouble concentrating, organising my files, my orientation is all over the place, etc. Due to my disabilities I am hardly capable of doing housework. The tasks I do take weeks, and some things are just impossible to do. Like I said, my husband usually cooks, does the dishes, the ironing, some of the cleaning and sees to it that I get everywhere I need to be. But, due to financial difficulties, we are not able to afford the necessary help, such as cooking and cleaning, transportation, care, etc. Most of the supportive treatments and food supplements prescribed to me are not reimbursed. We are adjusting our home ourselves without reimbursed benefits. I have been put on retirement due to my illness but I do not have any benefits that come with being retired. ME also has consequences for my family, my husband and children. I cannot do the things I would like to do with my children because they are not physically possible. I once got angry with my husband because the bus stopped too far from the parking lot and I could not Page 57 of 82

Journal of IiMER walk that far anymore. But that was not his fault. I do not qualify for a disabled parking permit because my physical condition is too good. And my family cannot do what they want to do because they have to be quiet or need to do something they do not want to. Intimacy is also a problem in ME. Sometimes I joke about this and say: “I’m getting tired just thinking about it.” What people do not know is that there is truth in what I say, which causes marriages to fail and patients to get isolated. Overall, my ME is an invisible disease, people cannot see I am sick and I am usually not showing it. Even on bad days I keep hearing: “You look fine”. As an ME patient I have learned pretty quick to shut up and say I was fine no matter how I felt. On days when I stay at home, I am completely invisible. Like severe ME patients who are bedridden and housebound. Conclusion From my story you can gather that there are little positive aspects to having ME. However being a volunteer for the Belgian ME Association and the European ME Alliance has brought meaning to my life. Something that had disappeared since my retirement in 2007. I have watched my life go by because of ME. Not being able to participate in my own life and if I did/do, I pay the price. So I am here to raise awareness and advocate for a disease called ME that hinders people, who are disabled in various degrees included long-term physical, cognitive or sensory impairments, to participate fully and effectively in society on an equal basis with others. patients. We use diagnosis to get a shared reality. It is a common language between patients, medical professionals and the healthcare system. Patients with more unexplained symptoms, patients with many symptoms do not always have this luxury of a shared reality and a common language. They may not get a diagnosis, they may get many different diagnoses or they may get misdiagnosed. So patients with many unexplained symptoms, ME patients, they are to some degree very often invisible. They do not pop-up in our studies, when we do witness studies and they do not belong to a dedicated medical specialty. When you get a heart attack you go to a cardiologist, when you have ME or symptoms like ME you do not belong to a medical specialty which is a huge problem. ME has its own WHO ICD-10 diagnose-code G93.3 which puts it in the group of Neurological Disorders. It is a syndrome diagnosis, which means its diagnosis is built on the presence of symptoms and the typical ME symptoms that ME patients will tell you that they have. The symptoms also included in the different diagnostic criteria are, first and foremost, profound fatigue and fatigability, Post Exertional Malaise (PEM) and Post Exertional worsening of all their symptoms. All their symptoms get worse when they exert themselves too much. Dr. Louise Brinth – Challenges and care Dr. Louise Brinth is a medical doctor and said that medical professionals use diagnosis to sort/classify www.investinme.org We have many different names for this disorder and it is very difficult and almost impossible to ascertain to what degree these diagnostic entities overlap. The medical aetiology is very unclear. A lot Page 58 of 82 Journal of IiMER of very exiting research is going on at the moment and we are gathering a piece of the puzzle but we do not have a coherent medical hypothesis so far and we do not have a clear cut diagnostic biomarker for ME. We have very different diagnostic criteria - she thinks there are more than a hundred all together. So, all in all, you can see that this is quite a diagnostic mess. She has seen ME patients when she was asked to co-author the paper on quality of life in ME patients and it was first and foremost the work of Michael Hvidberg who should have all the credit for this and who sends his regards. He used a questionnaire, a standardised nondisease specific questionnaire, which is used to describe and value healthrelated quality of life in patients. It is called the EQ-5D-3L and it has five dimensions. It describes:  mobility  self-care  usual activities  pain and discomfort  anxiety/depression and each of these five dimensions can be valued in three levels of severity: Level 1: Level 3: indicating no problems whatsoever. signifying severe problems So, if you have a very good health, no problems, you will score: 1-1-1-1-1 If you are in the worst possible health condition, you will score: 3-3-3-3-3 We got these raw answers from the completed questionnaires, and then based on these each subject is given a single score. One number which is in a linear scale, from - 0.6 to 1- (1 is perfect health and - 0.6 is absolutely terrible health). And this funny scale anchored around zero which equals www.investinme.org death. So if you have a negative value, you have a health state that’s conceived worse than death. So we compare 103 Danish ME patients to the average population and we found in line with the others, that the typical ME patient is a woman, and found that the ME patients were significantly higher educated than the average population but they were not significantly more depressed than the average population. And this is actually a quite Page 59 of 82

Journal of IiMER important finding because when you hear about the symptoms of ME patients many will at a first glance think, oh maybe they are just depressed, they are a bit tired, a bit withdrawn from everything but these patients are NOT depressed! This is not depression, this is something completely different and the patients are not more depressed than the average population. We also found that ME patients are more disabled and socially marginalised than the average population, they have fewer relationships than the average population, the have a very high degree of unemployment (only 8% were employed), and more than half were disability pensioners, 12% reported being bedridden, more than half of them were unable to perform usual daily activities, in line with what Nancy told you about her own life, and 28% reported being in extreme pain or extreme discomfort. When you hear about the symptoms of ME, you may think these are common symptoms, trivial symptoms. It is a bit like a hangover. I also have these symptoms but this is not just being fatigued. This is not triviality, this is extremely ill, and seriously disabled people. Dr. Brinth told us how they transformed the completed questionnaire into one single score per patient and per subject. So they did that for the ME patients and they got this score of 0.47 and the same has been done for other patient groups in Denmark. From the results one can see that ME is the category of patients with the lowest score. They score lower and report a lower quality of life than any other condition. They have a lower quality of life than lung cancer patients, patients with stroke, diabetes, breast cancer, lung disease, …. What are the consequences?: Most patients never regain their pre-morbid level of health and functioning so often they learn to live with their symptoms but few of them regain premorbid level of functioning. ME is a massive burden, not only for the patients www.investinme.org And this problem is causing a serious controversy Page 60 of 82 but also for the caregivers, and also for all of us for society as such. And it is difficult to ascertain what the burden is for society because they are invisible, undiagnosed, late diagnosed, misdiagnosed. So we cannot count, do the maths or identify how much money this all costs and how much they are suffering. It is a massive problem. She said that patients often live outside society. In the beginning we may meet them, as medical professionals, as frustrated and angry patients because they are tossed around from specialty to specialty and seen by all sorts of different doctors without given any information or treatment. We find they live outside society because they give up on us, and they are even afraid of medical professionals because they are afraid of what will happen. Patients very often report that the feel they are met with scepticism and even hostility of care providers. Conclusion ME is a debilitating and often chronic disease and it is difficult to estimate – affecting maybe 1,000,000 EU citizens. The disease is very poorly understood and, unfortunately, we have several quite contradictory, explanatory models. Some doctors see an ME-like patient and think this is a functional disorder – that is a patient who converses psychological problems into physiological symptoms. Other doctors, other people see these people as patients with physiological severe immunological, mitochondrial, autonomic dysfunction. We do not have any convincing evidence-based treatments so what do we do with the treatment that makes sense in one of these explanatory models? It may seem very harmful for patients from another explanatory model. Graded Exercise Therapy (GET) makes perfectly good sense if you think these patients are young women converting psychological symptoms into physical symptoms, then it is a good thing to push them but if you think they are multi-system ill patients than you will harm them immensely. So it is a matter of should you challenge the patient or should you shield them? Journal of IiMER among medical professionals, and causing grief to patients and everybody else too which also is reported by Dr. Olli Polo. And it is very difficult to understand what this controversy is all about when you are no part of it. It is very bad! In 2015 the American Institute of Medicine (IOM) made a report on ME where they concluded many things based on a very thorough investigation - the main conclusion being that ME is a physiological and NOT a psychological disease. And, they concluded, we should all agree that ME patients need to be recognized, respected and treated. Unfortunately, many of the patients Dr. Brinth has met have not been recognized, or respected and they re not treated. So we need help from the politician, not just for money but we all need to work together to put ME on the agenda and we need to change the culture surrounding these disorders because now it is counterproductive. People are afraid to getting into this business, the patients are afraid of the medical professionals so we have a problem and it is a problem that should affect all of us because it affects many patients! We cannot afford to just let it be! speakers about the disease area and the activities. He touched upon three areas: The Convention itself, Cooperation and coordination in relation to the implementation of the convention, Issues of actively planning and implementation of NGOs The Convention The Convention is the first human rights treaty in the 21st century and became a very popular convention among the Member States Parties. More than 160 countries have joined the Convention. It is very important to know that NGOs themselves played a very important and active role when the Convention was adopted and prepared and that they still do when it comes the standards and the obligations of the Convention being met. In relation to this he highlighted the essential role of the experts when it comes to dialogue and consultations between State Parties and NGOs because the NGOs are the steer provider of very crucial and valuable information for experts and for the cost-active dialogue during the sessions of the Committee. He mentioned that all experts can be approached by NGOs and that they are open for information from them specifically about a given country’s implementations, procedures and feedbacks Dr. László Lovászy – Convention on Rights of Persons with Disabilities (CRPD) Dr. László Lovászy started by introducing himself to the audience. He is a lawyer, a doctor, has a PhD and is the first and only Member of the UN in the Committee on Persons with Disabilities and interested in Biomedical and Technological Development in terms of Disability. He was also interested in learning from the www.investinme.org He mentioned that the International Disability Alliance is also an important player when meeting the NGOs. Governments normally have to learn how to implement the obligations of the Convention via mutual progress, mutual learning and mutual understanding. It is very crucial to realise that there is no perfect country because each and every country has difficulties or challenges in terms of Page 61 of 82

Journal of IiMER implementing the Convention. Cooperation and coordination The definition of disability is an interesting thing From Art.1 – Purpose of CRPD (‘Convention of Rights of Persons with Disabilities’) include: “Persons with disabilities include those who have long-term physical, mental, intellectual or sensory impairments which in interaction with various barriers may hinder their full and effective participation in society on an equal basis with others.” “(e) Recognizing that disability is an evolving concept and that disability results from the interaction between persons with impairments and attitudinal and environmental barriers that hinders their full and effective participation in society on an equal basis with others” h) Recognizing also that discrimination against any person on the basis of disability is a violation of the inherent dignity and worth of the human person, (i) Recognizing further the diversity of persons with disabilities, (j) Recognizing the need to promote and protect the human rights of all persons with disabilities, including those who require more intensive support, Mutual cooperation is important because the Convention strengthens the aspect of international cooperation in Art. 32. The recognition of the importance of independent living and understand reasonable accommodation in an ageing society is not a burden but rather an opportunity. But how because it is a crucial problem we need to fight. Understanding the spirit of the CRPD in terms of research (g) To undertake or promote research and development of, and to promote the availability and use of new technologies, including information and communications technologies, mobility aids, devices and assistive technologies, suitable for persons with disabilities, giving priority to www.investinme.org ME STORY “I have since been sent to another neurologist after my doctor found I was Rhomberg's positive, who made me walk, did a scratch test on my feet, checked the weakness in my legs, and said quite rudely, "you have ME, I am not going to waste time doing tests on you" And that was it. I walked away feeling like I had wasted this man's time. I pray one day a cure will come our way.” - Rowan “Personal Stories of ME Sufferers “ http://www.investinme.org/mestorygall ery1.htm Page 62 of 82 technologies at an affordable cost – Art. 4 – general obligation Recognition of available good practices and possible overlapping interest Art. 4 is quite relevant to the recommendation of good practices we all already heard today because when it comes to more efficient lobby work and the current situation of the EU approach towards rare diseases including the existing cooperation among Member States is very important to understand. Planning and implementation Identifying trends in technology, societal phenomenon and legislative and non-legislative procedures in the EU Parliament in order to visualise and understand how the international bodies and United Nations operate. In relation to this it is important to present and identify the costs and benefits to society and the communities. It is also worthwhile to explain what happens if more people can contribute to society. Journal of IiMER The European ME Alliance The European ME Alliance is a collaboration of ME support charities and organisations in Europe who intend to provide a common view and the scientific facts regarding the neurological illness myalgic encephalomyelitis (ME/CFS). The alliance has been created with a basic set of principles (see EMEA principles and rules regarding membership). The members of the European ME Alliance are currently from Iceland, Norway, Sweden, Finland, Denmark,Germany, Holland, Belgium, Switzerland, Italy, Spain, UK and Ireland. The objectives of the European ME Alliance are to provide a correct and consistent view of myalgic encephalomyelitis (ME/CFS) for healthcare organisations, healthcare professionals, government organisations, the media and patients and the public. Our web site will consist of accurate descriptions of the illness and details of research which has or is taking place. The member groups in the alliance will be working together to promote awareness of ME/CFS and will work closely with organisations and researchers who are interested in finding treatments and cures for ME/CFS. EMEA Principles The members of the European ME Alliance have agreed the following –  That members of the European ME Alliance endorse the principles of the 2003 Canadian Consensus Document for Diagnosis and Treatment for ME/CFS.  That members of the European ME Alliance endorse the principles of the 2006 paediatric definition from Dr www.investinme.org Page 63 of 82 Leonard Jason et al.  Thet members of the European ME Alliance promote the fact that ME (myalgic encephalomyelitis) is a neurological illness in the World Health Organisation’s International Classification of Diseases.  The members of the European ME Alliance understand the necessity to use the composite term ME/CFS at the moment for ease of reference/standardisation.  The members of the European ME Alliance support biomedical research into establishing sub groups of ME/CFS which will lead to treatments and cures for this illness.  That the European ME Alliance has, as an objective, the preparation and promotion of a common set of documentation, in all languages, for Alliance use that is supplemented by local information. http://www.euro-me.org

www.investinme.org Page 64 of 82 https://www.justgiving.com/investinm-e

Journal of IiMER #IIMEC12 PRESENTERS Keynote Speech Professor Ian Charles Leader Quadram Institute, Norwich, UK Professor Ian Charles joined the Institute of Food Research in May 2015 to lead the programme to develop the UK’s new Centre for Food & Health – the Quadram Institute - to be based at the Norwich Research Park. He returned to the UK from Australia where he was Director of the ithree institute, University of Technology, Sydney. Professor Charles has over 30 years’ experience in academic and commercial research. His academic career has included being a founding member of The Wolfson Institute for Biomedical Research at University College London, one the UK’s first institutes of translational medicine. He has also worked in the pharmaceutical industry at Glaxo Wellcome, and has been founder and CSO of biotech companies in the area of infectious disease, including Arrow Therapeutics, sold to AstraZeneca, and Auspherix a venture capital backed company founded in 2013. His current research interests include infectious diseases as well as the microbiome and its impact on health and wellbeing. The new Centre for Food & Health will provide a step change for food and health research, and the translation of science by industry, to benefit society and the UK economy. The Centre will be located at the Norwich Research Park, one of Europe’s largest single-site concentrations of research in Food, Health and Environmental sciences. The multidisciplinary Centre aims to bring together the Institute of Food Research and aspects of the University of East Anglia’s Faculty of Science and the Norwich Medical School with the regional gastrointestinal endoscopy facility at the Norfolk and Norwich University Hospital. With a unique integration of diet, health, nutrition and medicine under one roof, linking closely to world class plant and crop research at the John Innes Centre and bioinformatics at The Genome Analysis Centre (both also located on the Norwich Research Park), it will have the potential to deliver clinically validated strategies to improve human health and wellbeing. Abstract: Not available at time of going to press. Abstract for IIMEC10 Conference in 2015 - http://investinme.org/Documents/Journals/Journal%20of%20IiME%20Vol%209%20Issue%201.pdf www.investinme.org Page 66 of 82 Journal of IiMER Keynote Speech Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Abstract: NIH Research Into ME Vicky Whittemore, PhD National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA Significant progress is being made on many research fronts impacting individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Dr. Whittemore will highlight recent scientific findings from investigators supported by research grant awards from the National Institutes of Health (NIH) and the need for expansion of collaborative research on ME/CFS. In addition, she will provide an update on NIH research funding plans on ME/CFS, including continued support of investigator-initiated research grants and support for the new ME/CFS Collaborative Research Centers and ME/CFS Data Management Coordinating Center. She will provide updates on other NIH activities, including the ME/CFS Intramural Research Study, ME/CFS stakeholder conference calls, and activities of the Trans-NIH ME/CFS Working Group and the CFS Advisory Committee (CFSAC). www.investinme.org Page 67 of 82

Journal of IiMER Professor Sonya Marshall-Gradisnik The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Professor Marshall-Gradisnik is one of Australia's foremost researchers in the area of neuroimmunology and has been instrumental in establishing the Public Health and Neuroimmunology Unit (PHANU) at Bond University. Much of her work relates specifically to autoimmunity in Chronic Fatigue Syndrome sufferers and she is regularly asked to speak to community groups on behalf of Queensland Health and NSW Health. Her research in the area of exercise immunology has also contributed to the body of knowledge relating to the effect of doping in sport and she serves as Sports Medicine Australia's national spokesperson in this area. The vital research conducted by Professor Marshall has attracted more than $1 million in grant funding and she has produced 21 peer-reviewed papers, five book chapters and one provisional patent. In 2008 Dr Marshall was joint leader of the Bond University team responsible for developing the the BioSMART program. The team was awarded a prestigious Australian Teaching and Learning Council Award (formerly known as the Carrick Award) for Outstanding Contribution to Student Learning and for the quality of student learning over a sustained period of time. Professor Marshall-Gradisnik leads The National Centre for Neuroimmunology and Emerging Diseases (NCNED), a research team situated at Griffith University on the Gold Coast. The team focuses on Myalgic Encephalomyelitis. Professor Donald Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia. Professor Staines has been a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as cross-disciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. He is now CoDirector at The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths www.investinme.org Page 68 of 82 Journal of IiMER University in Australia. Abstract: Impaired calcium mobilization and dysregulation of transient receptor potential melastatin 3 ion channels in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis. Staines, D.R1,2., Nguyen, T., 1,2 , Johnston, S1,2., Smith, P 2 and Marshall-Gradisnik, S1,2 1. School of Medical Science, Griffith University, Gold Coast, Australia 2. The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia. Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is disorder with hallmarks of varying changes in immune cells and molecular related mechanisms. Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Ca2+ flux, TRPM3 and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2‐aminoethoxydiphenyl borate (2APB) and ionomycin on CD56dimCD16+NK cells and CD56brightCD16dim/– isolated NK cells. Unstimulated CD56brightCD16dim/– NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). PregS‐stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+flux and NK cell lysis. TG‐stimulated CD56dimCD16+ NK cells significantly increased NK cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity in CFS/ME. Professor Nancy Klimas Director, Institute for Neuro Immune Medicine, Nova Southeastern University Director, Clinical Immunology Research, Miami VAMC Professor of Medicine, Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University Chair, Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University Professor Emerita, University of Miami, School of Medicine Nancy Klimas, MD, has more than 30 years of professional experience and www.investinme.org Page 69 of 82

Journal of IiMER has achieved international recognition for her research and clinical efforts in multi-symptom disorders, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), Fibromyalgia, and other Neuro Immune Disorders. She is immediate past president of the International Association for CFS and ME (IACFS/ME), a professional organization of clinicians and investigators, and is also a member of the VA Research Advisory Committee for GWI, the NIH P2P CFS Committee, and the Institute of Medicine ME/CFS Review Panel. Dr. Klimas has advised three Secretaries of Health and Human Services, including Kathleen Sabelius, during her repeated service on the Health and Human Services CFS Advisory Committee. Professor Klimas has been featured on Good Morning America, in USA Today and the New York Times. Abstract: The Gene Study – a Patient Science Partnership Goes Viral Nancy Klimas, MD 1,2 , Kelly Gaunt Hilton, OMS-III 1 , Kristina Gemayel, OMS-IV1 ,Melanie Perez3 , Rajeev Jaundoo3, Travis Craddock1, Lubov Nathanson PhD1 1Nova Southeastern University College of Osteopathic Medicine, Ft Lauderdale Florida 2 Miami Veterans Medical Center, Miami FL 3 Nova Southeastern University Hamlos College of Natural Sciences and Oceanography The ME/CFS Gene study is truly unique. Two medical students were challenged to create a study using a social media based platform to ask one of the biggest unanswered questions of our time: what are the genetic underpinnings that put a person at risk for ME/CFS? Why would one person recover from a common infection and the next spin into a chronic disabling illness? Does the genetic signature give us new clues to predict therapies? The challenge was a big one – it takes several thousand volunteers and an expensive genetic assay, then complex analysis to begin to answer questions of genetic risk. The budgets of these studies exceed NIH and foundation caps for funding, and access to that many subjects simply has not happened yet. The study group partnered with advocacy groups across the country and created a novel design: ask patients to donate data not dollars. Use social networking to reach out to the community and ask for access to data from genetic studies that are becoming increasingly common in our society: genomic ancestry platforms. Millions of people have taken advantage of the ancestry platforms at their own expense to have studies of genetic signatures completed. We are asking ME/CFS patients to donate their data to launch the gene study. Using 23 and Me or Ancestry.com data sets owned by the volunteers, we asked that they log on to our study site, review and sign the informed consent, then take the surveys that ask about their illness, its severity, the way it started etc. At the end they upload the raw data sets from their ancestry studies. More student power is then employed to align the data in spread sheets, then check its quality. Students working with Dr. Lubov Nathanson the gene targets are reviewed for function and likelihood that they would indeed impact important pathways that effect cell function. Then we start with analysis – at this point we have enough data to query specific pathways, asking questions about specific genes, but we do not have enough data to ask the larger questions, find the surprises locked in the gene set that could lead to the “eureka” moments. We need the effort to go viral to be truly successful, and we need your help. We have 800 volunteers so www.investinme.org Page 70 of 82 Journal of IiMER far, about half have uploaded the gene data. But we need several thousand to ask the most important questions. So link everyone you know to the website: http://www.nova.edu/nim/research/mecfsgenes.html or email: MECFSGenes@nova.edu. And feel good about this study as it is proof that patient driven, patient sponsored research can lead the way to new treatments. The Blue Ribbon Fellowship, provided by the Blue Ribbon Foundation and the Wisconsin ME/CFS Association, sponsored fellowships for medical students to create the platform and the social media outreach campaign. Patients and advocates helped launch this study and continue to help us promote it. And of course patients and advocates are the participants needed to make this successful. If anyone in the patient community would use their social media skills to get the word out, we could do something truly remarkable: through your efforts partnered with this new generation of physician scientists, answer questions that have been waiting to be answered for far too long. Dr Jakob Theorell Jakob Theorell started his medical training at Karolinska Institutet in 2007. He is currently enrolled in the MD-PhD Program at Karolinska Institutet. He works in the Yenan Bryceson Group in Karolinska Institutet in Stockholm. His work focuses on understanding the mechanisms of disease in patients suffering from chronic immunodeficiency syndromes. The Yenan Bryceson Group is based at the Center for Infectious Medicine and employs a wide range of techniques including multiparameter flow cytometry, confocal microscopy, live-cell imaging, next-generation sequencing, and biochemical techniques. To gain clinical and scientific insights into human diseases, we collaborate closely with clinicians at Karolinska Institutet, across Scandinavia and the rest of the world. Abstract: Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections. Cytotoxic lymphocytes combat intracellular infections. Multiple studies have investigated cytotoxic lymphocyte phenotype and function in ME/CFS, but their specific role in this disorder remains to be established. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, we aimed to re-assess the role of cytotoxic lymphocytes in ME/CFS, especially for biomarker purposes. To this end, 48 patients fulfilling both Fukuda and Canada criteria for ME/CFS from two independent cohorts were investigated. The phenotype and function of cytotoxic lymphocytes in frozen and thawed PBMC was evaluated by flow cytometry, one cohort at the time. Results were compared to values obtained from simultaneous analysis of cells from age- and sex matched healthy controls. Consistent differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, cytokine production or reprogrammed NK cell expansions. No clear subgroups were identified in unsupervised www.investinme.org Page 71 of 82

Journal of IiMER dimensionality reduction analyses. One patient showed lower levels of perforin, explained by homozygosity for the PRF1 p.A91V variant, previously associated to haematological malignancies. Among the other patients however, this variant was present in heterozygous state at the expected population frequency, and no additional homozygous carriers were identified. In summary, the results of this study does not support the use of NK cell function as a biomarker for ME/CFS. Furthermore, it does not point to a general role for defects in lymphocyte cytotoxicity in the etiology for ME/CFS. Professor Geraldine Cambridge Dr Jo Cambridge is Professorial Research Associate, Div of Medicine Faculty of Medical Sciences, UCL Her group focuses its interests on B cell depletion (an idea which they introduced (with the Professor Jo Edwards) approximately 10 years ago for the treatment of rheumatoid arthritis), exploring more precisely how the technique works and trying to explain the marked variation in response between different patients Fane Mensah Fane Mensah is a research assistant and PhD student studying the immunology of ME in Dr Jo Cambridge’s group at UCL. Fane’s main area of study is B-cell research. Abstract: Not available at time of going to press. www.investinme.org Page 72 of 82 Journal of IiMER Professor Simon Carding Leader, Gut Health and Food Safety Programme Institute of Food Research, Norwich Research Park, UK Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body's immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. Abstract: Not present at time of going to press. Associate Professor Mady Hornig Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth www.investinme.org Page 73 of 82

Journal of IiMER biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Abstract: Not present at time of going to press. Professor Olav Mella Department Director, Oncology, Haukeland University Hospital, University of Bergen, Norway Professor Mella has performed clinical trials to test the benefit of B-cell depletion therapy using Rituximab in ME/CFS patients. Professor Olav Mella of Haukeland University Hospital in Bergen, Norway began his investigation of Rituximab’s effects on CFS after treating several Hodgkin’s Lymphoma patients who had long standing cases of CFS prior to developing cancer. Professor Mella and Dr Fluge have published a paper "Benefit from BLymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study" Abstract: Status of the Norwegian drug intervention studies on ME (RituxME and CycloME) Olav Mella: for the Norwegian cooperative trial group at Haukeland University Hospital (Bergen), Oslo University Hospital, Telemark Central Hospital – Notodden, St. Olav Hospital (Trondheim) and University Hospital of Northern Norway (Tromsø) Haukeland University Hospital has previously performed studies indicating that immune manipulation by B-lymphocyte depletion may result in symptom improvement in a subgroup of patients with ME, pointing at defects in immune function to be important factors in the disease mechanisms. Following www.investinme.org Page 74 of 82 Journal of IiMER previous Phase II studies with the B-cell depleting CD20 monoclonal antibody rituximab, a decision was made to conduct a Norwegian multicenter, Phase III, double blind, placebo controlled intervention study with rituximab, given mainly as outpatient treatment at Day 0 and 14, and at 3, 6, 9 and 12 mths, with follow-up for 24 mths. The number of patients filling Canadian criteria to be recruited at each hospital was predefined, and there was block-randomization to reduce possible practice differences between institutions. The first of the patients started infusion in September 2014, the last patient in September 2015. One primary endpoint is the course in changes of subjectively measured fatigue over 24 mths, with retrospective registration of symptom changes from baseline, every two week periods through follow-up. The other primary endpoint is number of patients achieving clinical response according to predefined criteria. Secondary endpoints are quality of life (SF 36, FSS), changes in physical performance (electronically recorded for 5-7 consecutive days), physical function level at 6, 12, 18 and 24 mths, length of response duration, and patients still in response 24 mths after inclusion. Toxicity is also a secondary endpoint. There is external monitoring of the trial, with full insight into the data. 152 patients were enrolled, but one withdrew before start, leaving 151 evaluable patients. The trial has been performed according to the protocol. There have been hospital admissions, but the safety committee has reported no serious and unexpected toxicity. The randomization and data handling was done through a professional trials company (Viedoc) and the quality of data is judged good by the external monitors. The final follow-up of the last included patient in the trial will be at the end of September 2017. After that the data quality will be checked and locked, thereafter the trial key unlocked and the study analysed. Publication is expected in 2018. Based on a small pilot study, the open-label Phase II (CycloME) cyclophosphamide intervention study with 40 patients at two centers was initiated in March 2015. The trial includes patients previously exposed to rituximab, and patients without previous immune manipulation. The patients were given infusions of the cytotoxic agent cyclophosphamide 600-700 mg/m2 every 4th week, given 6 times. Endpoints were as in the RituxME study, with follow-up for 18 mths. The last patient will have finished follow-up in July 2017 and the data then analyzed. Compliance has been good, with practically no hematologic toxicity. However, acute nausea and vomiting was experienced to a greater extent than seen in cancer patients at the same drug level, and some patients reported initial and transient worsening of ME-symptoms after infusions. Patients reporting improvement from ME-symptoms generally did so after the final infusion. Although the data has not officially been analyzed, a preliminary observation is that also a more unspecific, immune modulating agent than rituximab can improve the clinical course, in a subgroup of ME patients. Trial sponsors: Norwegian Research Council, Norwegian Ministry of Health and Care Services, the Regional Health Trusts, MEandYou fundraising, the Norwegian ME Association, private donations, the Kavli Foundation www.investinme.org Page 75 of 82

Journal of IiMER Dr Øystein Fluge Chief Physician, Department of Oncology, Haukeland University Hospital, University of Bergen, Norway Dr Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. Abstract: Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS patients Øystein Fluge, Department of Oncology, Haukeland University Hospital, Bergen, Norway. Metabolic dysfunction has emerged as a plausible contributing factor to ME/CFS. Previous studies have shown reduced levels of selected amino acids in serum or urine from ME/CFS patients. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the tricarboxylic acid (TCA) cycle. The levels of amino acids that may convert to acetyl-CoA independent of pyruvate dehydrogenase (PDH), and also of anaplerotic amino acids that may replenish TCA cycle intermediates thus increasing the cycle capacity, were particularly reduced mainly in female ME/CFS patients. Amino acids that may convert to pyruvate, and are dependent on PDH for oxidation in the TCA cycle, were not reduced in ME/CFS patients. Serum 3methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases (PDKs) 1, 2 and 4, sirtuin 4, and of peroxisome proliferator-activated receptor δ, in peripheral blood mononuclear cells from both genders. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The pattern of amino acid changes could not be explained by symptom severity, disease duration, age, body mass index, or physical activity level among patients. These data support a metabolic “obstruction” in the central energy pathway in ME/CFS, a functional impairment possibly at the PDH level with difficulties in metabolizing glucose to energy in the TCA cycle, and with compensatory use of alternative substrates for acetyl-CoA such as ketogenic amino acids and fatty acids. Presently, we are investigating lipid alterations and B-vitamins in the same serum samples. We hypothesize that the inhibition of energy metabolism is caused by an aberrant immune response, in a subgroup of ME/CFS patients with a central role for B-cells and possibly antibodies. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP www.investinme.org Page 76 of 82 Journal of IiMER generation by oxidative phosphorylation and excessive lactate generation upon exertion. Professor Warren Tate Group Leader, Biochemistry Department, School of Biomedical Sciences, University of Otago, New Zealand Professor Warren Tate from University of Otago in New Zealand - is an internationally respected biochemist, winner of the Royal Society of New Zealand's top science honour - the 2010 Rutherford Medal, and was also named a Companion of the New Zealand Order of Merit. His honour citation noted that Professor Tate was a molecular biologist, whose research had "revolutionised understanding" of how proteins were synthesised in living cells. His research had shown how proteins contributed to memory formation and neurological disease, and had important implications for HIV, Alzheimer's and chronic fatigue syndrome. Professor Tate is a Fellow of the Royal Society of New Zealand and of the New Zealand Institute of Chemistry. He has been a Fellow of the Alexander von Humboldt Foundation of Germany, and an International Research Scholar of the Howard Hughes Medical Institute of the United States. Abstract: Intense molecular study of well characterised patients to understand the acute phase, perpetuation, and relapse/recovery cycles in ME/CFS Warren P. Tate, Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, PO Box 56 Dunedin, New Zealand From the moment of my first exposure over 20 years ago to ME/CFS as the illness afflicting a vibrant young teenage daughter, I have puzzled over what physiological ‘control centre’ could mediate such a range of dramatic body-wide responses. As my daughter’s illness progressed into a long-term condition this question evolved into what is preventing recovery and not allowing perpetuation of ME/CFS, and then what physiological changes are occurring during the frequent relapses experienced throughout the chronic phase of the disease. On a brighter note a significant improvement occurred during a pregnancy –why did that happen? Resolution of these unresolved yet important questions would give significant benefit to patients, as well as being of marked scientific interest. As research into ME/CFS has progressed in recent decades there has been a pressing need to collect comprehensive molecular data on well-characterised patients so a framework can be created for evidence-based approaches to the disease. This would have relevance for developing a diagnostic test, and to set directions towards better patient management and therapies. We have studied purified www.investinme.org Page 77 of 82

Journal of IiMER blood fractions from two small patient cohorts, each of 10 patients with age and gender matched controls, one of which was focussed on exercise intolerance and ‘post exertion malaise’. Initially we collected data on the immune cell expressed genes (transcriptome) and proteins (proteome) as well as plasma microRNAs and cytokines with an aim of integrating the data to elucidate linkages between different classes of molecules and give insight into physiological changes. We are currently extending these studies to mitochondrial function and epigenetic changes in the DNA following the recently published research suggesting energy delivery and modulation of expression of specific genes might be significant factors in changes in physiology for perpetuation of the disease. Can a model be developed that might explain most of the diverse symptoms? Evidence of chronic inflammation in the limbic system of the brain and glial cell activation has been shown in neuroimaging studies of Japanese ME/CFS patients, with a degree of inflammation that correlated with severity of disease symptoms. These observations, coupled with the known disturbance of the hypothalamus/pituitary/adrenal axis in ME/CFS, and the hypersensitivity of ME/CFS patients to stress of any kind, has lead us to develop a model whereby the paraventricular nucleus (PVN), the ‘stress centre ‘of the hypothalamus, might be a possible ME/CFS perpetuating centre. The PVN is responsible for absorbing and processing incoming stress signals and chronic fluctuating auto-inflammation in the brain affecting the threshold for managing stress could explain perpetuation of the disease and relapses in the chronic phase of ME/CFS. Detailed molecular and neuroimaging data from patients using cutting edge technologies will allow new models to explain ME/CFS and should provide meaningful benefits for patients for managing and living with their disease. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical www.investinme.org Page 78 of 82 Journal of IiMER genomics. Abstract: Establishing new mechanistic and diagnostic paradigms for ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the last major disease we know almost nothing about. To date, very little is understood about the cause of ME/CFS: years of searching for a common triggering pathogen have been fruitless, and no biological assays exist to facilitate diagnosis. Recent evidence strongly supports ME/CFS as a molecular disease, even if many of the symptoms are cognitive and muscular, which indicates that molecular studies will help to understand and diagnose this disease, and that molecular therapies have the potential to treat it. The time is ripe for this change in perspective, because researchers now have highly advanced, sensitive, and comprehensive molecular technologies at their disposal, and the beginnings of a molecular understanding with which to unravel this disease. We are working to unravel the molecular path from health to ME/CFS, and develop cost-effective technology for diagnosis and drug discovery – offering a new level of precision for researchers and physicians to tackle this complex illness. All of this research is being carried out in close collaboration with physician, patient, and advocate communities, including direct involvement of patient partners and dedicated outreach efforts to broaden awareness of the disease. We aim to implement an interdisciplinary, integrative, inclusive precision approach to ME/CFS to fundamentally change how this disease is understood and managed, and most importantly, to give new hope to patients. Invest in ME Research www.investinme.org Page 79 of 82

Journal of IiMER The 12th Start 07.45 08.55 09:00 09:05 09:25 09:45 10:15 10.45 11.15 11:40 12.05 12.30 13.30 14:00 14:30 15.10 15:40 16.10 17.00 17.30 IiMER International ME Conference 2017 #IIMEC12 CONFERENCE PROGRAMME Presenter Registration Invest in ME Research Dr Ian Gibson Professor Ian Charles Dr Vicky Whittemore Professor Don Staines Professor Nancy Klimas Break Dr Jakob Theorell Dr Jo Cambridge / Fane Mensah Professor Simon Carding Lunch Professor Mady Hornig Professor Olav Mella Dr Øystein Fluge Break Professor Warren Tate Professor Ron Davis Dr Ian Gibson Adjourn www.investinme.org Studies of NK cells and cytotoxic T-cells in ME-patients from one Swedish and one Norwegian cohort Update on Immunoregulation in patients with ME – new paper immunological review UEA/Quadram Inst. Gut Virome in ME - Students Gut-metabolome-immune disturbances in ME/CFS subsets Status of the Norwegian drug intervention studies on ME (RituxME and CycloME) Metabolic profiling in ME/CFS Intense molecular study of well characterised patients to understand the acute phase, perpetuation, and relapse/recovery cycles in ME/CFS Big Data Approach: Severely ill ME Patient Cohort Plenary Session Presentation Opening Welcome to IIMEC12 A UK Centre of Excellence for ME Keynote Speech: NIH Research into ME Dysregulation of Transient Receptor Potential (TRP) ion channels and calcium in natural killer cells in CFS/ME patients Genetic Signature Study Page 80 of 82 Mike Harley is running 28 European marathons – raising funds for Invest in ME Research’s Centre of Excellence for ME research and raising awareness of this disease. Please help us in supporting Mike http://www.investinme.org/ce-IIME-Newslet-1504-02.shtml Raising Awareness of Myalgic Encephalomyelitis - The European Way Journal of IiMER #12 Lithuania 10 September 2017 #13 Amsterdam 15 October 2017 #14 Ljubljana 29 October 2017

Journal of IiME Invest in ME International ME/CFS Conference 2007 Special VOLUME 1 ISSUE 1 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 2 Welcome from Invest in ME Welcome to the first Journal of Invest in ME – a combination of research, information, news, stories and other articles relating to myalgic encephalomyelitis (ME). Facts About ME An estimated 250,000 people suffer from ME in the UK This first version is also serving a dual purpose in that it is acting as a component of the delegate’s conference pack for the 2nd Invest in ME International ME/CFS Conference 2007, held in Westminster, London, UK. Invest in ME welcomes delegates, presenters and media from ten ME Story I fell ill with the flu the same time as Antony, my then boyfriend/fiancé. He got over it, I didn't..... It was a struggle to get the illness recognized - Wendy countries around the world to the conference – emphasising that ME recognises no international boundaries. The interest in the conference also demonstrates the need for some of IiME’s main objectives – more education and proper funding for biomedical research into ME. In this document we include articles from renowned ME experts who were not able to be present at the conference this year as well as those who are. We also include other ME experts who are presenting. IiME hope to publish our journal throughout the year. As with the IiME conference it will allow a platform for researchers, scientists, healthcare staff and politicians to be able to share and provide information relevant to those supporting, campaigning for or suffering from ME. IiME are firmly committed to raising ME awareness, facilitating education and lobbying for proper biomedical research into ME. We shall publish articles even though we may share different views – as long as an honest and transparent debate can occur. However, one thing we shall never lose sight of is the tragedy of ME and the way it is treated - and so stories of real life with ME will be featured from people who are living with this illness on a daily basis, showing the tragedy, the courage and also the humour which people with ME and their families endure.. Facts About IiME Invest in ME is made up of volunteers, ME sufferers and parents of children with ME We hope our efforts and those of our regional and international contacts will ultimately avoid the need for all of our combined work and we can look forward to a treatment and cure for ME. Welcome to IiME. Welcome to London. Disclaimer The views expressed in this brochure by contributors do not necessarily represent those of Invest in ME. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 1st and 2nd May 2007 Inside This Issue 3 Introduction – Professor Malcolm Hooper 4 Invest in ME 5 The IiME International ME/CFS Conference 15 IiME Awareness Campaigning 8 Professor Leonard Jason 6 Dr. Ellie Stein 16 ME Clinical Conundrum - Dr. Neil Abbot/Dr. Vance Spence 19 Biomedical research – Dr. Neil Abbot/Dr. Vance Spence 21 The Strategy of the MRC for Research on CFS.ME 25 UK FINE Trials 27 Jane Colby 28 Speaker Profiles 34 News from Abroad 34 ME in Norway 35 ME in Denmark 37 ME in Sweden 36 ME in Germany 35 ME in Spain 37 ME in USA 39 ME/CFS – by a Carer 40 NICE Guidelines 41 Gibson Inquiry 42 Information on ME/CFS - Margaret Williams Introduction – Professor Malcolm Hooper Achievements, Hope, and Future Actions All three are brought together in this conference. We celebrate the successes of the last year in the high quality research studies that have consolidated the understanding of ME-CFS as a multi-system, multiorgan illness with an increasingly understood biological basis that offers a sound basis for challenging the spurious attempts to make ME an illness that is primarily psychogenic in origin - in contradiction to the established international system of nomenclature. A Quotable Quotes booklet available at the Conference illustrates this dishonourable conflict. These achievements include advances in diagnosis and the increasing adoption of what are known as the Canadian Criteria/Guidelines. In truth these are North American Guidelines that involved co-operation between major clinical practitioners in both Canada and the USA. These should now be adopted as the international criteria and guidelines for the diagnosis of ME-CFS. The removal of the term CFS from any description of this illness would be a great advantage and provide clarity about both diagnosis and treatment. Much more is needed to define subgroups within ME-CFS with several useful schemes now available. Scientific and clinical research has continued apace despite the reluctance of the MRC and Government in providing funding for such studies. Immunology has identified low NK, natural killer, cells as a key marker that could be adopted whilst the significance of oxidative stress provides another reliable marker in hsCRP, high sensitivity C-reactive protein. The importance of a diffuse inflammation associated with ME has been found in autopsy examinations of spinal cord and brain tissue and underlines the importance and accuracy of its designation as an inflammatory illness involving the central nervous system and new understandings of neurogenic pain also provides a mechanism for the severe pain experienced by many people with ME. The details of a common underlying mechanism continue to emerge involving PKR, protein kinase R, nitric oxide and intracellular responses to viruses, other micro-organisms, such as borrelia, rickettsia, chlamydia, leading to immune dysregulation. The role of chemicals and heavy metals are accommodated in these overarching and comprehensive mechanisms. A very important new area of research concerns genetics which is beginning to address the complex issue of the interaction between genes and the environment and the questions of patient susceptibility to this and related overlapping syndromes. Hope for others is emerging from all these activities. The scientific and clinical studies are identifying good tests to aid diagnosis and also new (and confirming some old) ways of treating this debilitating illness. Mitochondrial support linked to diagnostic tests is now available in one therapeutic regimen that many find helpful. Cytokines and their inhibitors may also provide effective treatment. (continued on page 4) long and 3 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Professor Malcolm Hooper (continued from page 3) A catalogue of vested interests has been exposed which has given rise to the misleading judgements of the insurance industry and their advisors as well as the lack of the proper provision of appropriate benefits. The implications of the Inquiry for NICE and the MRC, who have become party to the machinations of the psychiatric lobby, are still being worked through. An essential requirement for future progress is the need for all organisations concerned with ME-CFS to provide a coherent and unified approach to the illness and not to be distracted by the large sums of money being put into the current clinics that have been predicated on ME-CFS as a psychiatric illness. Together we shall succeed but divided we shall fail. Finally there is the growing international collaboration that has now become apparent and provides grounds for rapid advancement in understanding ME. Canada, USA, Australia and New Zealand, and Norway have all made big strides forward. We have much to learn from each other and contribute to each others activities. There is much to celebrate, there are real grounds for hope, and future effective actions can be recognised and agreed. Invest in ME Invest in ME (IiME) was formed by parents of children with ME and sufferers in September 2005 and registered as a UK charity in May 2006. The day to day running of the charity takes place in Hampshire and Norfolk. IiME was formed to break with the established way of looking at ME. We are aiming to change positively the situation for people with ME and their families and carers. IiME has no paying members and no salaried staff – all of our work is voluntary. During 2006 we established and strengthened regional and international contacts which we will develop in the future. Our campaigning for more informed education of doctors and for appropriate funding for biomedical research into ME has led to a busy year in which we have spoken with the Deputy Chief Medical Officer, the head of the MRC and numerous politicians. As part of our campaigning we have responded to the proposed NICE guidelines which were, in our opinion, unfit for purpose; attended and given evidence to the Gibson report into M.E. which was published in November 2006; commented on the inadequate and misinformed NHS Plus Guidance leaflet and made representations to the Department of Work and Pensions on their guidance for M.E. and benefits. The media have an important role to play in our efforts to raise awareness and change attitudes. To this end we have continued to build a good working relationship with many journalists, writers and broadcasters. This has been complemented by responding vigorously whenever possible to articles in the press. During the last year we have attended the inquest of Sophia Mirza who died, “… as a result of acute renal failure due to dehydration arising as a result of Chronic Fatigue Syndrome (M.E.)”. Her mother has lodged complaints with the GMC and the Social Services involved in Sophia’s case and we will notify the outcome as soon as we can. We are determined that what happened to Sophia must never be allowed to happen again. Invest In ME will continue to campaign during 2007 and will build on the close working relationships we have with groups and clinicians around the world, as well as continuing to cooperate with ME Research UK in our joint endeavour to improve the lives of people with ME. Invest in ME Charity Nr 1114035 www.investinme.org IiME LOGO What’s in a logo? The IiME Logo is based on a double helix – indicating our firm commitment to treating myalgic encephalomyelitis as the biological illness it is and enforcing our view that only biomedical research will bring about a cure for ME. 4 Journal of IiME Volume 1 Issue 1 5 The IiME International ME/CFS Conference The idea of an international conference began shortly after Professor Malcolm Hooper and Bruce Carruthers gave presentations at a meeting by ME Support Norfolk, in England at the start of 2005. IiME came into being in September 2005 and the need for similar presentations brought about the proposal to host a conference with more ME experts. IiME decided London was the best place to hold the conference as it would allow easier access by politicians and prominent healthcare staff. The first IiME ME conference was held on ME Awareness Day, 12th May, 2006, with Professor Hooper, Dr. Bruce Carruthers, Dr. Byron Hyde, Dr. Jonathan Kerr, Jane Colby, and Professor Basant Puri and with Dr. Ian Gibson giving the key-note speech. The timing was prescient as Dr. Gibson would be soon embarking on his inquiry into ME by a group of parliamentarians – the Group for Scientific Research into ME (see later story). ME Story I remember asking my doctor one day when I would stop feeling so tired!!! ...... She said give it time - Robyn Speakers and delegates from eight countries were present and the presentations from the conference subsequently appeared in the Journal of Clinical Pathology. Invest in ME’s chairman was interviewed by the BBC and ITV and the conference was referred to in the New Scientist and several national newspapers. The DVD of the conference was distributed to over twenty countries and is now sold as an educational DVD for healthcare and education professionals. Those in ME Support Norfolk who initiated the presentations in 2005 and Professor Hooper planted a seed. From this grew the idea of the IiME International ME/CFS Conference. Facts About ME ME Research UK have a document (available also on the IiME website) which has references to a multitude of research publications collected by Dr. J. Gordon Parish concerning possible ME epidemics. The IiME Conference – the Future It is Invest in ME’s intention to continue with the London conference until a treatment and cure is found for ME. This will be our way of raising awareness by providing a platform for researchers, healthcare staff, support, educational professionals, ME support groups and people with ME and the media, to enable the most relevant science, research, information and news to be heard. The conference is now an annual event in May – ME Awareness Month. Invest in ME welcome the support of all ME groups, charities and individuals to make this an even better event next year. We shall be working with our UK regional and international contacts to enable this and, even as we are organising the 2007 conference, we are looking ahead to the conference in May 2008. Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Behavioral Interventions in ME/CFS. What a difference a decade makes! Written for participants of the May 2007 UK ME Awareness Month events By Dr Ellie Stein MD FRCP As research progresses it becomes more clear that ME/CFS is heterogeneous group of biomedical disorders in which disabling fatigue, dysfunction, pain, autonomic dysfunction, cognitive/neurological immune dysfunction and gastrointestinal dysfunction are concurrently and chronically present. There is increasing evidence, much presented during the UK ME Awareness month, that ME/CFS is pathophysiologically distinct from other medical conditions and from psychiatric disorders. In terms of the etiology of ME/CFS, the pendulum has swung from assumptions of infection as a primary linear precipitant in the 1950s to hypotheses of psychological/behavioral causation in the late 1980’s to early 1990’s. Now opinion is swinging back towards biomedical causes. But instead of a linear cause and effect, current research assumes the interaction of a group of facultative vulnerabilities (genetic, biochemical, environmental) with precipitants such as infection, environmental exposure or trauma to cause disease in a complex way which may differ in each individual. Does behavioral medicine have a role to play in ME/CFS? Research suggests that the psyche plays a similar role in ME/CFS as in other biomedical conditions such as arthritis, heart disease and cancer. How one thinks about and reacts to one’s illness does not in most cases change the underlying pathophysiology, but it certainly affects happiness, hopefulness and quality of life. What is the evidence for this statement? A review of all published, controlled behavioral ME/CFS shows that there are subjective benefits in: fatigue, pain and health status. interventions in No other symptom groups have been reported upon. Neither cognitive function nor exercise tolerance seem affected by behavioral intervention. Furthermore, the subjective changes wane after 24 months (Edmonds et al, 2004;Price & Couper, 2000). These results are similar to those found in Fibromyalgia (Koulil et al, 2006). Cognitive and exercise strategies are used in other disorders with similarities to ME/CFS such as Multiple Sclerosis and Rheumatoid Arthritis. is agreed that the role of behavioral symptom self management and In these conditions it intervention is psychological adaptation. Therefore using CBT/GET lacks controversy. Invest in ME Charity Nr 1114035 After more than a decade of debate, I posit that the ME/CFS community has moved beyond the bio-psycho debate. A close read of the methodology of the two most recent behavioral studies in ME/CFS show vastly expanded definitions of CBT and GET (Pardaens et al, 2006;O'Dowd et al, 2006). These studies bear little resemblance to the early studies which angered so many. The field has shifted significantly since the early 1990’s. Does behavioral medicine have a role to play in ME/CFS? Research suggests that the psyche plays a similar role in ME/CFS as in other biomedical conditions such as arthritis, heart disease and cancer. How one thinks about and reacts to one’s illness does not in most cases change the underlying pathophysiology, What is the next step in behavioral research in ME/CFS? Self Management is used in many chronic disorders especially arthritis, metabolic syndrome and pulmonary disease. The most common self management model world wide is the Stanford Model developed by Kate Lorig and others. This is a public health model in which lay patient experts facilitate groups for self referred persons with mixed disorders. The model has proven, positive, long term impact in disorders such as arthritis where evidence based medical care accessible to all participants. However in ME/CFS where many patients cannot find a disease literate physician, the Stanford model may not be as effective. model with more illness specific content are being studied in Australia and we are awaiting publications of that data. Given that neither pharmacological nor behavioral interventions seems sufficient in ME/CFS, it prudent to recommend integrated models is in which biological, psychological and social factors are assessed and addressed. (continued page 7) www.investinme.org 6 Different adaptations of this Journal of IiME Volume 1 Issue 1 (continued from page 6) This requires: • Increased funding for multidisciplinary ME/CFS research • Understanding the pathophysiology of ME/CFS illnesses • Defining distinct subgroups • Educating health care professionals • Ensuring integrated assessment ME Story I attended the graded exercise programme 22 months ago. I was "sold" the programme under an amazing high degree of pressure and selling. I could not do the increase of 30% of my activity, realistically though it was supposed to be 10%. and treatment is available to all persons with ME/CFS independent of financial means References References for this article may be obtained from Dr. Stein Dr. Ellie Stein Dr. Stein is a psychiatrist in private practice in Calgary, Canada [espc@shaw.ca] The physio refused to believe that I could not do it! She told me I must be able to do it after I had tried and failed. My entire immune system seemed to break down and since those few weeks I am now on high doses of anti viral medication from my GP and will be for years. I would never do get/gat again or recommend anyone to do so. Try the pacing, but please refuse to do the Enforced targets. I was an innocent fool. -M (UK person with ME) 7 Facts About ME Due to relatively little funding given to biomedical research in the UK (compared to the extensive funding being given to psychiatric paradigms for therapies and trials) the amount of proper scientific research has been limited. However, there are over 4000 papers of biomedical research which contain indisputable facts related to the organic basis for ME. More ME stories, including all of these contained in this brochure, are available at – http://www.investinme.org/mestorygallery1.htm Stories from parents of people with ME may be found at - http://www.investinme.org/mestorygallery2.htm Order our free newsletter. We aim to publish monthly via email, plain text or PDF. Go to http://www.investinme.org/IIMENewslettersubs.htm Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Professor Leonard Jason Exploratory Subgrouping in CFS: Infectious, Inflammatory, and Other Karina M. Corradi, Leonard A. Jason,∗ Torres-Harding Introduction Professor Leonard Jason Professor of Clin. & Community Psychology, Director, Center for Community Research, DePaul University, Chicago Dr. Leonard Jason, Ph.D., is among the most prolific of all CFIDS researchers. more than a decade, Dr. Jason and his team at DePaul University’s Centre for Community Research have worked to define the scope and impact of CFS/ME worldwide. Professor Jason was intending to speak at our London conference but was forced to cancel due to other engagements. Similar to other disorders such as cancer, it is likely that a number of distinct types of CFS exist, and that grouping all individuals who meet diagnostic criteria together is prohibiting the identification of these distinct biological markers of the individual subgroups Chronic fatigue syndrome (CFS) affects an estimated 836,000 adults in the United States (Jason et al., 1999), and is 3 to 5 times more common in women than men. CFS can impact any number of bodily systems including For neurological, immunological, hormonal, gastrointestinal, and musculoskeletal (Friedberg & Jason, 1998). CFS is a diagnosis of exclusion. There are currently no specific diagnostic tests for its identification. Researchers have reported various biological abnormalities when investigating CFS, including hormonal abnormalities (Cannon et al., 1998; Moorkens, Berwaerts, Wynants & Abs, 2000), immune activation (Miller, Cohen & Ritchey, 2002), neuroendocrine changes, (Farrar, Locke & Kantrowitz, 1995) and neurological abnormalities (Cook, Lange, DeLuca & Natelson, 2001) among others. However, studies involving basic blood work appear to show no typical pattern of abnormality among individuals with CFS (Johnson, DeLuca & Natelson, 1999). It has been suggested that a number of unique subgroups exist within the overall cluster of individuals diagnosed with this disorder (Cukor, Tiersky & Natelson, 2000; Jason et al. 2001; Johnson, DeLuca & Natelson, 1999). In the p aper specifying the current US case definition for CFS diagnosis (Fukuda et al., 1 994), the working group that developed the criteria referred to the importance of subgrouping within cohorts of individuals diagnosed with CFS. This demonstrates that, even as the current definitional criteria were being presented, there was an awareness of the heterogeneity within the identified group. After the publication of these criteria in 1994, many attempts to subgroup have been undertaken, but to date, no one method has proven to be consistently superior in differentiating subgroups. Psychiatric comorbidity has often been considered a differentiating variable in research studies aimed at subgrouping (Borish et al., 1998; Cukor, Tiersky and Natelson, 2000; DeLuca, Johnson, Ellis & Natelson, 1997a; Masuda, Munemoto, Yamanaka, Takei & Tei, 2002). However, when Tiersky, Matheis, DeLuca, Lange, and Natelson (2003) examined individuals with CFS with and without psychiatric co-morbidity, they found that physical functional capacity was not worse in individuals with CFS and a concurrent psychiatric illness. Morriss and associates (1999) also found that depression was not associated with the reporting of pain, FM, with CFS. Similarly, Ciccone, Busichio, Vickroy, and Natelson (2003) did not find that psychiatric illness, alone or in combination with a comorbid personality disorder, was associated with physical impairment. (continued page 9) Susan R. Keywords: chronic fatigue syndrome, subgrouping, physical disability, mental disability, psychiatric comorbidity 8 IBS, or medically unexplained symptoms in individuals Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) In contrast to the findings above, Borish, Schmaling, DiClementi, Streib, Negri, and Jones (1998) found evidence of low level inflammation, similar to that of allergies, in a subgroup of individuals with CFS. Borish et al. suggested that there might be two subgroups of individuals with CFS, those with immune activation (infectious or inflammatory) and those devoid of immune activation with other illness processes, including psychiatric disorders. Lutgendorf, Klimas, Antoni, Brickman, and Fletcher (1995) found that those patients with immune activation had the most severe cognitive deficits, while Natelson, Cohen, Brassloff and Lee (1993) found that those with ongoing inflammatory processes reported greater cognitive and mental disabilities. Buchwald, Wener, Pearlman, and Kith (1997) found individuals with CFS and chronic fatigue to have significant abnormalities in C-reactive protein (an indicator of acute inflammation) and neopterin (an indicator of immune system activation, malignant disease, and viral infections) when compared to controls. Buchwald et al. (1997) stated that groups of individuals with active low-level inflammatory, infectious processes could be identified and that this was evidence of an organic process in these patients with CFS. Cook, Lange, DeLuca, and Natelson (2001) found that individuals with an abnormal MRI and ongoing inflammatory processes had increased physical disability, suggesting an organic basis for some individuals with CFS. Conceivably, individuals without evidence of these infectious or inflammatory processes on basic laboratory screening tests might be more likely to contain individuals who had other neuroendocrine or neurologic illnesses that might not be readily identified using the minimum battery of laboratory of tests recommended by Fukuda and colleagues (1994) in order to diagnose CFS. However, those with infectious or inflammatory processes might be expected to be more physically impaired compared to those without these processes, based on research by Cook, Lange, DeLuca and Natelson (2001) and Lange, et al. (1999). There is also evidence that those individuals with CFS and with inflammatory processes report greater mental difficulties when compared to those individuals without them (Natelson, Cohen, Brassloff & Lee, 1993). Clearly, individuals diagnosed with CFS are heterogeneous with varying illness course and disability patterns (Jason, Corradi, Torres-Harding, & Taylor, 2005). Similar to other disorders such as cancer, it is likely that a number of distinct types of CFS exist, and that grouping all individuals who meet diagnostic criteria together is prohibiting the identification of these distinct biological markers of the individual subgroups. When specific subgroups are identified, even basic blood work may reveal a typical pattern of abnormality on diagnostic tests (DeLuca, Johnson, Ellis & Natelson, 1997b; Hickie et al. 1995; Jason et al., 2001). This exploratory study considered several possible subgroups that fall under the umbrella diagnosis of CFS. It was expected that clinically significant groups would be found on the basis of abnormal blood tests. The laboratory tests that formed the basis for subgrouping were part of the battery of laboratory screening tests recommended by Fukuda et al. (1994). These groups consisted of an ongoing infectious group, an ongoing Inflammatory group, and an “Other” group (having neither infectious or inflammatory processes). Using these subgroups, this study sought to explore the relationships between membership in a subgroup, reported disability (both mental and physical), and psychiatric co-morbidity. It was hypothesized that the individuals with CFS would evidence higher levels of physical and mental disability than those in a control group, and that those in the Infectious and Inflammatory subgroup would exhibit higher levels of physical and mental disability when compared to the Other group. It was also hypothesized that the Inflammatory group would report greater mental difficulties when compared to the Infectious and Other groups. Method Procedure Procedures developed by Kish (1965) were used to select one adult from each household contacted. The person with the most recent birthday was asked to complete the interview. A stratified random sample of several neighborhoods in Chicago was used, and a random sample of adults was screened. In stage one, 28,673 telephone numbers were contacted, with 18,675 adults completing the initial interview (see Jason et al., 1999 for further details). Persons who completed the initial screening stage of the study with indications that they may have had CFS, as well as a group negative for CFS (control group), were invited to participate in the second and third stages of the research study. Stage two involved administration of a structured psychiatric interview, the SCID, conducted by telephone. Stage three involved a (continued page 10) Invest in ME Charity Nr 1114035 www.investinme.org 9

Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) medical exam at Mercy Hospital, including a physical exam, laboratory tests, including a complete blood count (CBC), white blood cell differential, antinuclear antibodies (ANA), sedimentation rate (Sed rate), rheumatoid arthritis (RA factor), chest X-ray, a detailed medical interview, and a structured medical questionnaire. Participants were also asked at this time to release previous medical records to the research study. The authors received IRB approval for conducting the study. Individuals who participated in the medical examination were provided financial compensation. When each participant completed the study, a team of four physicians and a psychiatrist made the final diagnosis of CFS, Idiopathic Chronic Fatigue, Fatigue explained by a medical condition, or no fatigue. These physicians were familiar with the CFS diagnostic criteria and were blind to the experimental status of the participant. Two physicians independently rated each case to determine whether the participant met the CFS case definition (Fukuda et al., 1994). If a disagreement occurred, a third physician rater was used to arrive at a diagnostic consensus. Participants The participants for this project consisted of individuals with CFS and a control group. For the purposes of this study, it was important that the control sample include only individuals who presented themselves as mentally and physically healthy, due to the fact that abnormal medical test results were a primary variable. A total of 19 of 47 individuals in the control group were excluded from this study (e.g., on-going medical, sleep or severe and untreated psychiatric problems). The final sample included 31 in the CFS group (1 CFS participant was excluded due to lack of data on a critical variable), and 28 healthy controls. The CFS group consisted of 23 females and 8 males. The control group had 18 males and 10 females. Further demographic breakdown indicated that the CFS group had 5 African American, 14 Caucasian, 9 Latino, and 3 individuals who identified themselves as “other”. The control group consisted of 4 African American, 20 Caucasian, 2 Latino, and 2 individuals who identified as “other”. Individuals with CFS were then sub-grouped into three groups according to medical evidence of possible inflammatory processes (as evidenced by abnormal eosinophils count, abnormal rheumatoid arthritis factor [RA factor], and abnormal sedimentation rate in the presence of one of Invest in ME Charity Nr 1114035 the prior mentioned inflammatory markers), medical evidence of possible current infection (as evidenced by abnormal results on lymphocytes count or sedimentation rate [Sed rate] without the presence of an inflammatory marker), and a group without evidence of either of these organic processes. Each of these medical markers is discussed in the measures section below. When subgrouped based on these criteria, 8 participants with CFS were categorized into the Other group, 8 in the Infectious group, and 15 in the Inflammatory group. Measures Measures used for this study included laboratory blood tests, a self-report of disability, and a structured clinical interview for the determination of psychiatric diagnosis. 1 [1All measures did not total 59 as all participants did not complete every measure.] Standard laboratory tests were conducted during phase three of the full-scale study. Results used in the current study include: White blood cell (WBC) differential (specifically lymphocytes and eosinophils), rheumatoid arthritis factor (RA factor), antinuclear antibodies (ANA) and sedimentation rate (Sed rate). These laboratory tests were chosen for inclusion into the study based upon the recommendations of Fukuda and colleagues (1994) for diagnosing CFS. These tests are all part of the recommended minimum battery of laboratory screening tests suggested by this group in order to exclude other physiological causes of fatigue or another disease process. All blood-work completed for this study was analyzed through the laboratories at Mercy Hospital in Chicago Illinois, or National Health Laboratories Incorporated-Chicago, in Elmhurst, IL.. Eosinophils and Lymphocytes Eosinophils and lymphocytes are specific leukocytes. To obtain 10 types of the values presented and considered in this study, automated white blood cell differentials were performed. Differential white blood count is part of the complete blood count (CBC) and is composed of five types of leukocytes (WBCs whose chief function is to protect the body against microorganisms causing disease). These five consist of eosinophils, lymphocytes, neutrophils, basophils, and monocytes. The differential WBC is expressed in cubic millimeters and percent of total number of WBCs. antinuclear antibodies [ANA], When elevated, eosinophil counts can indicate the presence of allergic inflammation, some forms of cancer, (continued page11) www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) and parasitic disease. Significantly higher rates of allergy and allergic type reactions have been reported in the CFS population (Borish, et al., 1998). Several studies have also reported significant elevations of the eosinophil counts of individuals with CFS (Conti, Magrini, Priori, Valesini & Bonini, 1996; Baraniuk, Clauw, Yuta, Gaumond, Upadhyayula, Fujita, et al. 1998; Priori, Conti, Luan, Aprino & Valesini, 1994). The normal range endorsed by Mercy Hospital Laboratories for eosinophil count is 100-300 mL. This variable was coded as normal or abnormal depending on the test results from Mercy Hospital Laboratory. When elevated levels of lymphocytes are found, this can be an indication of viral infection, chronic infection, and Hodgkin’s disease, among others. Elevated lymphocytes have been reported in the CFS population (Patarca, 2001), and abnormal lymphocyte responses have also been noted (Krueger et al., 2001). However, elevated levels and abnormal responses have not been found in all studies (Brimacombe, Zhang, Lange & Natelson, 2002). The normal range endorsed by Mercy Hospital Laboratories for lymphocytes is 800-4400mL. This variable was coded as normal or abnormal depending on the test results from Mercy Hospital Laboratory. Rheumatoid Arthritis Factor (RA Factor) RA factor measures antibodies in arthritis, individuals with rheumatoid arthritis. When this test occasionally, the serum of is abnormal, it indicates an inflammatory process such as rheumatoid autoimmune disease and infectious diseases. The presence of rheumatoid arthritis factor has been reported in the CFS population (Kerr et al., 2001). This laboratory test was conducted by National Health Laboratories Incorporated-Chicago, in Elmhurst, the degree of rapidity with which the red cells sink in a mass of drawn blood (Dirckx, 2001). Elevated Sed Rate can indicate bacterial infection, pelvic inflammatory disease, systemic lupus erythematosus, and red blood cell abnormalities (Kee, 2001). Abnormal sedimentation rates have been reported in CFS populations (Richards, Roberts, McGregor, Dunston & Butt, 2000). Results on this test are reported in millimeters per hour, and normal ranges depend on sex and age. The Mercy laboratories normal range for males < 50 is 010.4 mm/hr, and for males > 50, 0-11.4 mm/hr. For females < 50 the normal range is 0-11.0 mm/hr and for females > 50, 0-20.0 mm/hr. This variable was coded as normal or abnormal depending on the test results from Mercy Hospital Laboratories. Antinuclear Antibodies (ANA) ANA tests for the presence of antinuclear antibodies in the blood. A normal result is negative. When positive, it is an indication of systemic lupus or other rheumatoid disorders, which are inflammatory diseases. Occasionally this test can be positive in the presence of specific types of infections. Elevated rates of ANA have been reported in the CFS population (Nesher, Margalit & Ashkenazi, 2001). Several reports of a specific type of ANA found in some individuals with CFS have been published (Itoh et al., 2000; Nishikai, et al., 2001). Psychiatric Diagnosis To measure current and lifetime psychiatric diagnosis, the Structured Clinical Spitzer, Gibbon & Williams, 1995) was used. IL. Serum samples were first run undiluted, and if a positive result was found, the sample was then run diluted at a 1:10 dilution. The reference value for a normal result is < 1:20 titer. Ranges of 1:20-1:80 are positive for rheumatoid and other conditions. Results falling above 1:80 are positive for rheumatoid arthritis. Any positive results on this test were coded as abnormal. As Rheumatoid Arthritis is an exclusionary disorder for CFS diagnosis, all participants were screened for Rheumatoid Arthritis during their medical exam and this disorder was ruled out. Sedimentation Rate (Sed Rate) Sed rate measures the sinking velocity of blood cells, or Interview for the DSM (SCID; First, Previous studies have indicated that the SCID is a reliable measure of psychiatric diagnosis in the CFS population (Taylor & Jason, 1998). The SCID requires administration by master’s level clinicians. To create the categories used in this study, all diagnoses identified as anxiety disorders by the DSM (such as generalized anxiety disorder, phobias etc.) were grouped together into one Anxiety Diagnosis variable, all disorders identified as depressive disorders (such as major depressive disorder, seasonal affective disorder, bipolar disorder etc.) into one Depressive Disorder variable, and all other psychiatric diagnoses (such as substance abuse disorders, somatization etc.) were grouped into an Other Psychiatric Diagnosis variable. Disability To determine disability level, the SF-36 (Stewart, Hays & (continued page 12) 11 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) Ware, 1988) was completed by all participants. The SF-36 is a 36-item questionnaire that in the past assesses individuals’ self- report on physical and emotional health currently, four weeks, and compared to the same time last year. The SF-36 has eight subscales, and one reported health transition score. Two composite scores are available for the SF36, the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Internal consistency coefficients range from .89 -.94 for the PCS, and .84 -.91 for the MCS across age, gender, race, education, medical diagnosis, and disease severity. The current study used these summary scales to determine differences in physical health, and mental health (Ware, Kosinski & Keller, 1994). Results Initial analyses were conducted to determine if any significant differences existed between the control and the entire CFS group on sociodemographic variables. There was only one significant difference, which occurred for gender. Therefore, gender was run as a covariate in all subsequent analyses. Subgroup Differences for Physical and Mental Disability To consider the relationship between subgroup membership and reported physical disability, an ANCOVA was run with subgroup as the independent variable, PCS as the dependent variable, and gender as a covariate. Analyses indicated that significant differences could be found between the subgroups on the PCS (p < .01). Least Significant Difference post hoc analyses indicated that all three CFS subgroups reported significantly higher levels of physical disability than the Control group (M = 56.1). The Other group reported significantly higher levels of physical disability when compared to the Inflammatory group (Ms = 29.2 vs 39.2, respectively), but it was not significantly different from the Infectious (M = 34.7) group. Next, an ANCOVA was conducted with a subgroup as the independent variable, MCS (a measure of mental disability) as the dependent variable, and gender as the covariate. Analyses indicated that significant differences did exist between the subgroups for the MCS variable (p < .01). Following the significant omnibus test, post hoc analyses indicated that the Inflammatory group had significantly greater mental disability compared to the control group (Ms = 36.5 vs 50.8, respectively), but was not significantly different from the Other (M = 43.6) or Infectious (M = 39.7) groups. Invest in ME Charity Nr 1114035 Relationships between Subgroups and Psychiatric Diagnoses To attempt to understand the relationships that might exist between subgroups and psychiatric diagnoses, logistic regressions were conducted considering subgroups as the independent variables (e.g., Other, Infectious, Inflammatory, and Control) and one psychiatric diagnosis per logistic regression (with the following dependent variables in separate analyses: current depression, current anxiety, and current other psychiatric diagnosis). No significant differences were found among the subgroups and the presence of depression, anxiety disorder, or other psychiatric diagnosis. Because prior studies have indicated that the CFS groups have significantly higher rates of current and lifetime psychiatric co morbidity, the analyses above were performed on current and any lifetime psychiatric diagnoses. Two logistic regressions used current psychiatric diagnosis and lifetime psychiatric diagnosis as dependent variables. The odds that an individual in the Infectious group also had a current psychiatric diagnosis were 6.13 times higher when compared to individuals in the control group. The odds that individuals in the inflammatory group had a current psychiatric diagnosis were 12.65 times higher when compared to control group members. The second logistic regression considered lifetime psychiatric diagnosis of any kind between membership in one of the subgroups, and membership in the control group. Analyses indicated that the odds that individuals in the inflammatory group had a psychiatric diagnosis at some time in their lives were 18.66 times higher when compared to individuals in the control group. Ethnic Differences Prior to sub grouping, no significant differences existed between the control and CFS groups on ethnicity. However, when examining the three subgroups separately with the control group, chi square analysis indicated that significant differences did exist between the four groups [χ2 (3, N = 59) = 10.00, p = .019]. The Infectious group (91% minority, 9% Caucasian) were significantly more likely to be of minority status than the Other (32% minority, 67% Caucasian) and control (37% minority, 63% Caucasian) groups, but they were not significantly different from the Inflammatory (56% minority, 44% Caucasian) group. (continued page13) www.investinme.org 12 Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) Discussion While it was hypothesized that the Infectious and Inflammatory groups would be significantly more physically impaired compared to the Other group, we found that the Other group reported significantly greater physical impairment compared to the Inflammatory group. In the present study, the Other group might have reported greater physical impairment because of other on-going physiological processes. For example, supplemental analyses indicated that the Other group was significantly more likely than the Infectious group to present with symptoms of orthostatic intolerance, specifically, having a mental disability when inflammatory dizziness immediately following standing, and dizziness when turning the head. The Other group might have contained individuals with ongoing illness processes that were not identifiable by the laboratory tests available for this study. Orthostatic intolerance is best diagnosed using tilt-table testing, which was beyond the scope of the current study. The Inflammatory group was significantly different only from the control group. This result is consistent with past findings of greater mental disability in the Inflammatory group when compared to the control group, and is consistent with past research indicating individuals with ongoing inflammatory processes are more likely (Natelson, Cohen, Brassloff & Lee, 1993). When measuring participants’ psychological status, the Other group was the only chronic fatigue subgroup that did not have significantly elevated psychiatric diagnoses. No significant relationships emerged between membership in the Infectious, Inflammatory, and Other groups, and current diagnosis of depression, anxiety, and any other psychiatric diagnosis. However, when examining simply the presence or absence of any current or lifetime psychiatric disorder, the Inflammatory group was more likely to have a current or lifetime psychiatric diagnosis when compared to controls. Also, individuals in the Infectious group were found to be more likely to have a current psychiatric diagnosis when compared to controls. It is possible that the presence of a chronic illness may put enough psychological strain individual on an that this strain contributes to or caused psychiatric diagnosis, or that the same processes that increase an individual’s likelihood of processes are present, may increase the likelihood of a psychiatric diagnosis. It is also possible that the psychiatric symptoms are completely unrelated to the CFS diagnosis (Abbey, 1996). The relationship between psychiatric diagnosis and CFS diagnosis is one that is far from being understood and therefore is much in need of further study. Finally, the Infectious group had a greater number of minorities compared to other subgroups and the control group. It is well documented that minority and low SES populations are less likely to have access to health care (Richman, Language barriers, healthcare system, past Flaherty & Rospenda, 1994). experiences with the religious beliefs may all contribute participants being less likely and different medical and to minority to utilize health care, even if they have the access (Borrayo & Jenkins, 2003; Johnson et al., 1995). It is also possible that minorities who are immigrants are more likely to travel to their country of origin and be exposed to different infectious agents in their travels. In addition to this, minority participants may be more likely to be employed in hazardous or environmentally stressful occupations with exposure to infectious agents. to report greater mental difficulties It is possible then that minorities in the present study had poorer health care utilization, and therefore were less likely to have had infectious processes treated. The current exploratory investigation had several limitations. First, the medical tests used as the basis of subgrouping in this study were not exclusive indicators of infection or inflammation. Further, the distinction between infection or inflammation is often one that cannot clearly be made, as these two processes frequently occur together. While inflammation generally accompanies infection, there are distinct instances when inflammation occurs in the absence of known infection, such as allergic inflammation, or sub-clinical level rheumatoid arthritis. Future studies should seek to determine if clear differentiation can be made, with more accurate infection and inflammation. tests, between Second, the limited sample size for African American, Latino, Asian, and other minority groups necessitated the grouping of all minority participants into one larger minority group. It is difficult to be certain if the relationships found (i.e. that of minority participants being more likely to present with on-going infectious processes) are more likely in individuals who (continued page 14) Invest in ME Charity Nr 1114035 www.investinme.org 13

Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) have minority status in general, or if differences in findings are due to a specific minority group. The current study had small sample sizes, and this could contribute to instability of results, generalizability and lack of statistical power. limited Logistic regressions with small sample sizes can over-fit models and generate high odds ratios. Future research should consider larger sample sizes of each minority group to explore within-group and betweengroup differences. It is notable that these findings emerged when forming subgroups utilizing only a basic battery of laboratory screening tests. These laboratory conducted primarily ME Story tests were for the purpose of screening out other major illnesses that might explain a person’s chronic fatigue, as recommended by Fukuda and colleagues (1994). Many people with CFS exhibit only minimal or subtle abnormalities on these tests, and these abnormalities often are inconclusive or may not be acknowledged by the primary care physician because they do not lead to a diagnosis of another, more recognized disease process. Further, the more commonly reported physiological abnormalities reported in people with CFS, such as the presence of RNase L (Suhadolnik et al., 1997), adrenal insufficiency with subsequent low cortisol levels (Addington, 2000), the presence of orthostatic intolerance (Schondorf, Benoit, Wein, & Phaneuf, 1999), and immunological abnormalities (Patarca-Montero, Mark, Fletcher, & Klimas, 2000), can only be assessed using highly specialized, expensive, or experimental tests to which people with CFS and their physicians typically have little access. This study demonstrates that subgrouping is possible using laboratory tests that are readily available and can easily be ordered by primary care physicians. The identification of clinically significant subgroups is the logical next step in furthering CFS research. There might be multiple pathways leading to the cause and maintenance of the neurobiologic disregulations and other symptoms experienced by individuals with CFS. Depending upon the individual and subtype, these may include unique biological, genetic, neurological, psychological, and socioenvironmental contributions. Previous research examining people with CFS as a homogenous group may have missed real differences that might exist among subgroups of people diagnosed with this illness. Subgrouping might be the key to understanding how CFS begins, how it is maintained, how medical and Invest in ME Charity Nr 1114035 I was assessed for one ME clinic but they said I was too disabled and that there were other issues that needed to be worked on. They also said that because I was confined to a wheelchair they thought that would be too upsetting for the other members of their group - Gary psychological variables influence its course, and in the best case, how it can be prevented, treated, and cured (Jason et al., 2005). Acknowledgements & references Request for these and reprints should be addressed to Leonard Jason, Community Research, DePaul University, 990 W. Fullerton Avenue, Chicago, IL 60614. 14 Center for ME Story 3 yrs ago I came down with what I thought was the flu, but I never recovered. After many doctors I was diagnosed with ME. At this time last year I was able to still care for my own needs but as the summer progressed so did my illness. My ability to get up by myself declined. I had to have help getting to the recliner in the living room and to the bathroom. I started having problems feeding myself, my hands would shake so bad that the food and my drink ending up all over myself. Then it got to the point that walking was impossible. I had a bedside commode that I used and my husband would carry me to the recliner. In Nov it was decided that my mom would move in with us to help care for me. By that time I was totally bedridden unable to care for myself. - Blaze www.investinme.org Journal of IiME Volume 1 Issue 1 INVEST in ME CAMPAIGNING for ME AWARENESS ME AWARENESS MONTH ME Awareness has traditionally consisted of a week in May – with 12th May being recognized as ME Awareness Day. IiME have been suggesting that only a ME Awareness Month is sufficient to mark the seriousness of this illness, with 12th May being recognized as the focal point of the month. We are happy to join with ME Research UK to promote ME Awareness Month – a chance for people around the world to highlight the issues surrounding ME, to recognize the devotion of many carers and the courage of many sufferers of ME. It will also give more opportunity for serious discussion of research and enable ME to be seen more as a mainstream illness. ME AWARENESS MONTH MAY 2007 HAVE a CUPPA for ME ME as a Notifiable Illness Invest in ME are happy to work with other groups and charities for the benefit of people with ME and to make progress regarding the urgent issues which need to be tackled. Our recent campaign to have ME recognised as a notifiable illness in schools was made from an idea by Jane Colby. Jane is a former head teacher who has ME and who formed Tymes Trust. It is now ten years since Jane and Betty Dowsett made the report on ME. These studies along with those of Dr Nigel Speight have clearly shown that ME-CFS is a major illness responsible for most school absenteeism. Although IiME and other ME support groups are campaigning for ring-fenced funding for biomedical research into ME we also recognize that we need to help raise money via a voluntary donation effort. In late 2005 Invest in ME launched the Have a Cuppa for ME event. A simple idea to hold tea or coffee mornings with friends, relatives and neighbours. Around the country groups have organised HACFME events and raised thousands of pounds which has gone towards biomedical research to charities such as ME Research UK. More details can be found on the IiME site – www.haveacuppaforme.org. Invest in ME Charity Nr 1114035 Our campaign called on the Chief Medical officer to make ME a notifiable illness in schools. With no government funding being directed at biomedical research we need as much data as possible in order to apply necessary diagnostics to this illness. By making ME a notifiable illness it would be possible to collate more exact figures for occurrence and geography of the illness. It would have a further advantage in ensuring that children’s lives are not irreversibly disadvantaged due to lack of awareness. were better understood Health and Education Authorities could better target their limited resources for the benefit of these sick children. More on this may be found at – http://tinyurl.com/ypnv2q www.investinme.org If the demographics Energising ME Awareness 15

Journal of IiME Volume 1 Issue 1 Dr Vance Spence & Dr Neil Abbot ME/CFS: a research and clinical conundrum This presentation was given at the ME research UK Colloqium in 2003. My role is to provide an overview of the difficulties surrounding the illness, especially for those of you who are coming fresh to the topic from other scientific areas and specialties. One of our aims is to bring together experts from a variety of disciplines, some with little or no experience of ME/CFS, as we attempt to energise research into this condition with new ideas and novel approaches to solving its inherent problems. The most widely-used definition of “Chronic Fatigue Syndrome” is that developed in 1994 by a consensus conference: the CDC-1994 (Fukuda et al., 1994) definition. This was developed in response to criticisms that previous definitions (including the CDC-1988) were too restrictive. It requires the presence of chronic fatigue of six months duration which is persistent or relapsing, of new or definite onset, not substantially alleviated by rest, not the result of ongoing exertion, resulting in a substantial reduction in activities, and leading to substantial functional impairment. In addition, at least four of the following are required: sore throat, cognitive symptoms, tender lymph nodes, muscle pain, multi-joint pain, headaches, unfreshing Figure 1 Australia (Lloyd et al., 1990) CFS “Oxford Criteria”, UK (Sharpe et al., 1991) CFS World Health Organisation, 1994 (non-clinical) US Centers for Disease Control and Preventation (Fukuda et al., 1994) CFS “Canadian” Expert Consensus Clinical Case Definition for ME/CFS, 2003 Diagnostic criteria (adults) for “CFS-like” illness 1988–2003 London (Dowsett et al., 1990) ME US Centers for Disease Control and Prevention (Holmes et al., 1988) CFS Previous literature Epidemic Neuromyasthenia (Parish, 1978) Myalgic Encephalomyelitis (Acheson, 1959) Epidemic Neuromyasthenia (Henderson & Shelokov, 1959) Invest in ME Charity Nr 1114035 www.investinme.org sleep and post-exertional malaise. Cognitive or neuropsychiatric symptoms may be present, but the definition excludes clinically important medical conditions such as melancholic depression, substance abuse, bipolar disorder, psychosis and eating disorders. Some would argue that I could just mention this definition and sit down again; but in fact it is part of the problem, and it examining why that is so. As you can see, the definition relies on “fatigue” as its major criterion. For that reason many patients who fall under this diagnostic label hate the name — they call it the F-word — since for many of them “fatigue” per se is not the major problem, and does not best represent how they would explain their condition. Thus, this CDC-1994 definition is now widely recognised to have a number of limitations. These include the fact that symptoms are mainly self-reported (e.g. the clinical signs required in the CDC-1988 definition have been removed); the terminological criteria are vague (e.g., “fatigue”, “malaise”, “unrefreshing specificity of sleep”, the definition etc.); the is poor, allowing heterogeneous groups of patients (e.g., those with somatoform disorders, fibromyalgia syndrome, etc.) to coexist under the one umbrella term (Salit, 1996; Jason et al., 1999); and it makes no attempt to differentiate is worth 16 (continued on page 17) Journal of IiME Volume 1 Issue 1 ME/CFS: a research and clinical conundrum (continued) patients on the basis of severity of illness or level of functional disability. Indeed, there is a growing realisation that the current CDC-1994-defined “CFS” term is an impossibly inclusive diagnostic construct, begging Simon Loblay (1995) to ask the ontological question: “Is CFS a recognisable disease entity with a unique pathophysiology, or is it a ragbag of common non-specific symptoms with many causes, mistakenly labelled as a syndrome?” As an example, our work in Dundee has compared three groups of patients each fulfilling the CDC-1994 criteria: Syndrome and patients with a definite history of exposure to rganophosphate pesticides. We showed clear differences between the groups in terms of measured parameters, including muscle pain, and physical and mental status (Kennedy et al., 2004). Importantly, a high proportion of people in each group had measurable signs of muscle weakness in arms or legs, indicating that clinical signs can, in fact, be found in these patients if physicians take care to do a full physical examination. explore such important findings. Future work will There have been other definitions apart from the CDC-1994 Fukuda one (see Figure 1). The most recent attempt to revise the definition (Carruthers et al., 2003) is based on clinical experiences with very large numbers of patients. It will, however, be some time before this new “Canadian” description of ME/CFS replaces the CDC1994 definition in clinical and research practice. When comparing scientific studies, it is important to patients with ME, those with Gulf War bear in mind that different definitions of ME/CFS may have been used, and this complicates interpretation and comparison of data. It can also be seen from the Figure below that there have been several attempts in the past decade to define diagnostic criteria for the illness. Each definition has been problematic, reflecting in part the special interest of the author, and taking little account of the extensive literature prior to 1988 (see Figure) that made the case for myalgic encephalomyelitis as a distinct clinical entity based on reports of epidemic and endemic cases. What was this condition “Myalgic Encephalomyelitis” that existed before 1988, when it was subsumed within the “CFS” construct, and which is still referred to by patients in the lay literature as “ME”? Myalgic encephalomyelitis was first defined by Acheson (1959). It had been found to occur in epidemic and sporadic forms, and was believed to result from a continuing or persisting viral systemic illness, infection. It has been defined as a characterised by marked muscle fatigability (not just weakness); muscle (continued on page 18) Figure 2 Orthostatic Hypotension (Streeten et al., 2000; Stewart, 2003) Brain perfusion (Schwartz et al, 1994; Costa et al, 1995) Endothelial dysregulation (Spence et al., 2000; Khan et al., 2003; Khan et al., 2004) Vascular 2002; Tiev et al., 2003) Anti-viral dysregulation (Suhadolnik et al., 1994; De Meirleir et al., 2000; Shetzline SE et al., et al., 2003; Vecchiet et al., 2003) Oxidative stress (e.g., Richards et al., 2000; Manuel et al., 2001; Pall & Scatterle, 2001; Kennedy Biochemical Physiological and biochemical abnormalities found in “CFS” cohorts Enteroviral sequences in muscle (Lane et al., 2003) Abnormal recovery after exercise (e.g., Paul et al., 1999; McCully & Natelson, 1999) Metabolism (e.g., Fulle et al., 2000; Vecchiet et al., 2003) Muscle Metabolic abnormalities (Tomoda et al., 2000; Puri et al., 2002; Chaudhuri et al., 2003) Brain Invest in ME Charity Nr 1114035 www.investinme.org 17

Journal of IiME Volume 1 Issue 1 ME/CFS: a research and clinical conundrum (continued) pain, tenderness and swelling; variable involvement of the central nervous system (ataxia and cranial nerve involvement); muscle weakness and/or sensory changes due to neuronal damage; impairment of memory; sleep disorders, etc.; vascular tachycardia, pallor); involvement (orthostatic reticulo-endothelial dysfunction; and recurrences of flu-like symptoms with myalgia. From 1934–90 there were at least sixtythree outbreaks of epidemic proportions, all well-documented, distributed geographically in North America (29 outbreaks), the UK (16), the rest of Europe (11), Australasia (4), Africa (2) and Asia (1). One of the most studied, and possibly the most controversial, of these outbreaks occurred at the Royal Free Hospital, London, in 1955, during which 292 people were affected. Indeed, outbreaks may still be occurring, and some of the patients who currently come under the CDC-1994 CFS definition have clinical features similar to the classical description of post-infectious ME patients defined above. The fact that we are still aware of these details is in no small measure due to Dr J. Gordon Parish who is attending this workshop today. Dr Parish has over many years collected reports of these outbreaks of ME (Parish, 1978; Shelokov & Parish, 1989), and has a complete archive of the relevant literature. A complete listing of these references can be found on the MERGE web site (www.meresearch.org.uk). Given the heterogeneous nature of the term CFS, and the different ways of defining it, it is probably no surprise that many of the biomedical studies conducted into the illness — a relatively small number given the scale of the problem — have had inconclusive results. Despite this, however, a range of abnormalities have been found by a number of different research groups, and these are summarised in the Figure 2 (previous page). Today’s workshop will concentrate on the vascular and biochemical aspects of ME/CFS, but MERUK intends to facilitate further workshops concentrating on other aspects of ME/CFS pathophysiology, such as muscle metabolism and function, and neuro-imaging and brain function. References A full list of the references mentioned can be obtained from Dr Neil Abbot, ME Research UK (Charity Number SC036942), The Gateway, North Methven St, Perth PH1 5PP; e-mail meruk@pkavs.org.uk; website www.meresearch.org.uk Invest in ME Charity Nr 1114035 www.investinme.org Facts About ME ME is estimated to cost the UK economy over £6 BILLION per year Dr Vance Spence and Kathleen McCall and Sue Waddle from Invest in ME – at a presentation for Invest in ME entitled Making the Breakthrough [http://tinyurl.com/yreh7a] ME Story At work I have been asked to go to see the company doctor as noone believes I'm unwell yet they see me struggling to walk on occasions! - Clare Dr Vance Spence and Dr Neil Abbot, ME Research UK, The Gateway, Perth, UK. Based on a presentation given at the Royal Society of Edinburgh Research Workshop on ME/CFS 18 Journal of IiME Volume 1 Issue 1 Biomedical Research into ME/CFS Dr Vance A. Spence and Dr Neil C. Abbot Chairman of ME Research UK (charity number SC036942), and Hon Senior Research Fellow, Institute of Cardiovascular Research, University of Dundee, UK Specific research findings from the University of Dundee As a supplement to the talks you are to hear during the IiME Conference 2007, this hand-out presents a brief overview of the recent research findings from the Vascular Diseases Unit in the University Dundee,. One of the cardinal facts about research work generally is that breakthroughs follow funding (since without it there is no possibility of starting the exploration!). This group, with Research UK, has uncovered several blood vessel sensitivity to acetylcholine? c) Increased neutrophil apoptosis of Also, we also have new data indicating that ME/CFS patients have detectable abnormalities in a type of white blood cell (called neutrophil) – specifically a larger proportion of dying (apoptotic) cells than in healthy subjects – consistent with an activated inflammatory funding from ME interesting findings in people with ME/CFS. These findings have been reported in a series of scientific papers published from 2003–2006. a) Increased oxidative stress In our experiments, we have found a pattern of significantly increased oxidative stress – increased oxLDL and isoprostanes with decreased HDL and GSH – in ME/CFS patients (Kennedy et al, 2004). As isoprostanes also act as vasoconstrictors, for ME/CFS patients their presence, accompanied by additional free radicals during exercise may be responsible for some of the symptoms – such as pain - seen after exercise. These findings have now been confirmed by at least four other research groups worldwide who have also shown excessive free radicals in blood, urine and muscle tissues of ME/CFS patients. Isn't it important to discover the source(s) of these molecules, whether from excessive immune activity, chronic infections or abnormalities within muscle tissue? b) Abnormal acetylcholine metabolism Acetylcholine is a substance produced by the layer of endothelial cells lining all blood vessels, causing them to open. Our group has found that vascular responses to acetylcholine are increased compared with matched control subjects (Spence et al 2000; Khan et al, 2004, a and b). This finding is in contrast with research into a wide variety of cardiovascular diseases – such as diabetes, stroke and high cholesterol – where blood flow responses to acetylcholine are normally blunted. Why should ‘CFS’ patients have this thumbprint of increased Invest in ME Charity Nr 1114035 seemingly unique (continued on page 20) www.investinme.org process which is possibly the consequence of a past or present infection (Kennedy et al 2003, 2004a). Accompanying these markers of neutrophil apoptosis, we found that highsensitivity C-reactive protein levels, recognised as a marker of the inflammatory process, were also significantly increased. Might some people with ‘CFS’ disorder, albeit an unusual one? d) Presence of "signs" of physical illness Importantly, a high proportion of the patients investigated in this unit have had measurable signs of muscle weakness in the arms and/or legs, indicating that clinical signs (rather than self-reported symptoms) can, in fact, be detected in these patients if physicians take care to do a full physical examination (Kennedy et al 2004b). Intriguingly, reports in the older literature (1950s and 1960s) on epidemics of ‘classical’ ME included the presence of clinical signs (e.g., muscle weakness/swelling; sensory nerve changes; observable recurrences of flulike illness, etc). Will the presence of clinical signs - believed by many healthcare professionals today to be non-existent in ME patients - come to be recognised as important markers of physical illness? Our purpose here is not to answer these questions, but to show that biomedical investigation can uncover, within a proportion of ME/CFS patients, biological anomalies that might well help to explain many of the clinical features associated with the illness, and might also indicate areas for therapeutic treatment. 19 have a chronic inflammatory

Journal of IiME Volume 1 Issue 1 Biomedical Research into ME/CFS (continued) General research findings from groups worldwide For the first time in many years, there is optimism about the potential for biomedical advances in ME research. A range of groups are beginning to report physiological abnormalities in many patients with ME/CFS, showing what can be achieved if scientific effort and funding are targeted towards biomedical research, leading to therapeutic intervention and treatment. The Table below (from ME Research UK’s report of the Royal Society of Edinburgh/Wellcome Trust workshop on ME - available on our website) lists some recent areas of progress that may prove to be important. The Future? All these results are very exciting, and they may well help us to explain some of the unusual symptoms that these ME/CFS patients experience. It is also important to recognize, however, that these tests are not diagnostic markers. We are currently formulating new hypotheses and designing new experiments in order to unravel the significance of acetylcholine sensitivity, increased oxidative stress, increased early death of neutrophils etc, in the ME/CFS patients. Experience has convinced us, however, that funding will be difficult to maintain, and that the funding strategy for ME must mirror that of cancer research which obtains 85-90% of its revenue from private sources and ground-level fundraising. It is a huge task, but much can be achieved by a determined and collaborative ME community. References A full list of the references mentioned can be obtained from Dr Neil Abbot, ME Research UK (Charity Number SC036942), The Gateway, North Methven St, Perth PH1 5PP; e-mail meruk@pkavs.org.uk; website www.meresearch.org.uk Table: Physiological and biochemical abnormalities found in groups of ME/CFS patients. BIOCHEMICAL Oxidative stress (Richards 2000 et al. ; Manuel 2001 et al.; review by Pall 2001; Kennedy et al. 2003; Vecchiet et al. 2003) Dysregulation of anti-viral pathways - i.e. abnormal activity of the anti-viral immune responses (Suhadolnik RJ et al. 1994; De Meirleir et al. 2000; Tiev et al 2003) VASCULAR – Endothelial dysregulation - i.e. abnormal responses of small blood vessels selectively to acetylcholine (Spence et al. 2000; Khan et al. 2003 and 2004) Altered brain perfusion i.e. areas of reduced blood flow in the brain (Ichise et al 1992; Costa et al. 1995; Tirelli et al. 1998) Orthostatic hypotension i.e. physiological changes to blood pressure/cardiovascular mechanisms on standing (Streeten et al. 2001; Naschitz et al. 2002; Stewart et al. 2003) BRAIN MUSCLE Metabolic abnormalities e.g. alterations of brain choline (important in brain function). (Tomoda et al. 2000; Puri et al. 2002; Chaudhuri et al. 2003) Altered metabolism - e.g. changes in muscle composition or use of fuel. (Fulle et al. 2000, Vecchiet et al. 2003, Fulle et al. 2003) Abnormal response to exercise (Lane et al. 1998; Paul et al. 1999; McCully et al. 2004). Enteroviral sequences in muscle - i.e. evidence of a persisting virus in some CFS patients (Lane et al. 2003; Douche-Aourik F et al. 2003) Invest in ME Charity Nr 1114035 www.investinme.org 20 Journal of IiME Volume 1 Issue 1 The Strategy of the Medical Research Council for Research on CFS/ME By Professor Colin Blakemore Chief Executive, Medical research Council The development of MRC’s CFS/ME Strategy Following the publication of the Report of the Chief Medical Officer’s Independent Working Group in 2002, the MRC convened a CFS/ME Research Advisory Group (the Membership and Terms of Reference of which appear in Annex 1 below). This Group was asked to advise the MRC on a broad strategy for advancing biomedical and health services research on CFS/ME. The Advisory Group met three times between September 2002 and March 2003, and also undertook a consultation exercise, in July and August 2002, using a set of structured questions. The results were independently analysed by the NHS Public Health Resource Unit, Oxford. The lay members of the MRC CFS/ME Research Advisory Group met with ME charities, CFS/ME patients and their carers, in order to improve understanding of their perspectives. A preliminary draft research strategy was made available to key stakeholders, as well as national and international researchers, for external, open consultation. It was also considered by the MRC Research Boards between December 2002 and February 2003. The preliminary draft research strategy was revised by the MRC CFS/ME Research Advisory Group in the light of the results of this consultation, and the final version was presented to the governing body of the MRC, its Council, in March 2003. In May 2003 the MRC published the report of the independent Research Advisory Group. The report can be viewed or downloaded from the MRC website: (http://www.mrc.ac.uk/Utilities/Documentrecord/inde x.htm?d=MRC003412). The Research Advisory Group agreed that the research community should be encouraged to develop high-quality research proposals addressing key issues for CFS/ME research in areas that were considered amenable for study at the present time. In particular, the Group drew attention to the potential for progress in certain areas, for instance in research that addresses: • • the understanding of symptomatology improved case-definition • new approaches to management. Invest in ME Charity Nr 1114035 21 Invest in ME had invited Professor Blakemore to speak at the IiME International ME/CFS conference but unfortunately he was not able to make it. The MRC were invited to send another speaker, and were offered the chance to send representatives to attend as delegates, but these offers were also declined. The MRC CFS/ME Research Advisory Group concluded that there is probably a multiplicity of potential causal factors for CFS/ME and they reviewed the widely disparate results of research so far reported in the scientific literature concerning the biological basis of the condition. They concluded that, as in many other areas of medical progress, valuable treatments might be developed and tested, even if there is not a full understanding of the triggers and causal pathways that lead to CFS/ME. Therefore, the Advisory Group recommended to the MRC that the most likely route to rapid help for patients was through support for research on interventions for CFS/ME, even while there remains incomplete knowledge of its causes and underlying pathogenesis. This recommendation does not debar the consideration of applications exploring the mechanism and aetiology of the condition, if high-quality proposals can be developed. The MRC does not normally set aside specific amounts of money for particular illnesses, not (continued on page 22) www.investinme.org

Journal of IiME Volume 1 Issue 1 MRC Strategy for Research on CFS/ME (continued) even for the most common conditions, although in areas of serious unmet clinical need, we do sometimes issue highlight notices, to alert the research community to our strong interest in funding good research. The MRC issued such a highlight notice for CFS/ME and that highlight notice is still in effect. Thus, the MRC continues to encourage research applications in CFS/ME, and our Research Boards have agreed to prioritise this area. However, applications must not fall below the scientific standards set by our rigorous peer review process, through which applications are judged in open competition with other demands on funding. The main factors in our Research Boards’ funding decisions are: • research excellence; • • the likelihood of major advances in knowledge; and the clinical importance of the topic. This is to ensure that the research supported by the MRC will have the best chance of delivering knowledge that will be useful in tackling medical conditions, and that we therefore use taxpayers’ money to good effect. Needless to say, the MRC has a responsibility to encourage the strong UK research community to contribute as widely and effectively as possible to improving the health of the nation. So, the MRC is very keen to support high-quality studies on CFS/ME that stand a good chance of delivering their stated aims. It would obviously not be acceptable to the public as a whole for the MRC to support research applications that are judged, in open competition, to be of lower quality than other proposals that are more likely to yield results of real value to the sufferers of other conditions. Challenges to understanding the causes and biological bases of CFS/ME There are a number of challenges to advancing the understanding of CFS/ME arising from individual variation in the spectrum of signs and symptoms associated with fatigue conditions, and hence uncertainty about the cardinal signs of CFS/ME. A related problem in the design of research is the variability of response of sufferers to potential interventions, possibly because of differences in underlying aetiology and pathology. Invest in ME Charity Nr 1114035 The intensity as well as the nature of the symptoms vary considerable, not only between patients but also over time for individual patients, and at different stages in the progress of the condition. The lack of consistency of data from experiments on people with CFS/ME presents a huge challenge to the interpretation of the results of research. The fact that some, perhaps many patients have one or more other comorbid conditions, particularly mood and anxiety disorders, makes research even more difficult. The complexity of this condition led the Advisory Group to recommend that researchers should develop high-quality research proposals addressing key issues for CFS/ME research that are amenable for study at the present time. It is hoped that improved definition of the phenotypes of potential subgroups that may come under the CFS/ME spectrum, will help to underpin future research on causes and mechanisms. However, the MRC remains committed to funding scientific research into all aspects of CFS/ME at any time and will consider funding research into the biological basis of the condition, provided it meets the quality thresholds set out above. Another challenge for CFS/ME is the lack of researchers with an adequate understanding of the condition and training in the multidisciplinary approaches that might facilitate ground-breaking discoveries. Unfortunately, the openly expressed frustration of many CFS/ME sufferers has led many researchers to feel under attack from the very community that they are trying to help. The frustration, even hostility, expressed against researchers can only discourage the necessary influx of new researchers to take the field forward. Current MRC funding for CFS/ME The MRC is currently funding six research projects on CFS/ME (see Annex 2) – a total investment of more than £3m. For comparison, this is similar to the level of MRC support for research on autism and on skin cancer. The MRC’s portfolio includes two large clinical trials of new approaches to treating CFS/ME – the PACE trial (£2,076,363) and the FINE trial (£824,129). The PACE trial will be comparing three treatments given to patients in a clinical setting, one of which is Adaptive Pacing Therapy (APT). This (continued on page 23) www.investinme.org 22 Journal of IiME Volume 1 Issue 1 MRC Strategy for Research on CFS/ME (continued) treatment is popular with many patients but has not been scientifically evaluated before. With the help of Action for ME, APT has been adapted to enable the researchers to test it rigorously within the trial. The FINE trial will also test three different treatments. They are delivered to patients at home by specially trained nurses, so are particularly suitable for patients who are too ill to attend a specialist clinic. Conclusions The MRC recognises the scale of suffering caused by the spectrum of disorders characterised by fatigue and wants to use public funds sensibly and productively to help CFS/ME patients. We maintain our highlight notice as an indication of the priority that we attach to this area, and we shall support research on any aspect of CFS/ME that is of high quality and is likely to lead to real advancement of knowledge. Colin Blakemore Chief Executive, Medical Research Council April 2007 Annex 1 MRC CFS/ME Research Advisory Group & Terms of Reference Chair : • Nancy Rothwell, University of Manchester • Jacqueline Apperley, MRC Consumer Liaison Group • Philip Cowen, University of Oxford • • Janet Darbyshire, MRC Clinical Trials Unit Diana Elbourne. London School of Hygiene and Tropical Medicine / Institute of Education • Sue Haslehurst, MRC Consumer Liaison Group • Alan McGregor, Guy’s, King’s and St Thomas's • Jon Nicholl, University of Sheffield • • Jackie Oldham, University of Manchester Chris Verity, Addenbrooke's Hospital • Jonathan Weber , Imperial College School of Medicine • Til Wykes, Institute of Psychiatry Invest in ME Charity Nr 1114035 www.investinme.org Note: All members of the MRC CFS/ME Research Advisory Group acknowledge that inevitably in their professional or personal life they may have indirect connections with individuals who may have undertaken research in this area, or who either themselves or a family member may have or have had CFS/ME. The Group agreed there to be no conflict of interest in such cases. Observers / Secretariat • Susan Lonsdale, Department of Health • 23 Chris Watkins, Medical Research Council • Elizabeth Mitchell, Medical Research Council The Terms of Reference for the MRC CFS/ME Research Advisory Group • To consider the Report of the CMO’s Independent Working Group on CFS/ME, including its recommendations for research, • To consider other recent reviews of current knowledge and understanding of CFS/ME, • To take account of patient and lay perspectives, • To recommend to MRC a research strategy to advance understanding of the aetiology, epidemiology and biology of CFS/ME and, • In the light of current knowledge suggest what areas of further research are needed with regard to possible prevention, management (including diagnosis) and treatment. The MRC CFS/ME Research Advisory Group agreed not to revisit the areas considered by the CMO’s Independent Working Group, but to recommend how research might be undertaken that would improve understanding and treatment of CFS/ME. It was agreed that it was beyond the remit of the Research Advisory Group to decide how the recommendations for a research strategy should be implemented, since this would be the responsibility of funders and sponsors. (continued on page 24)

Journal of IiME Volume 1 Issue 1 MRC Strategy for Research on CFS/ME (continued) Annex 2 - Current MRC support for CFS/ME research 04/05 Expenditure Peter Denton White, G0200434 The PACE trial; A RCT of Cognitive Behavioural Therapy, graded exercise, adaptive pacing and usual medical care for chronic fatigue syndrome, Queen Mary and Westfield College, St Barts Hospital (Trials Grant) Alison Joan Wearden, G0200212 Randomised controlled trial of nurse led self-help treatment for primary care patients with chronic fatigue syndrome, University of Manchester, (Trials Grant) Richard K Morriss, G0100809 Exploratory RCT of training General Practitioners to manage patients with persistent Medically Unexplained Symptoms (MUS), University of Liverpool, (Trials Grant) Kamaldeep Bhui, G0500978 Chronic Fatigue & Ethnicity, Queen Mary and Westfield College, St Barts, London (Research Grant, New Application) Francis Creed, G0500272 The feasibility of a population based study of CFS, IBS and CWP, University of Manchester (Research Grant, New Application) Total expenditure figures Related grant Michael Sharpe, G0300876 A complex intervention for patients with medically unexplained symptoms in neurology clinics: Trial platform Total, including Sharpe ME Story The psychiatrist visited Sophia for 20 minutes one morning. The psychiatrist gave her no physical examination, which I found strange, given that her blood pressure was 80/60 and was unable to understand that Sophia’s “clock” was constantly on the move and that mostly her day-time was in our night-time. The psychiatrist did not seem to understand any of her myriad symptoms and the following day gave a lecture on M.E. to a large number of doctors; never having asked Sophia for her consent. The psychiatrist wanted me to be present, though I had reservations, and gave everyone there a handout about Sophia and our family, (which I only received later as part of the pack of Sophia’s notes). It read like a novel with some horrendous so called “facts” that I did not recognise as a true representation. I was also shocked at the misrepresentation of Sophia’s symptoms to the doctors and started to object, at which point I was ushered out of the room. (from The Story of Sophia and M.E. – http://www.investinme.org/Article-050%20Sophia%20Mirza%2001.htm) Invest in ME Charity Nr 1114035 www.investinme.org £617,354 £870,679 £559,377 £57,977 £751,923 £118,756 Intervention study Intervention study Epidemiology £159,809 £187,488 Intervention study £244,791 05/06 Expenditure £459,208 24 £154,777 £83,925 - - Epidemiology - £21,302 Journal of IiME Volume 1 Issue 1 FINE Trials - Set Up & Objectives ‘..complementary trials into The UK FINE Trials – A view from a Participant Reasons: These trials are funded by the Medical Research Council (MRC) alongside another set of trials called PACE trials. Both are described by the MRC[1] as various treatments options for CFS/ME which aim to improve quality of life for those who are ill.' ‘FINE (Fatigue Intervention by Nurses Evaluation) will test two different treatments that are particularly suited to those who are too ill to attend a specialist clinic.' 'The FINE trial will involve patients in the North West of England and North Wales.' The recruitment of patients for both trials was started in 2004 and, according to the MRC, were expected to take up to five years to complete. The FINE trials are headed by Dr. A. Wearden from Manchester University whose rehabilitative therapy. FINE treatments would be delivered in patients’ own homes (‘so the trial Inclusion Criteria The MRC claims that the trials will use the most inclusive criteria for CFS/ME to determine eligibility to take part (the Oxford criteria) in order for the results to be generalised to the largest number of people possible. FINE TRIAL COSTS The FINE trials cost £1,147,000. background is 1 Data they collected about me was misleading. Only questionnaires were used in the 2 sessions I had with the researchers and the questions were leading and did not reflect my true feelings. Also the researchers spent 2-3 hours with me each time which was so exhausting that I think I didn't really know what my replies were. is particularly suited to those who are too ill to attend specialist clinics.’ – according to the MRC) 2 The trial totally disregards ME/CFS as an illness. It is based on a theory that our symptoms are due to deconditioning and maladapted beliefs about exercise. I was initially suspicious of this but agreed to it because it provided me with a lifeline (was great for me to believe I could get better through exercise) and also because in the initial session the nurse gave me a presentation which lasted over three hours. I was so exhausted. The disregard of the illness was reflected on a practical level. For example, they said that if I recover from exercise in ten minutes then I am working at the right level. I abided by this rule and later crashed due to delayed and accumulated effects (which are widely accepted features of this illness). How this is ethical I do not know! 3 The program was hypocritical. They had strict rules for me to live by regarding pacing (yet gave me very little practical advice on this). Yet they felt it was okay to do 3 hour long sessions with me! It felt unworkable. 4 I crashed after the last session with them, so although my report was not glowing, it is highly misrepresentative of the actual outcome (probably my most important point)!! I am now worse than I have been in the duration of this condition. FINE Trials - EXPERIENCE by Alice I have been phoning the trial office but no answer yet! I want to withdraw (from the FINE trials) for a whole load of reasons. I will try to explain some of them here but may not make much sense due to brain-fogginess so please excuse that. Invest in ME Charity Nr 1114035 5 The therapist who provided the intervention had very selective hearing and she would adapt whatever I said to fit into what she wanted to hear (I have examples of these but won't bore you). 6 The therapist was critical of me and unsupportive. She was defensive when questioned things. I (continued on page 26) www.investinme.org 25

Journal of IiME Volume 1 Issue 1 (continued on page 25) 7. ME Story I believe the consent process was unethical. I was not aware what I was letting myself in for. (they did not explain the details of the intervention until after I had consented). In addition, the deconditioning theory was presented as fact and there was no mention of a balanced viewpoint (I have since read research that goes against this deconditioning theory). 8. Another example of my data not being represented properly: I suspended from University a couple of weeks before the start of the program and had started to improve from the rest. I continued to improve for a little while into the program. I made sure I highlighted that the cause of this improvement could be the effects of the program, or the rest I was getting. They were not interested in this - the fact that there was basically another aspect of my life that could be causing changes in my condition. I was unhappy during the study but wanted to continue because I thought (stupidly) that in some small way I was helping the fight against ME. It is in realising that my data will probably be used in some way to support this program - that I feel made me so much worse - that makes me want to withdraw. Blimey, I have written all this and still don't feel like I've painted the picture. The doctor put me forward for this trial because this was all he knew of to do. I so wish I had done my research first. I will be so much more cautious in the future. It frightens me to think that this research will be used to support clinics offering this in the future. Anyway, I hope that is of help to someone. I can provide more information if anyone is interested. Thanks for your replies and I hope this is a good day for you. Alice x ME Story Despite strenuous efforts on my part ME Story Even if it had been the right treatment, by that time it was too late: so many years of neglect, disbelief, wrong medication, wrong diagnoses; so many times referred to psychiatrists, who to a man sent her away because they couldn’t find anything wrong – with a prescription for an anti-depressant just in case....... - Richard to keep well and fulfil my duties to the best of my capabilities, I suffered a complete collapse in September, 2003 and was almost bed-bound for many months. I have been unable to work full-time since then and even very small, parttime jobs cause the flu-symptoms, severe headaches, blackouts, loss of balance, nausea, weak limbs, IBS, brain-fog and exhaustion to start up again. I'm one of the lucky ones…. - Daphne Invest in ME Charity Nr 1114035 www.investinme.org How do I deal with family that say things like "stop researching that...don't you think your just wallowing in it just the more?" How do you stop looking for answers? When is it time to give up? Why don't people that have known you all their lives...know you and what your suffering is REAL?? Why do doctors still say this doesn't exist and yet look at many of us ...completely destroyed by this disease....... - Cynthia 26 ME Story When I try to get medical care, the strain of trying to convince someone I am ill and the hurtful things they say to me practically make me crack up. Just the physical demands of leaving the house, even in the wheelchair, are enough to make me sicker for weeks. I can't describe how ill it makes me feel - Shannon Journal of IiME Volume 1 Issue 1 Jane Colby Invest in ME are happy to work with other groups and charities for the benefit of people with ME and to make progress regarding the urgent issues which need to be tackled. Our recent campaign to have ME recognised as a notifiable illness in schools was initiated from the work performed by Jane Colby. Jane is a former head teacher who has ME and who formed Tymes Trust. It is now ten years since Jane and Betty Dowsett published their work. Here Jane recalls a historic day for children with ME and describes the day that the term ME Plague was coined. Invest in ME book 2007 - “Schools swept by ME Plague” On 12th May, ME Awareness Day 2006, I was honoured to speak on ‘Children with ME’ at the Invest in ME Conference. I called for ME to be made notifiable due to its encephalitic symptoms and I am delighted that Invest in ME have since been campaigning for this. I was then invited to write a Review for the Journal of Clinical Pathology; called Special Problems of children with ME/CFS and the enteroviral link, it can be read online at www.cfids-cab.org/rc/Colby.pdf and in the printed Journal. On ME Awareness Day 2007 I am in a very different venue - Brentwood Cathedral - for our Remember the Children concert. But 10 years ago it was the 22nd May that caused a storm, when the headline above was splashed across The Guardian front page. I had no idea how big my joint research with Dr Betty Dowsett, a legend in her own lifetime, would become. I’d pre-recorded interviews for the morning television news and was booked for radio news shows, but as the phone rang constantly while I tried to get ready, and I had to use my fax to make outgoing calls, I began to get the message. Dr Dowsett went to ground like Badger in Wind in the Willows! Arriving at the studios at 7.45am I was asked: “Have you seen The Guardian?” I hadn’t. Then I was asked to fit The Today Programme in between the others. Guest Simon Wessely was saying: “I’m sure Jane would agree…” I didn’t, and I’m afraid I ignored his question. There was too much else to discuss. Mainly the fact that ME had just been revealed as the key reason for children and young people missing school long-term due to illness. ME was causing over half of all long-term sickness absence, almost twice that of cancer and leukaemia combined (51% against 23%). Getting the figures had taken five years. We studied a school roll of a third of a million children and over 27,000 staff. Not easy to ignore, although the British Medical Journal discouraged the profession from giving it credence. Six months later, however, published a 450 word letter from Dr Dowsett and myself, choosing the headline: ‘Journal was wrong to criticise study in schoolchildren’. At this distance in time it is easy to forget that it was a school epidemic that sparked off our study. What was the pattern in other schools, we wondered? Almost 40% of cases we uncovered were in clusters of 39 and 21% were in pairs. The clusters involved staff and pupils. We found a prevalence of 70:100,000 in pupils and 500:100,000 in staff. Associated with the clusters were other long term absences caused by viral illness, not yet diagnosed but often described as gastro-intestinal or flu-like. (Enteroviruses, the suspected culprits in many cases of ME, produce both these symptom profiles.) We concluded that the early investigation of infective agents associated with such a serious illness in schools should be instigated, and we recommended this. To our knowledge, nothing has been done. I feel another campaign coming on… You can read all the results of the survey as described by Dr Dowsett at www.tymestrust.org/pdfs/dowsettcolby.pdf 27 it Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE Norman Lamb MP Member of Parliament for North Norfolk, Liberal Democrat Shadow Health Secretary Norman Lamb entered Parliament at his second attempt in 2001, gaining this seat from the Conservatives. Norman Lamb read law at the University of Leicester. He worked for Norwich City Council as a senior assistant solicitor before joining Norfolk solicitors Steele and Co., where he became a partner and head of the firm's specialist Employment Unit. He worked for a year as a Parliamentary Assistant for Greville Janner, QC, MP. He was a member of Norwich City Council 1987-91, leading the Liberal Democrats for the last two years of his term. He has built a strong reputation in Norfolk as a campaigner for improved health services. He has been a critic of cuts in bed numbers and has highlighted the resulting unacceptable level of cancelled operations. As an MP his work on local issues includes adjournment debates on: orthopaedic waiting times in Norfolk; the lack of school transport services in North Norfolk; police funding in Norfolk; funding for Further Education Colleges; the provision of care for people with dementia; and coastal erosion. Norman has been Lib Dem Deputy Spokesperson for International Development (2001-02), a Treasury spokesman (2002-03), PPS (Parliamentary Private Secretary) to Charles Kennedy (2003-05) and Shadow Trade and Industry Secretary (2005-06). He was a principal author of the party’s policy on Royal Mail. From March to December 2006, Norman was Chief of Staff for party leader Sir Menzies Campbell. In December 2006 he was appointed Liberal Democrat Shadow Health Secretary. He has a particular interest in Africa: he has led Adjournment Debates on the HIV/AIDS crisis facing Africa and Asia, the controversial sale of military air traffic control system in Tanzania and the situation in the Great Lakes region of Africa. Dr. Derek Pheby - Project Coordinator, National ME Observatory, and Senior Fellow, University of Hull Dr Derek Pheby is an epidemiologist, and was Director of the Unit of Applied Epidemiology at the University of the West of England, Bristol. He has a long-term interest in ME, and was a member both of the National Task Force on ME and of the Key Group of the Chief Medical Officer's Working Group on CFS/ME. His unit had an active programme of research into chronic fatigue syndrome and ME. Dr Pheby is a member of the Editorial Board of the International Journal of Chronic Fatigue Syndrome. 28 Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Jonathan Kerr Jonathan Kerr was born in Belfast in 1963, qualified in medicine from Queen’s University of Belfast (1987), and completed training as a medical microbiologist (1995). He has worked as a microbiologist in Belfast, Manchester and London, taking up post as a Consultant Senior Lecturer in Microbiology at Royal Brompton Hospital / Imperial College in June 2001, and then Sir Joseph Hotung Clinical Senior Lecturer in Inflammation at St George’s University of London in 2005. His interest in Chronic Fatigue Syndrome (CFS) began during a study of the consequences of parvovirus B19 infection, when he showed that a percentage of infected cases developed CFS which persisted for several years. He is now the principal investigator in a programme of research in CFS. This involves development of a diagnostic test using mass spectrometry, analysis of human and viral gene expression in the white blood cells, and clinical trials of immunomodulatory drugs. Dr. Jonathan Kerr and colleagues at St. George’s University of London reported in the July 27, 2005 issue of the Journal of Clinical Pathology that a preliminary study of 25 CFS patients and 25 matched healthy controls revealed abnormalities in 35 of 9,522 genes analyzed using microarray technology. Polymerase chain reaction studies showed the same results for 16 of these genes. The study, and its results, raises some important questions. The first of which pertains to the need for funding of microbiological CFS research. He is funded (>£1million) by the CFS Research Foundation (www.cfsrf.com), a charitable organization based in the U.K., and leads a group of 5 scientists at St George's. The Foundation needs private support to continue their research efforts. They also openly post the results of their efforts on their website http://www.cfsrf.com. Dr. Ian Gibson MP for Norwich North Dr. Ian Gibson has been the MP for Norwich North since his election in 1997. He is originally from Scotland and was born in Dumfries on the 26th September 1938. He went to school at Dumfries Academy and acquired a passion for all things scientific- especially biology. He pursued his passion for science by going on to study at Edinburgh University where he gained a BSC and later on a PhD in genetics. He served as the Dean of the School of Biological Sciences at UEA from 1991 to 1997 and headed a research team investigating various forms of cancer, including leukaemia, breast and prostate cancer. In 2003, the university made Fr. Gibson an Honorary Professor. Dr. Gibson first stood for Parliament in 1992. Although losing that election by just 266 votes he tried again in 1997 and won the Norwich North seat by 9470 votes. He has been re-elected twice since 1997- in 2001 and most recently in May 2005. His work in Parliament and in Norwich has primarily consisted of advocacy work and pushing the government to take more notice of the role that science plays (and can play) in the UK. His scientific background has meant that he has been involved in numbers of groups and charities in Parliament. Invest in ME Charity Nr 1114035 www.investinme.org 29

Journal of IiME Volume 1 Issue 1 Professor Hooper Professor Hooper graduated from University of London and had held appointments at Sunderland Technical College, Sunderland Polytechnic and the University of Sunderland, where he was made Emeritus Professor of Medicinal Chemistry in 1993. He has served at many UK universities as well as in India and Tanzania. He has inaugurated links with Indian research institutions and universities and celebrated 25 years of productive and on-going links which have, particularly, 30 involved the design and development of new drugs for tropical diseases and an exploration of natural products associated with Ayurvedic medicine. He has published some 50 papers in peer-reviewed journals in the field of medicinal chemistry together with major reviews on the Chemotherapy of Leprosy, the Chemistry of Isatogens. Edited one book on the Chemotherapy of Tropical Diseases. He acted as a referee for a number of important journals and served on one editorial board. He has served on committees of the Council for National Academic Awards (CNAA), the World Health Organisation (WHO) and the Science and Engineering Research Council (SERC). Professor Hooper is a member of a number of learned bodies, including the Royal Chemical Society, the British Pharmacological Society and the Society for Drug Research (SDR), now renamed the Society for Medicines Research, where he has served on the committee for 12 years and served as Chairman for 2 years. This involved the planning and organising of major national and international conferences. He was appointed Chief Scientific Advisor to the Gulf Veterans Association (GVA) and accepted by the Ministry of Defence (MoD) as their nominee on the Independent Panel established to consider the possible interactions between Vaccines and NAPS tablets. He has also served on the Gulf Support Group convened at the Royal British Legion. His involvement with the GVA brought contact with Chronic Fatigue Syndrome/Myalegic Encephalomyelitis (CFS/M.E.) and related disorders. Gulf War Illness/Syndrome (GWI/S) has much in common with M.E./CFS. He is Patron of the Sunderland and South Shields M.E. Association and a member of the Newcastle Research Group, which includes eminent physicians and scientists performing research in to CFS/M.E., where one recent aspect has been the identification of organochlorine pesticide poisoning being misdiagnosed as M.E./CFS. He has addressed meetings of the Pesticide Exchange Network and consulted to the OrganoPhosphate Information Network (OPIN). He worked with the Autism Research Unit (ARU) at the University of Sunderland for over 20 years, leading to involvement in biochemical studies to offer help, support and treatment for people with autism. This has also lead to research and urine-analysis of Indolyl-Acroyl-Glycine (IAG), which is an unusual metabolite found in excess of 90% of people examined in different groups of GWV, M.E./CFS and Organo-Phosphate (OP) poisoning sufferers. He served on the General Synod of the Church of England from 1970 to 1980 and he is a Christian Lay Leader, Preacher and Teacher. He is currently involved in three environmental campaigns: • Toxic waste dumping, including campaign against sewage in the sea presenting to the Select Committee on Sewage Treatment and Disposal • GWI/S, presenting to the Defence Select Committee • M.E./CFS and OP/Pesticide poisoning Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Abhijit Chaudhuri Dr. Chaudhuri was appointed as a Senior Lecturer and Consultant Neurologist in July 2000. Research on fatigue in common neurological disorders is the main theme of Dr. Chaudhuri's work. He takes special interest in myalgic encephalomyelitis (ME). His other areas of interest are multiple sclerosis, neuroimmunity, neurological infections and adult neurometabolic diseases. Dr. Chaudhuri was responsible for examining spinal tissue from Sophia Mirza prior to the inquest into Sophia's death. Professor Kenny De Meirleir Dr. De Meirleir is a world renowned researcher and is professor of Physiology and Internal Medicine at Free University of Brussels in Belgium. He is co-editor of Chronic Fatigue Syndrome: A Biological Approach, co-editor of the Journal of Chronic Fatigue Syndrome, and reviewer for more than 10 other medical journals. Dr. De Meirleir was one of four international experts on the panel that developed the Canadian Consensus Document for ME/CFS. He assesses/treats 3,000 to 4,000 ME/CFS patients annually. Professor Kenny L. De Meirleir, MD received his medical degree at Vrije Universiteit Brussel, Magna cum laude. His research activities in Chronic Fatigue date back to 1990. His other research activities in exercise physiology, metabolism and endocrinology have led to the Solvay Prize and the NATO research award. He is director of the Human Performance Laboratory and Fatigue Clinic at the Vrije Universiteit Brussel, as well as consultant in the Division of Cardiology and director of the cardiac rehabilitation program at Vrijie Universiteit Brussel. [4/10/01] Dr. Daniel Peterson Dr Peterson is an affiliate of the Sierra Internal Medicine Associates in Incline Village, Nevada; ME/CFS researcher and clinician; a board member of the American Association for Chronic Fatigue Syndrome; and member of the International Chronic Fatigue Syndrome Study Group. Dr. Daniel Peterson was one of the two physicians who identified the original outbreak of CFS in Incline Village, Nevada, in 1984. 31 Dr. Vance Spence Dr. Spence is a graduate of the Universities of London and Dundee. He was a Principal Clinical Scientist responsible for vascular services and research and, in 1997, he rejoined the University of Dundee Medical School as Honorary Senior Research Fellow in the Department of Medicine, with the objective of stimulating research into the causes of ME. Dr. Spence was instrumental in the founding and launching of ME Research UK. Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Mrs. Annette Whittemore Reno resident Annette Whittemore is President and Co-founder of the foundation. She became active in starting the foundation because she is the parent of a young adult who was severely affected by CFS and HHV-6 for the last 15 years. She and her husband are business owners and philanthropists in Reno and Sparks. She started the foundation with Kristin Loomis from California after a brief meeting in Incline, NV. with Dr. Daniel Peterson, a leading clinical researcher in CFS and HHV-6. "We wanted the ability to stimulate communication and research into the cause and effects of this illness. We've both felt the frustration of seeing too many doctors who could not help," she said. "Unfortunately for the sufferers of this disease, there have been very few doctors who have been able to understand the severe disability that HHV-6 and CFS can cause. By bringing world class researchers together we hope to unravel the path of this disease and develop new therapeutics while searching for a cure." Annette's husband Harvey is a prominent attorney and developer who is currently developing Coyote Springs a 43,000-acre master planned golf community in southern Nevada. Harvey and Annette are both supporters of the University of Nevada's academics and athletics, with a particular interest in the future Knowledge Centre on the Reno campus. The couple is also actively involved philanthropically with several churches and community organizations. 32 Dr. Byron Hyde Dr. Byron Hyde attended the Haileybury School of Mines and worked as a geophysicist. He then did premedicine in the Faculty of Medicine and University College, University of Toronto, obtaining a degree in chemistry and nutrition. He graduated in medicine from the University of Ottawa where he was the Director and Chief of the International Exchange Program for the Canadian Association of Medical Students and Interns (CAMSI). Dr. Hyde founded the International Summer School in Tropical Medicine. He interned at Hotel Dieu in Montreal, was a resident at St. Justine Hospital in Montreal and at the Ottawa Civic Hospital. He also studied in Munich at the University Kinderklinik and in Paris at the Necker Hospital for Children. He was a research chemist at the Roscoe B. Jackson Laboratory at Bar Harbour, Maine, a leading world laboratory in immunological research. Following this, he was Chief Technician in charge of the Electron Microscope Laboratory in Toronto at the Hospital for Sick Children, followed by a similar post at the University of British Columbia. Dr. Hyde has authored a book on Electron Microscopy and two non-medical books. Dr. Hyde has been a physician for 25 years and has performed charitable work as a physician in Laos and the Caribbean. He held the position of Chairman of the Ottawa Community Health Services Association, and is presently Chairman of The Nightingale Research Foundation. In 1984, Dr. Hyde began the full-time study of the disease process then known as Myalgic Encephalomyelitis (renamed in 1986 by Dr. Gary Holmes in the USA to Chronic Fatigue Syndrome). He has worked exclusively with M.E./CFS patients since 1985. In 1988, Dr. Hyde organized an association and founded The Nightingale Research Foundation, dedicated to the study of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. He has also acted as Chairman of the 1990 Cambridge Easter Symposium and of the Workshop on Canadian Research Directions for Myalgic Encephalomyelitis / Chronic fatigue Syndrome in May, 1991, at the University of British Columbia. (The above was extracted from the Nightingale Foundation website) Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Sarah Myhill Dr. Myhill is a general practitioner with a particular interest in chronic fatigue syndrome. She qualified from Middlesex Hospital Medical School with honours in 1981 and has worked in the NHS and in private practice. Dr. Myhill is an active figure in the British Society of Allergy, Environmental and Nutritional Medicine, and its Secretary and has been medical advisor to Action for ME. Dr Myhill is interested in diagnosis in the correct sense, finding the cause of illness, not simply in treating the symptoms. She has a special 33 interest in treating chronic fatigue syndrome (CFS) and have consulted over 100 farmers with CFS following organophosphate poisoning and 100 women with CFS following silicone poisoning either from breast implants or injection. Over the past twenty years Dr. Myhill estimates to have seen over 1,500 cases of chronic fatigue syndrome largely caused by viral infection. During the early years she reported these cases individually to the Medical Devices Agency. Ellen Piro President Norwegian ME Association Ellen Piro is the president of the Norwegian M.E. Association. In 1995 she circulated a worldwide petition to get the CFS name changed and she personally brought it to the Dublin CFS conference to urge the scientists to make a change. Recently Ellen has been involved in the investigation into the use of meningitis vaccines in Norw New Zealand and which has ben connected with the cases of over 250 ME patients. She has also contributed to the debate on the Norwegian equivalent of the NICE guidelines. Dr. Nigel Speight Consultant Paediatrician at Durham University Hospital Working as a consultant paediatrician at The University Hospital of North Durham, County Durham, Dr Speight is the best ME children's consultant in the UK. ay and Professor Martin Pall Professor of Biochemistry and Basic Medical Sciences, Washington State University USA Professor Pall has long-term interests in biological regulatory mechanisms. His current research is focussed on a theory he has developed on the cause (etiology) of chronic fatigue syndrome and the overlapping and related conditions of multiple chemical sensitivity, fibromyalgia, and posttraumatic stress disorder. According to this theory, each of these is initiated by stresses that induce increased levels of nitric oxide and its oxidant product peroxynitrite, followed by a biochemical vicious cycle mechanism associated with chronic elevation of these two compounds. Symptoms of these conditions are produced by both nitric oxide and peroxynitrite and treatment should focus on downregulating this vicious cycle mechanism. Vitamin B-12 injections commonly used to treat these conditions are proposed to act through the action of one form of B-12 (hydroxocobalamin) which is a potent nitric oxide scavenger. Dozens of biochemical and physiological observations provide support for this theory. The most puzzling features of these conditions are explained by this novel theory. Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 ME News from Around Europe Invest in ME believe that the seriousness and the scale of myalgic encephalomyelitis requires an international focus and this requires scientists, researchers, healthcare professionals and ME Support groups in all countries to work together. Collaboration may be the key to success and this means taking a consistent approach to research, diagnosis and treatment. The following updates from around Europe and USA were some of those Invest in ME received for the conference from people working in the ME community in other countries and illustrate the current status and problems in these countries. Norway – A Breakthrough? Recent news from Norway gives hope that changes are afoot in the way myalgic encephalomyelitis is being perceived and treated. After much campaigning the results of the Norwegian ME-forening (the Norwegian ME Association - the main support group for people with ME in Norway) is bearing rewards. On Thursday 29th March Stortinget (Norwegian Parliament) completed a 1 hour and 10 min debate about ME and what should be done about the situation. This has led to the Norwegian Minister for Health and Care Services announcing publicly a long list of proposals which she stated will be put into action to ensure that ME-patients get proper care. The minister, Sylvia Brustad, has now engaged herself personally in the case of ME. The health minister is on record as stating that more knowledge, support, research and funding is required to provide an adequate approach to this illness which is estimated to affect 10,000 Norwegians. "This is an illness which is difficult to diagnose and treat, and it is an illness to which health services have, up till now, given too little attention. This the government will change, and we will follow this up in the budget process" said minister Brustad. Severe ME - A story from Norway The story of the Krisner family from Norway was shown on the Invest in ME Conference DVD from 2006 – a story of one family where three siblings severely affected by ME. The mother, Kjersti, is a brave, resourceful and inspirational woman who manages still to see positives from the terrible situation. For those who have not seen the Norwegian TV channel Puls’ film please go to – http://www.investinme.org/Mediatelevision3.htm We called Kjersti to ask her how things were a year on. Her children are still very ill. Katrine, 28 years old in May, has been ill since the age of 20. She is the worst affected. She cannot communicate at all and touching her even gently hurts. She is being tube fed and in nappies. There are moments of hope but they are very tiny and don’t last long – sometimes a smile or being able to hold her mother’s hand. Once her mother was able to give her a hug. Bjornar, 30, is still lying in total darkness but can talk a little bit in the afternoon. He is getting mentally stronger and wants so much to get out of his situation but the body is too weak. The family can’t see him because he cannot tolerate any light and his room has to be kept in total darkness. Frode, 20, can get out in an electric wheelchair and work on a computer a couple of hours a day. He has started an internet company and is stable as he knows his limits. The Krisner family now have help in the form of a community nurse who comes and helps in the daytime. Before, the family had to manage all the care themselves and that has meant that Kjersti hasn’t been able to sleep much for many years as the children are so severely affected and have all different sleep patterns. Kjersti is optimistic and despite everything they laugh a lot in the family and she is constantly helping others in a similar situation. She is collating information on people with M.E. in Norway who are bedbound and who are tube fed. She says it is easier to do that in a small country and it gives vital information for the politicians. Kjersti feels patients themselves, and carers, are the experts in this illness and should be listened to. She wished us well with the conference and would have liked to attend but obviously she can't - but said she believes one day her turn will come. Such a strong and inspiring family despite everything. Invest in ME Charity Nr 1114035 www.investinme.org 34 Journal of IiME Volume 1 Issue 1 Denmark The situation for ME/CFS patients in Denmark deplorable. Although the disease it is is officially accepted as a physical one, the health care community and the media treat like a psychological one. There are no governmentappointed specialists and there are very few doctors who believe the disease is real. Of these very few, we know for sure that two have been told by their hospital supervisors that they may no longer treat “that type of patient.” Given this environment, very few doctors dare to give the G93.3 diagnosis. Some patients have been forced to accept a F48 diagnosis in spite of the fact that no psychological illness was found just to get a much-needed pension. Needless to say, there are no hospitals or clinics that treat or monitor the disease. Only one study has ever been done about ME/CFS in Denmark: "Illness and disability in Danish CFS patients at diagnosis and 5-year follow-up" by Andersen, Permin and Albrecht. The 9-year follow-up paper is soon to be published. It because it shows that is an important study, “recovery and substantial improvement are uncommon” – around 6% - and that “good mental health does not predict improvement.” So although the patient’s mood improved over time as they learned to cope with their illness, their physical symptoms worsened. This should give the pushers of CBT-as-cure something to think about! Overall, ME/CFS patients in Denmark are horribly neglected and many have given up hope of ever being taken seriously by the Danish health care system. The hope of the Danish ME/CFS Association is that we can soon bring about change like that which has recently been seen in Norway - Rebecca Hansen Consultant Association /Danish ME/CFS Spain Dear friends and colleagues far and near, Yesterday, the Catalan Parliament accepted the Popular Legislative Initiative on Chronic Fatigue Popular Legislative Initiative on Chronic Fatigue Syndrome/ME and Fibromialgia (FM), presented by representatives from 80% of the people with CFS/ME or FM who are Catalonia. This acceptance is the first step towards a worldfirst: Invest in ME Charity Nr 1114035 in associations in a law that would ensure proper services for people with CFS/ME and FM and a fair treatment by medical inspectors. No one thought that a group of ill people like us, in a not so user-friendly country would be able to pull this off. So we are all very happy and it is a big boost for the CFS/ME and FM community here. Now that it has been accepted, the signature gathering can begin. We need 50,000 signatures and we have a team of 150 signature- collection coordinators ("fedetarios") ready to roll. Once the signatures are gathered, the law will be discussed in parliament and voted. This will probably take place in the fall. Up to now, it has been a lot of work for us sick folks: writing the law and the document to justify each article of the law (thank you to all of you who sent me the necessary bibliography!), working with all the associations to create unity and the much needed empowerment, meeting with all political groups and sub groups (we have the support of all the political parties, except, of course, the party that runs the Health Ministry), campaigning to recruit signature coordinators, meetings with unions, women's groups others. It has not been easy as we are presenting a proposed law that puts totally into question the government's plan to keep CFS/ME and FM solely in Primary Health Care (where most doctors do not believe these illnesses exist or do not want to work with them and are not allowed to do any relevant tests), while our law, amongst other things, demands CFS-FM units. So we have had (and continue) to deal with pressures, intimidations, etc, from government and government-related organizations. We are also having to deal with the two foundations (one run by the government party, the other run by businessmen) who, up to now, had managed to control and manipulate the CFS and FM associations in Catalonia and create division. Encouraging the associations to be independent and to create unity has been hard but the most rewarding work. The documents (the law, the justification document and other documents) are available in Catalan and some in Spanish. If anyone is receiving them, let us know. -Clara Valverde (Promoting Commission of the CFS/ME-FM Popular Legislative Initiative, Catalonia, Spain) www.investinme.org interested in 35

Journal of IiME Volume 1 Issue 1 ME News from Around Europe (continued) Wasn’t that a headline of “The Economist” some years ago? Referring to the economic situation the magazine certainly didn’t think of the situation of people with ME/CFS in Germany. Though there’s said to be a slight upswing now, “The Economist’s” description still applies to the health care provisions for people with ME/CFS. They are more or less non existent. Germany is – compared to the UK – indeed the sick man of Europe. From our point of view the establishment of 50 CNCCs and LMDTs for England alone is a great success. The public awareness seems to be much more advanced than over here. We admire your determination, resilience and efficiency by which you have achieved this. From our point of view all that is the result of years of tenacious work of hundreds of active people who did not allow themselves to be deterred by all the obstacles they met on their way to a better care for people with ME/CFS. In a way you are our great role model when it comes to the situation of people with ME/CFS – in spite of all shortcomings and tragic cases like that of Sophia Mirza and others who died or are treated badly. Here in Germany the situation is by far not as advanced. There isn’t a single clinic which is specialised in ME/CFS. People are more or less left on their own and depend on their GPs. Only a handful of physicians are interested in the subject and care for people with ME/CFS, among them unfortunately also some quacks and cutthroats. Those who do serious work keep themselves in the hiding because otherwise they would be swamped with desperate and extremely needy people, searching for help and support. However, the patients sometimes have GPs who are sympathetic and willing to support them though their knowledge of ME/CFS mostly is quite limited. The physicians themselves are in a fix because there is no structure like a CFS society for physicians, no advanced training or other provisions where they can get information. Open-minded GPs read the information which is distributed via the national charity Fatigatio or websites like www.cfs-aktuell.de or www.cfs-portal.de . Germany the sick man of Europe? Thus the majority of the 250.000 or 300.000 sufferers in Germany do not even have a diagnosis. Those who suspect having ME/CFS or whose GPs assume this might be the case don’t have a place where to go and confirm or exclude the diagnosis. There is no place where they can get a proper advice in medical, social or legal matters. Most people have difficulties to get incapacity benefits on the basis of having ME/CFS. Yet this is not a “recognised” diagnosis but things are gradually changing. The vast majority of sufferers still end up in a psychiatric ward or in the practice of a psychologist or psychiatrist – getting a psychological or psychiatric “diagnosis”. More often than not incapacity benefits are paid on grounds of such a diagnosis and people often accept it with resistance because they have no choice. The psychosomatic health care provisions in Germany are quite good and they serve as some kind of waste disposal for all diseases which the physicians are not familiar with or cannot diagnose. Small wonder, that almost all ME/CFS patients are given a psychiatric diagnosis, leaving them in an even more desperate situation. They are told they'd have a depression, a psychosomatic or somatoform disorder (meaning it only looks like a somatic disease but in reality is all in the mind), a minor and insignificant functional disease. In Germany ME/CFS is mostly considered to be a functional somatic syndrome, i.e. a more or less psychiatric disease. Only recently (in February 2007) some psychiatrists published an article in “The Lancet” titled “Management of functional somatic syndromes” (by Peter Henningsen, Herzog), Stephan in which completely ignored. There is one national charity for people with Me/CFS founded in 1993 with the name "Fatigatio e.V.". Of course, the few people who run the charity cannot come up with the demand. The charity does not have the necessary resources, neither financially nor personally. There are also some local self-help groups, however, with little influence on the overall situation. Yet, there are more and more physicians who say "Oh yes, I've heard about this," and who take matters seriously. (Continued on page 37) Invest in ME Charity Nr 1114035 www.investinme.org the biomedical Zipfel, Wolfgang research 36 is Journal of IiME Volume 1 Issue 1 ME in Germany – continued from page 36) After all, campaigns like SPARK in the USA and the good work that is done in Great Britain and all over the world has some trickle down effect. Looking to the UK and your achievements provides us hope and confidence that we will one day no longer be forced to living in the sticks. All in all you can see that we in Germany are lagging behind your developments at least 15 or 20 years! By Regina Clos Regina Clos has worked for some years for the national charity Fatigatio and is now running a German spoken website ( www.cfs-aktuell.de ) with up-to-date information on ME/CFS and many translations of articles and booklets published in Great Britain, Australia, the USA and Canada. She is a sufferer herself for more than 20 years and became a translator after she had to give up her job as a teacher for handicapped children. Sweden In Sweden, ME is largely unknown by doctors as well as the general public. To the extent it is discussed, it is under the name of “Kroniskt trötthetssyndrom”, which literally translates as “Chronic tiredness (not fatigue!) syndrome”. There are no ME specialists available for diagnostic evaluation or treatment management. The ME clinic at Huddinge Hospital in Stockholm was closed in 2000. Some patients have been diagnosed at the Gottfries Clinic in Gothenburg which specializes in Fibromyalgia and CFS, but getting a referral can be difficult or impossible depending on where in the country you live. This clinic is also under the threat of losing public funding and being forced to close down. There are a few individual doctors with some knowledge of ME, and some GPs who are willing to learn, but for the most part patients are left to GPs that range from ignorant to downright insulting. The view that all forms of chronic fatigue equal a somatoform syndrome is widespread, and reinforced through articles in the medical union’s member journal, “Läkartidningen”. We believe ME is tremendously under diagnosed in Sweden. The code G93.3 is virtually never used, and patients with this diagnosis code may have it changed by a new doctor without explanation. Most likely, sufferers are instead diagnosed with “burn-out syndrome” (or “exhaustion depression”), as this was a very common problem in Sweden particularly during Invest in ME Charity Nr 1114035 the 1990’s. The obvious problem with this misdiagnosis is that it leads to unreasonable expectations on recovery speed and capacity for physical activity. With time, when the patients don’t improve and claim to be unable to exercise, they are met with increasing disbelief from doctors and others. There is also a strong tendency in Sweden at the moment to question the “overuse” of sickness benefits and reduce the number of claimants by rejecting more claims. As in many other countries, special insurance doctors second-guess the patient’s own doctor, and some claim illnesses such as ME and Fibromyalgia don’t exist. This puts many patients in a desperate financial situation. Some fall between the chairs when they are considered too healthy for sickness benefits, but too sick to register as unemployed and claim unemployment benefits. The research being carried out has mostly focussed on the psychosomatic angle, and included larger groups of chronically tired patients who do not fulfil stricter ME criteria. However, Professor Gottfries and his colleagues in Gothenburg have conducted a very promising trial using a staphylococcus vaccine. 2/3 of patients experienced positive effects, especially on immune symptoms and recurring infections. Many were able to return to work or increase the number of hours worked, and generally increase their quality of life. Unfortunately, this research has now been stopped due to manufacturing problems with the vaccine, and patients doing well on the treatment for several years are being forced back to a life of illness as the supplies run out. The national patients’ organisation, RME, has approximately 370 members, and is working with very limited resources to improve the situation for sufferers and increase awareness. Some regional groups have been making limited progress, but it’s very much a process of one step forward and two steps back. Anna Fenander, RME Stockholm Facts About ME ME is now 5 times more prevalent in the UK than is HIV/AIDS. 37 www.investinme.org

Journal of IiME Volume 1 Issue 1 ME News from USA – Pat Fero – Wisconsin ME Group Investing in ME…from the other side of the pond By Pat Fero, MEPD I live In Wisconsin, which is the other side of the pond, and a few Great Lakes over to the Midwest, USA. It is only though information technology that I know about Myalgic Encephalomyelitis in 2007. When I first saw the words Encephalomyelitis, synthesize medical understanding of CFS issues. Myalgic I did not search with fervor to information into my growing Despite working as Executive Director of the WISCONSIN CFS ASSOCIATION and being on the Board serving in one capacity or another since 1987, it was 2003 or 2004 before I began to look at ME. Why is that? This is the landscape question, the backdrop for what follows, that is, my perceptions about ME and about CFS in the United States. Humans learn best when they have a need to know about a thing. When that happens they are ready to ask questions. Here in US, the need to know about ME exists with a few vocal advocates and people who have quietly investigated ME for the sake of “name change.” Within that group, controversy rages, but that is the only place CFS diagnosed patients give ME an iota of thought. Why is that? First, I believe that in the United States, with about 300 million people and a land area of over 9 million square kilometers, we do not have a CFS community. To foster community development that would create a shared understanding of CFS would mean organized education, awareness and advocacy. If we had a community, the vast numbers of diagnosed CFS patients would be far greater than a mere 20% of an estimated 800,000. By far, the majority of people ill have no diagnosis or are misdiagnosed. That being the case, MD’s and other medical professionals have little need to know about CFS and the few of us presenting in the doctors offices can easily be disregarded. In fact, sweeping CFS into a larger entity of fatigue and pain is the logical outcome. Investing in research centers to study pain mechanisms and fatiguing illnesses, denies the integrity of CFS. Integrity? Historically, ME has integrity as a distinct illness entity with diagnostic criteria until issues Invest in ME Charity Nr 1114035 muddled when the US became international researchers and MDs. involved with is a THIS generalization and an oversimplification. However, we can cite the mid 1950’s work of Melvin Ramsey and John Richardson. in CFS as a distinct illness entity with diagnostic criteria is impossible. I agree with Dr. Byron Hyde that once the Centers for Disease Control became involved in the Lake Tahoe epidemic, outbreak, incident and finally non entity, patients in the US suffering from ME, were left to wander about until the powers that be met in 1988 to label their illness chronic fatigue syndrome. In 1988, where I live, there was integrity in CFS. By this, I mean that my communications were with 100’s of people who had like illness experiences. 5 years and many 100’s of calls later, I knew that the “CFS” experience changed. Much later, I found that my perceptions were correct. The CFS pain and fatigue waste bin was huge as was my familiarity with lists of co morbid psychiatric conditions that heard of until the mid 90’s. In 2000, in WISCONSIN, our CFS organization decided that our mission of education and awareness was too narrow. What was the topic? How could we sort out this waste bin of misdiagnosis, over diagnosis and under diagnosis? What a mess. On a national level with a small group of people compared to the potential whole, we are a huge dysfunctional family. Bitter, personal tiny issues signals the loss of hope to stop the CFS nonentity spiral. I see ways to stop enabling and perpetuating chaos. In the US, community. first, we must work on developing CFS This means a massive information campaign in 52 states. Because our public health institutions are in the middle of the Chaos, the effort has to start grassroots from people like me and the wonderful people in Atlanta and Northern Virginia and Vermont and Chicago and…and. We cannot forget about the people in Wyoming or Montana or anywhere else where the population density is so low that we might think that sick people do not count. Secondly, I believe that existing US national, state organizations and regional groups must be inclusive to promote collaborative efforts that will stop sick people from reinventing the wheel. (continued on page 39) www.investinme.org I had never In contrast, looking for integrity 38 infighting over Journal of IiME Volume 1 Issue 1 (News from USA – continued from page 38) It is a waste time and energy. In addition, we have wonderful independent groups in the US totally devoted to ME. Those involved are sick, they are dedicated and they work. YES! A continuum of thought is as real as the color wheel. Do we say… pink is not a primary color…. OOPS…not allowed? What about sky blue pink? You know exactly what mind image you have of sky blue pink, that hue (s) is not on the color wheel at all. I don’t know how to promote collaborative efforts other than narrow the focus to the basis for all like human endeavors: people in need, people with fractured families, some on the streets need information and help. Many kind people here with CFS work on this every day. We just need a more organized effort and to find ways to help them help others. Thirdly, Chaos creates phantom enemies and it is easy enough for an institution and people to obstruct progress by perpetuating the same old stories. Are there real enemies? I think a combination of factors makes people behave badly and as a result; whole groups suffer with no understanding, let alone help. In addition, people interested in power and establishing an identity through CFS advocacy or CFS research perpetuate chaos because they tend to be exclusive. I mean and whatever My thought would be to ignore anyone who would obstruct by deceit, hostility and engaging in activities to merit a few, not the whole. I would seek out the 100’s of people working for the common good and forget the rest. really sick I am investing in ME by tackling problems in my own back yard. I have to work with what is and we have a long way to go before my ME will be recognized or diagnosed in the United States. I am Investing in ME. The founders, in the right place, at the right time, are bringing order from chaos. What a wonder it has been to watch from afar! HELLO from WISCONSIN and THANK YOU! 39 Story – A Carer of a Person with ME By Greg Crowhurst Caring for someone with severe ME - Five Stark Facts There is no support, there is no cure, there is no treatment, there is no government funded physical research and there is little truth in any of the official policy statements. The scale of the suffering is off the scale. The severely affected will experience not a moment’s relief, and carer are routinely pushed to the limits of human endurance. The severely affected are likely to be experiencing between intolerable symptoms all at once. This pain, paralysis, numbness, sickness, unbearable hypersensitivity and incredible physical disability. Fatigue is not the issue; it is only one symptom among many; Post Exertional Malaise is the major concern. Any exertion is likely to have a shocking after-effect, typically 24 to 48 hours afterwards, which can lead to days, weeks, years of worse symptoms or even death. Invest in ME Charity Nr 1114035 twenty and thirty includes Sufferer’s and carer’s are unwilling pawns in a political game. evidence of powerful There is overwhelming vested financial interests at work, across all levels of government, trying to suppress the physical reality of ME, which is far more prevalent than AIDS or MS. Currently, the main interventions on offer are psychiatric. often for decades on end. Sufferer ME Story My GP thought I had ME but kept saying, work through it, do lots of exercise you'll get over it. They sent me to a sports centre to do a fitness course but I went once and never again. It was about this time I saw the psych and he said there was nothing mentally wrong that feeling well again wouldn't fix - Jas www.investinme.org

Journal of IiME Volume 1 Issue 1 NICE - IiME Response to Draft Guidelines on ME The National Institute for Health and Clinical Excellence (NICE) have recently published their draft document for clinical guidelines. The document is being developed for use in the NHS in England and Wales regarding chronic fatigue syndrome / Myalgic Encephalomyelitis (CFS/ME). Although not an original stakeholder (IiME only became a charity in May 2006) we have nevertheless registered to become a stakeholder in these guidelines and have supplied our response directly to NICE. Our full response is available here – www.investinme.org/Documents/PDFdocuments/Invest%20in%20ME%20Response%20to%20NICE%20Draft%2 0Guidelines.pdf Summary of Response from IiME: The reaction to the NICE guidelines can be summed up as profound disappointment that NICE have chosen to highlight, yet again, Cognitive Behavioural Therapy (CBT) and Graded Exercise (GET) as the most effective forms of management (aka treatment) for ME. Psychiatric paradigms are referred to and recommended as therapies and as treatments for ME despite ME patients and groups stating they are ineffective or harmful. Graded Exercise Treatment (GET), already known to be potentially harmful to people with ME, is put forward as a therapy/treatment GET is put forward, along with Cognitive Behaviour Therapy (CBT), as treatments of first choice The NICE group formulating these guidelines show a disingenuous side by comparing the use of these treatments for ME with the use of these treatments for cancer and diabetes and other illnesses. Yet CBT is not offered as first line treatments for these illnesses which NICE are recommending here for CFS/ME. It is not for sensation that IiME would like to see a lawyer added to the NICE consultation group. The lawyer would be there to represent ME patients as one can foresee that there will be litigation against the people making recommendations for use of GET/CBT when a patient suffers, or dies, from putting into practice such guidelines. IiME believe these Draft Guidelines should state unequivocally that it is unacceptable for patients with ME to be subjected to “sectioning” by psychiatrists, supported by Social Services and the Police, simply because the person has ME. We dispute the frequent statements characterised by this text ‘There is little understanding of the nature of the disease ‘. There are over 4000 biomedical research papers on the illness which the NICE searches should have seen and analysed. The NICE guidelines do not carry a single reference to the relationship between vaccinations or epidemics. The document is inconsistent in a number of areas - especially terminology. The inclusion of as wide a possible base of chronic fatigue states in the draft guidelines is clearly evidenced and does a disservice to pwme Essential biomedical research which distinctly shows the biological nature of ME is ignored The lack of proper discussion of the Canadian guidelines shows not only a bias to outdated and flawed information but invalidates much of the data used to justify the proposals The layout and format of the document is poor. The objectives of the Nice Draft Guidelines are not met. The credibility of NICE is now severely compromised. Yet again ME patients seem to be on the receiving end of another counter-productive and biased analysis. The document shows little new thinking and is clearly lacking in impartial analysis of all areas of research into ME. Both the Chairman and CEO of NICE were invited to speak at the conference but both declined 40 Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 The Gibson Inquiry "This group believes that the MRC should be more open-minded in their evaluation of proposals for biomedical research into CFS/ME and that, in order to overcome the perception of bias in their decisions, they should assign at least an equivalent amount of funding (£11 million) to biomedical research as they have done to psychosocial research. It can no longer be left in a state of flux and these patients or potential patients should expect a resolution of the problems which only an intense research programme can help resolve. It is an illness whose time has certainly come.” Thus concluded the report from Dr Ian Gibson (MP)’s Group on Scientific Research in to Myalgic Encephalomyelitis (ME) – otherwise known as the Gibson Inquiry. Unfortunately, that time is too late for some of the victims who have lost their lives to this devastating illness. Invest in ME welcomed the broad message of this report when it was published in November 2006. The Inquiry called for ME to be given due recognition, alongside heart disease and cancer. It also called for ring-fenced money for bio-medical research as happened with AIDS. ME in fact affects five times as many people as does AIDS in the UK but can have a much more devastating impact on quality of life. The Inquiry recommended that research must be made a priority and suggested that £11 million should be made available for research to redress the balance in an illness where too much emphasis had been put on psychological “coping strategies”. The Inquiry accused the MRC of merely “paying lip-service” to the call for bio-medical research. Invest in ME felt that at last an official acknowledgment was given that ME is a severe, incapacitating, illness and that those who suffer from it, as well as their carers and families, may have their lives completely ruined. Invest in ME have been asking for a long time for very simple, common-sense things such as the adoption of comprehensive diagnostic criteria and epidemiological studies. We were delighted that the report agreed that this was vitally important. This report did not stint in its criticism of the Medical Research Council and NICE. NICE should rethink Indeed, it warns that very carefully one of its recommended treatments, Graded Exercise Therapy (GET), because of evidence that in 80% of M./E. sufferers there was diastolic cardiomyopathy. Invest in ME has warned NICE during our review of the Draft NICE Guidelines for ME that by recommending GET they would put patients lives at risk, and risk Judicial Invest in ME Charity Nr 1114035 Review. We still hope that NICE will take notice. Invest in ME also welcomed the call for an independent scientific committee to be established to oversee all aspects of research, as well as an inquiry into the vested interests of insurance companies whose advisors also act as advisors to the DWP. Dr Gibson’s Group recommended an investigation of these vested interests by a standards committee because, it stated, too often patients have to live with the double burden of fighting for both their health and their benefits. Invest in ME believe that we must use the positive aspects of the inquiry report and move forward and ensure that people are correctly diagnosed with this illness and that doctors and scientists treat patients knowing and accepting that they have a genuine and serious illness. Invest in ME have called on the government and MRC take this opportunity and work with the ME community and biomedical researchers to ensure that this illness can be understood, that proper biomedical research is funded and that archaic and unjust perceptions by government departments, sections of the health service and those responsible for deciding funding strategy are once and for all discarded. Dr. Gibson has created an opportunity to benefit patients and find a cure for this illness. Invest in ME ask the government to ensure that Full 41 this opportunity is not lost and that yet another generation of UK citizens is not abandoned. report available at - http://tinyurl.com/ynqhtc IiME’s reactions to the report are at - http://tinyurl.com/2aqnye ME Story We arrived at the doctors and the female doctor refused to see me, saying I was not her patient, and she wasn't prepared to see me. I was just in a state of shock and my partner was furious. The Doctor in question didn't come out to the waiting room to see me, instead wrote a prescription for three months of anti-depressants - Jan www.investinme.org

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS by Margaret Williams (updated) April 2007 ME/CFS is a complex, whole body systemic disorder and it is difficult to compile a unified reference list of the documented biomedical abnormalities, immunological, neurological, endocrinological, gastro-intestinal, reference papers themselves overlap considerably. ocular, cardiovascular, respiratory etc). since so many medical disciplines are involved (eg. musculo-skeletal, The The biomedical reference papers now number over 4,000 and some of these reference papers are listed in 92 pages of references online at http://www.meactionuk.org.uk/SUBJECT_INDEX.htm. The few illustrations below provide indisputable evidence of organic disease, thereby demolishing the psychiatric lobby’s assertions that there is no such evidence. The reference papers can be broadly categorised into the following sections and it is necessary to be familiar with all sections. HISTORICAL PAPERS ON ME These date from 1957 -- 1980 and include excellent clinical descriptions, laboratory-determined abnormalities and post-mortem findings. GENERAL PAPERS ON ME/CFS These papers cover more than one aspect of ME/CFS and include for example evidence of impaired oxygen delivery to muscle; evidence of delayed recovery from fatiguing exercise and documented symptoms commonly found in ME/CFS (which number over 60). LABORATORY FINDINGS IN ME/CFS Although there is as yet no single, specific, definitive test for ME/CFS (which is also the case in numerous other medical conditions including multiple sclerosis), nevertheless there is an entirely consistent and reproducible pattern of laboratory-determined abnormalities which have been observed and documented worldwide. Such abnormalities particularly include dysfunction of immunological, cardiovascular, pulmonary and cognitive parameters. QUALITY OF LIFE IN ME/CFS One international ME/CFS expert writes that in his experience, ME/CFS “is one of the most disabling diseases that I care for, far exceeding HIV disease except for the terminal stages”. Australian research describes ME/CFS patients as suffering more dysfunction than multiple sclerosis sufferers; the sickness impact profile (SIP) is more extreme than in end-stage renal disease and heart disease, and only in terminally ill cancer patients has the overall SIP score been found to reach that found in ME/CFS. neurological, neuro-endocrinological, musculo-skeletal, 42 American research found that the quality of life in patients with ME/CFS is significantly, particularly and uniquely disrupted, and that the illness causes marked disruption and devastation. Scandinavian research has shown that patients with “non-visible” disability suffer more stigmatisation than those with visible disability. CHRONICITY AND SEVERITY OF ME/CFS This section provides evidence of the natural history of severe ME/CFS, showing that the prognosis is extremely poor for the severely ill subset, with no symptom improvement (only 4% recovered) and it shows symptom patterns in longduration ME/CFS. PRECIPITATING FACTORS IN ME/CFS The syndrome is known to be related to a dysfunctional stress response, and there is evidence that precipitating factors include physical trauma (specifically a breakdown in the blood-brain barrier) and critical life events. Other factors include infections; anaesthesia; immunisations and exposure to certain chemicals. (continued on page 43) Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) EPIDEMIOLOGY OF ME/CFS Various papers on the epidemiology of ME/CFS reveal that considerable misinformation exists regarding the appropriate evaluation of ME/CFS (including age, gender, occupation, geographical location, length and severity of illness) but that there is increasing understanding of the prevalence, incidence, risk factors, illness patterns and prognosis of this complex multi-system disorder, and emphasis is placed on the importance of subgroups. Although ME/CFS is one of the commonest chronic neurological conditions in the UK today, no official government-sponsored statistical evaluation has yet been made, possibly due to the heterogeneity of the disorder and the lack of a concise case definition. NEUROENDOCRINE ABNORMALITIES IN ME/CFS This section shows evidence for and implications of the endocrine disruption found in ME/CFS, especially that associated with hypothalamic-pituitary-adrenal axis dysfunction. CT scans of the adrenal glands have revealed that both the right and left adrenal glands of some ME/CFS patients are reduced in size by 50% when compared with healthy controls. NEUROLOGICAL ABNORMALITIES IN ME/CFS (including vertigo and seizures) These papers show commonly found dysfunction in both the central nervous system and in the autonomic nervous system; they include papers on dysequilibrium and vertigo which are known components of severe ME/CFS, and there is evidence that seizures may occur in ME/CFS. DEMYELINATION IN ME/CFS Evidence of demyelination and cerebral oedema has been documented in the ME /CFS literature since 1988. OCULAR PROBLEMS IN ME/CFS There is evidence that such problems include intermittent jelly-like nystagmus; difficulty in accommodation / focusing / visual acuities; photosensitivity; photophobia; blurred vision; double vision; crusted eyes; dry eyes; itchiness; narrowed arterioles; retinal defects; fibrillar changes in vitreous; chorioretinal macular abnormalities and optic pallor (the latter is also observed in MS). Objective findings of the anterior segment suggest an organic aetiology. LIVER / SPLEEN INVOLVEMENT IN ME/CFS Published evidence shows that enlargement of the spleen and liver is not unusual. Evidence shows infiltration of the splenic sinuses by atypical lymphoid cells, with reduction in white pulp, suggesting a chronic inflammatory process. HAIR LOSS IN ME/CFS Hair loss in ME/CFS is documented in the literature. One author states “It is a rare woman with CFS who has not had hair loss, usually diffuse and non-scarring”. Elsewhere, it is documented as occurring in 20% of patients. MOUTH ULCERS IN ME/CFS Mouth ulcers have been documented in the ME literature since 1955. VIROLOGY IN ME/CFS Evidence reveals the known tropism of Coxsackie B viruses for muscle, brain, heart and pancreas, all of which are documented as being target organs in ME. There is also evidence of human herpes virus 6 (HHV6) reactivation playing a role in the pathogenesis of both ME/CFS and MS. HHV6 Variant A is more common in AIDS and ME/CFS, whilst Variant B is found in MS. HHV6 used to be called human B-lymphotropic virus (HBLV); it was discovered in 1986. It is possible that reactivation of a composite viral load occurs as an epiphenomenon of an underlying immune system dysfunction, thus giving rise to the protean symptomatology. (continued on page 44) 43 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) OVERLAP OF ME/CFS WITH POST POLIO SYNDROME Prestigious papers, for example, Annals of the New York Academy of Sciences 1995 (containing 50 papers on clinical neurology, neuroscience, electrophysiology, brain imaging, histology, virology, immunology, epidemiology, with contributors from the US, Australia, Canada, France, Sweden and the UK) point out the similarities between post-polio syndrome and ME/CFS, notably that the mechanism of the extreme fatigue (called “visceral exhaustion”) -- is exactly the same in ME/CFS as in PPS. STRESS ENHANCES SUSCEPTIBILITY TO INFECTION There is substantial evidence that concurrent stress at the time of viral exposure leads to more severe disease. Stress is known to increase susceptibility to those diseases that are immune-related, eg. infectious disease, cancer and autoimmune disorders. PSYCHONEUROIMMUNOLOGY There is a vast literature (from 1884 to date) on the pathway of causation whereby stress, especially traumatic stress, affects the immune system and potentiates disease development. CHEMICAL INJURY TO THE BLOOD BRAIN BARRIER There is published evidence to show that one mechanism of causation is likely to be a combination of stress and chemicals, resulting in chemical trauma to the brain via a breaching of the blood brain barrier (BBB): stress can intensify the effects of some chemicals, making them very harmful to the brain, nervous system, and liver (resulting in congested blood vessels, reduction of an important enzyme and abnormal fatty deposits), leading to cellular death, especially when chemicals are combined. The ability of chemicals to leak from one area of the brain to another holds the potential for much greater damage to occur in the entire brain. IMMUNOLOGY IN ME/CFS The most commonly found immune abnormalities are very low natural killer (NK) cells, with decreased cytolytic activity, and an increased CD4 - CD8 ratio; there is an increase in the CD8+ cytotoxic T cells bearing antigenic markers of activation on their cell surface; there are higher frequencies of low levels of various autoantibodies, especially antinuclear and anti-smooth muscle antibodies; there are low levels of circulating immune complexes; there are increased levels of IgE and decreased levels of IgG3. Low levels of IgG3 have been reported since 1986 in patients with aching muscles. Overall, these abnormalities are consistent with evidence demonstrating chronic, low-grade immune activation in ME/CFS. In 1994, an international ME /CFS expert (Dr Paul Levine of the Viral Epidemiology Branch of the National Cancer Institute, Bethesda, Maryland) stated “ the spectrum of illnesses associated with a dysregulated immune system must now include CFS” (ref: Clin Inf Dis 1994:18 (Suppl 1):S57-S60). Importantly, it has been convincingly demonstrated that changes in different immune parameters correlate with particular aspects of disease symptomatology and severity. ALLERGIES and MULTIPLE CHEMICAL SENSITIVITY (MCS) IN ME/CFS The relationship between viral infections and onset of allergic disease is well-documented in the medical literature. With specific relationship to ME/CFS, there is overwhelming published evidence that allergies, food intolerance and multiple chemical sensitivities (MCS) are very common; an increasing sensitivity and adverse reaction to many drugs / therapeutic substances is widely believed to be virtually pathognomonic of ME/CFS. Cells cannot be attacked by the immune system unless they display on their surfaces complex glycoprotein molecules known as Class II MHC antigens; cells can be induced to do this by gamma-interferon, which is an anti-viral chemical produced by the immune system when under viral attack. Allergies in ME/CFS are thought to be the result of this mechanism, which makes the body cells susceptible to on-going attack by the immune system. Because reference to allergies is so widespread throughout the ME/CFS literature, many of these references are to be found throughout the reference papers, mostly in the sections on General ME /CFS, Immunology, and Neuroendocrinology. More and more patients are presenting with “total allergy syndrome”; this is recognised as part of ME/CFS; whilst some psychiatrists are notoriously dismissive about its existence, the literature (from highly reputable internationally acclaimed experts) clearly shows that it does exist, and that such patients do indeed develop abnormal immune parameters whilst under observation. (continued on page 45) Invest in ME Charity Nr 1114035 www.investinme.org 44 Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) A leading professor of clinical immunology in the UK has published papers confirming that these are patients with multiple sensitivities, and that their symptoms are not all in the mind. ANAESTHESIA PROBLEMS IN ME/CFS It is well-established that patients with ME/CFS and others with neuromuscular dysfunction can have problems with anaesthesia: depolarising muscle relaxants have a known risk of causing potassium release from muscle, which can lead to cardiac arrest, and it respiratory failure. VASCULAR PROBLEMS IN ME/CFS References to vascular problems in ME/CFS have been in the medical literature from 1938. Such problems include vasomotor instability; impaired blood flow in the micro-circulation consistent with inflammatory processes; vasculopathy including Raynaud’s disease; cutaneous vasculitis; vasculitis of the liver and cerebral hypoperfusion due to vasculitis. CARDIAC PROBLEMS IN ME/CFS Documented problems include myocarditis; chronic pericarditis; paroxysmal attacks of chest pain, with the intensity of myocardial infarction; palpitations, with sinus tachycardia being particularly troublesome; flattening and inversion of T waves; a lower stroke volume and cardiac output (indicating a defect LUNG / RESPIRATORY PROBLEMS IN ME/CFS There is evidence of shortness of breath in ME/CFS patients (due in part to fatigue of the voluntary muscles of respiration); evidence shows that ME/CFS patients have a significant decrease in vital capacity (VC). The incidence of bronchial hyper-responsiveness is remarkably high. Compared with controls, ME/CFS patients showed a significant reduction in all lung function parameters studied. GUT DYSFUNCTION IN ME/CFS Irritable bowel syndrome (IBS) is a widespread and common problem in ME/CFS; reference to it throughout various sections of the reference papers. BRAIN IMAGING (NUCLEAR MEDICINE) IN ME/CFS The literature contains objective evidence of brain impairment in the majority of patients which is compatible with a chronic viral encephalitis. Patients have a particular pattern of hypoperfusion of the brainstem. Brain perfusion impairment in ME/CFS provides objective evidence of central nervous system dysfunction. COGNITIVE DYSFUNCTION IN ME/CFS Neuropsychological testing reveals a pattern of cognitive impairment which is compatible with an organic brain lesion. Tests on ME/CFS patients revealed a performance which was sevenfold worse than that found in either the controls or in depressed patients. Results indicate that the memory deficit in ME/CFS is more severe than has been assumed by the CDC criteria. A pattern has emerged of brain behaviour which supports neurological compromise in ME /CFS. PSYCHOLOGICAL PROBLEMS IN ME/CFS There is a substantial body of literature which strongly refutes claims that patients are overly suggestible; it is quite specific that patients are not somatising, and it confirms that patients are not exhibiting “abnormal illness behaviour” and that the illness is not explained by inactivity or psychiatric disorder. Any depressive symptoms present are more likely to be a consequence rather than a cause of illness. Serious doubts are raised about the validity of the application of a psychiatric label. A conviction by patients of physical illness is demonstrated to be understandable and legitimate. (continued on page 46) Invest in ME Charity Nr 1114035 www.investinme.org is to be found in the higher cortical modulation of cardiovascular autonomic control). ME/CFS patients have higher heart rates and lower pulse pressure and have baseline differences from normals. is important to avoid histamine releasers. Muscle weakness increases the risk of 45

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) COGNITIVE BEHAVIOURAL THERAPY IN ME/CFS Evidence shows it is at best ineffective and at worst harmful in authentic ME/CFS. GYNAECOLOGICAL PROBLEMS IN ME/CFS A number of gynaecological conditions have been found to occur more frequently in women with ME/CFS, for example endometriosis is reported to occur in up to 20% of women with the disorder; cystic enlargement of the ovaries may be present and can be seen on ultrasound scan. A history of ovarian cysts, including polycystic ovaries and uterine fibroids was found in one study to be more common in patients than in controls. Prostatitis is common in men with ME/CFS. SPECIAL PROBLEMS IN CHILDREN WITH ME/CFS It is not widely recognised that children and adolescents can suffer from ME/CFS, which has been found in children as young as five. There may be appalling problems with ignorant authorities, with children being forcibly removed from their homes and placed in the “care” of the State and the parents accused of child abuse; one consultant paediatrician who specialises in ME/CFS is on record as confirming that the number of such cases now amounts to an epidemic. The presentation in young people may differ from that in adults. Some children require tube feeding. Education may be a particular problem. There are many horrific stories of inappropriate and damaging psychiatric interventions. The Review Article by Professor Leonard Jason et al is essential reading (Chronic Fatigue Syndrome in Children and Adolescents: A Review. Karen M Jordan, Leonard Jason et al. Journal of Adolescent and Child Health 1998:22:4-18) SIMILARITIES AND DIFFERENCES BETWEEN ME/CFS AND FIBROMYALGIA Although there is some overlap of symptomatology in both conditions, there are significant differences between ME/CFS and FM: the WHO lists them as separate disorders in the ICD and there are important laboratory distinctions (eg. levels of somatomedin C; substance P; CBG levels; secretion of ATP; acetlycholine sensitivity; endlothelin-1 levels etc). Studies suggest that those with co-existent disorders face an additional burden of suffering and a worse outcome. GENETIC ABNORMALITIES IN ME/CFS There is unequivocal evidence of acquired abnormalities in numerous genes involved in energy production and with the neurological and immunological systems. PATTERNS OF MEDICAL MISDIAGNOSIS Misdiagnosis is very common in complex and poorly understood illness and patients are often ignored or dismissed by medical practitioners without justification. This increases their suffering. The literature abounds with evidence that patients have often been given an inappropriate label (usually by psychiatrists), and that such labels abruptly disappear when medical science and knowledge discover an underlying organic aetiology. Examples are legion, and include diabetes, hypothyroidism, pernicious anaemia, peptic ulcer, multiple sclerosis and Parkinson’s disease -- in the 1940s, psychiatrists claimed that the intention tremor was due to the inner conflict of the patient who wished to masturbate but who knew it was wrong, and that the intention tremor was a manifestation of such inner conflict; it was not until the discovery of the neurotransmitters and the role of dopamine that such views were abandoned. Unfortunately, some psychiatrists seem unable learn from past experience. (continued on page 47) 46 Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) 1957 A BRIEF SELECTION OF BIOMEDICAL REFERENCES ON ME/CFS 1983 An investigation into an unusual disease seen in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years. AL Wallis. Doctoral Thesis: University of Edinburgh, 1957. (This is an excellent and accurate description that details the varying clinical picture, the abnormal physical findings and post mortem histopathology). 1969 Disseminated Vasculomyelinopathy. M Poser. Charles Acta Neurol Scand 1969:S37:7-44. (This details postviral infectious states and subsequent development of allergies and is highly relevant in view of recent autopsy findings of severe inflammation in the dorsal horn in the case of Sophia Mirza). 1976 Benign Myalgic Encephalomyelitis or Epidemic Neuromyasthenia. September 1976:539-542. features). 1978 An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955. Nigel Dean Compston. Journal, November 1978:54:722-724. Postgraduate Medical (This documents the clear evidence of organic involvement of the CNS). 1979 Clinical and biochemical findings in ten patients with Benign Myalgic Encephalomyelitis. AM Ramsay; A Rundle. Postgraduate Medical Journal, December 1979:55:856-857. (This describes the dominant clinical features -- abnormal muscle fatiguability and pain; circulatory impairment and hypothalamic damage; cognitive impairment – and notes impairment of cell membrane permeability). 1981 Was it Benign Myalgic Encephalomyelitis? CS Goodwin. Lancet 1988; January 3rd: 37. (This notes the three major features of the disease and documents abnormal physical findings). Invest in ME Charity Nr 1114035 AM Ramsay. Update: (This sets out the cardinal Sporadic myalgic encephalomyelitis in a rural practice. BD Keighly; 1983:33:339-341. EJ Bell. JRCGP June (This provides a good clinical summary and notes a pattern to the complexity of symptoms). 1985 Electrophysiological studies in the postviral fatigue syndrome. Goran A Jamal; Stig Hansen. JNNP 1985:48:691-694. (This documents abnormalities in muscle, including type II fibre predominance, scattered fibre necrosis; bizarre tubular structures and mitochondrial abnormalities). 1987 Myalgic Encephalomyelitis (ME) Syndrome – an analysis of the findings in 200 patients. J Campbell Murdoch. The New Zealand Family Physician 1987:14:51-54. laboratory findings, including the presence of positive smooth muscle antibodies and antinuclear antibodies). 1987 Phenotypic and functional deficiency of natural killer cells in patients with Chronic Fatigue Syndrome. M Caliguri, AL Komaroff et al. J Immunol 1987:139:3306-3313. abnormally low numbers of NK cells). 1988 Chronic Fatigue chronic viral infections. AL Komaroff. Syndromes: relationship to Journal of Virological Methods 1988:21:3-10. (This documents unusual and abnormal findings, including hepatosplenomegaly). 1988 Allergy and the chronic fatigue syndrome. Stephen E Straus et al. J Allergy Clin Immunol 1988:81:791-795. (This documents the laboratory evidence for an allergy that is described as “substantial”). (continued on page 48) www.investinme.org (This describes 47 (This demonstrates

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) A BRIEF SELECTION OF BIOMEDICAL REFERENCES ON ME/CFS 1991 Chronic Fatigue Syndrome: clinical condition associated with immune activation. AL Landay et al Lancet 1991:338:707-712. (This documents evidence for three cell surface markers and notes that CD38 and HLA DR markers remain persistently raised). 1992 A chronic illness characterised by fatigue, neurologic and immunologic disorders, and active human herpes Type 6 infection. Gallo, AL Komaroff et al. 1992:116:2:103-113. Ann D Buchwald, R Intern Med (This describes a significantly increased CD4/CD8 ratio; brain scans show punctate subcortical areas of high signal intensity consistent with oedema or demyelination in 78% of patients, suggesting patients may have a chronic, immunologicallymediated inflammatory process of the CNS). 1993 Memory deficits associated with chronic fatigue immune dysfunction syndrome. al. Biol Psych 1993:618-623. (This demonstrates that cognitive impairment is seven-fold worse than in controls and depressives and is worse than assumed by CDC criteria). 1993 Clinical presentations of chronic fatigue syndrome. AL Komaroff. Ciba Foundation Symposium 173:4361. (This describes ME/CFS as a “terribly destructive disease”; it describes the abnormal physical examination and compares the clinical picture with that of lupus). 1996 Chronic Fatigue Syndrome: evaluation of a 30criteria score and correlation with activation. Hilgers A and Frank J. immune JCFS 1996:2:4:35-47. (This paper notes important and consistent symptoms that are not included in the CDC 1994 case definition; these include respiratory problems, Curt Sandman et palpitations; chest pain; dizziness; dyspepsia; parasthesia; nausea and loss of hair. A correlation between the 30-criteria score and immunological parameters occurred in 472 of 505 patients). 1996 Autoantibodies to Nuclear Envelope Antigens in Chronic Fatigue Syndrome. K. Konstaninov et al J Clin Invest 1996:98:8:1888-1896. 1997 Elevation of Bioactive Transforming Growth Factor Beta in Serum from Patients with Chronic Fatigue Syndrome. AL Bennett, AL Komaroff et al. J Clin Immunol 1997:17:2:160-166. (This paper documents the effects of TGF/beta on cells of the immune system and CNS and provides evidence that it may play a role in autoimmune and inflammatory disease). 1997 Elevated apoptotic cell population in patients with Chronic Fatigue Syndrome: the pivotal role of protein kinase RNA. A Vojdani, CW Lapp et al. J Int Med 1997:242:465-478. (This paper indicates abnormal mitotic cell division). 1997 Chronic Fatigue Syndrome: A Disorder of Central Cholinergic Transmission. A Chaudhuri, T Dinan et al. JCFS 1997:3: (1):3 -16. (This paper posits that the pathogenesis of ME/CFS involves upregulation of post-synaptic cholinergic receptors). 1998 Relationship between SPECT scans and buspirone tests in patients with ME/CFS. Richardson J; Costa DC. JCFS 1998:4:3:23-38. (This paper provides evidence that all patients tested had hypoperfusion of the brain: 62% in the brain stem and 51% in the caudate nuclei). Neurally mediated hypotension and chronic fatigue syndrome. PC Rowe H Calkins. Am J Med 1998:105: (3A): 15S –21S. (This paper provides evidence of an autoimmune component in ME/CFS). 48 (This paper documents neuroendocrine changes and shows the link with allergy). Invest in ME Charity Nr 1114035 (continued on page 49) www.investinme.org Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) 2000 A BRIEF SELECTION OF BIOMEDICAL REFERENCES ON ME/CFS 2005 Comparative analysis of lymphocytes in lymph nodes and peripheral blood of patients with chronic fatigue syndrome. MA Fletcher N Klimas et al. JCFS 2000:7:3:65-75. (This paper demonstrates the link with autoimmunity). 2001 Prevalence in cerebrospinal fluid of the following infectious agents in a cohort of 12 chronic fatigue syndrome patients: HHV6 & 8; chlamydia species; mycoplasma species; EBV; CMV and Coxsackievirus. Susan Levine. JCFS 2001:9: (1-2):4151. (This paper provides hard evidence of a high yield of infectious agents in the cerebrospinal fluid of patients with ME/CFS). 2002 Symptoms occurrence in persons with chronic fatigue syndrome. Psychology 2002:59:1:15-27. evidence of several cardiopulmonary and neurological symptoms that uniquely differentiate ME/CFS patients from controls). 2002 Cytokine response to physical particular reference to IL-6: clinical implications. activity, with sources, actions and Shepherd RJ. Crit Rev Immunol 2002:22:3:165-182. (This paper posits that exercise-induced modulations in cytokine expression may contribute to the allergies seen in ME/CFS). 2003 Abnormal impedance cardiography predicts symptom severity in Chronic Fatigue Syndrome. Peckerman A, Natelson BH et al. Am J Med Sci 2003:326:2:55-60. (This paper provides evidence of reduced cardiac output in patients with severe ME/CFS). 2004 Altered central nervous system signal during motor performance in chronic fatigue syndrome. Aiemionow V, Calabrese L et al. Clin Neurophysiol 2004:115:10:2372-2381. (This paper demonstrates altered CNS signals in controlling voluntary muscle). LA Jason et al. Biological (This paper provides Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Jones MG et al. Clinica Chimica Acta: International Journal of Clinical Chemistry. Epub June 28, 2005. (This paper provides evidence for underlying inflammatory disease and for a lower threshold for muscle micro-injury). 2005 Chronic fatigue syndrome is associated with diminished intracellular perforin. Maher KJ, Klimas NG, Fletcher MA. Clin Exp Immunol 2005:142:3:505-511. (This paper provides evidence of a Tcell associated cytotoxic deficit. As perforin is important in immune surveillance and the homeostasis of the immune system, its deficiency is likely to be an important factor in the pathogenesis of ME/CFS). 49 ME Petition to PM Blair Please support the E-Petition created by Konstanze Allsopp to enforce the acceptance of ME as a neurological illness. "We the undersigned petition the Prime Minister to get the Health Service and medical profession to accept the WHO classification of ME/CFS as an organic neurological disorder and not as a psychosocial syndrome." http://www.investinme.org/EPetition%202007.htm ME Story My family called the doctor to the house on one occasion after I had become too weak to walk or talk and couldn't make the bathroom without assistance. The GP advised me to go out for a jog in the sunshine. - Cathy Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 International ME/CFS Conference Agenda DAY 1 - 1st May 2007 - ME Awareness & Support Day Start Presenter Presentation 08:30 REGISTRATION & MEDIA INTERVIEWS 10:30 IiME Welcome to the Conference 10:40 Norman Lamb MP Opening Speech/Key Note Speech RESEARCH & FUNDING – A Review of Current Work & Requirements 11:05 Dr. Derek Pheby 11:30 Dr. Jonathan Kerr 12:00 Lunch 13:00 Professor Kenny De Meirleir 13:30 Annette Whittemore 13:55 Dr. Daniel Peterson 14:25 Dr. Vance Spence 14:45 Professor Malcolm Hooper Case Study – Epidemiology of ME/CFS Case Study - Biomedical research (A view of a biomedical research team, how it is funded, what it needs, how it could be improved, what the future research would look like) MODELS for TREATMENT of ME/CFS Treatments for ME/CFS Integrative & Complementary Medicine A Model ME/CFS Clinic - The CFS Clinic – Reno, Nevada, USA Experiences of Research into ME – Past, present and future Biomedical Research into ME/CFS: where does it go from here Future ME/CFS Projects - Research being planned & Common Aims - how to get researchers working together 15:15 Coffee/tea Break CURRENT ISSUES - NICE, GUIDELINES, CAMPAIGNS 15:35 Ellen Piro 16:00 Dr. Byron Hyde 16:30 Open forum NICE Guidelines – Experiences from Norway ME and Insurance companies Plenary Session • International alliances • Guidelines • Diagnostic testing • Tissue Banks • Local Services 17:30 Adjourn Invest in ME Charity Nr 1114035 www.investinme.org 50 Journal of IiME Volume 1 Issue 1 International ME/CFS Conference Agenda DAY 2 - 2nd May - Professionals Day Start Presenter Presentation 07:45 Registration & Media interviews 09:00 IiME 09.30 Welcome to the Conference 09:10 Dr. Ian Gibson MP Key Note Speech Professor Martin Pall 10:00 Dr. Abhijit Chaudhuri 10:30 Coffee/tea Break 10:50 Dr. Vance Spence 11:20 11:50 Dr. Sarah Myhill Professor Kenny de Meirleir 12:30 Lunch 13:30 Dr. Nigel Speight 14:00 Dr. Byron Hyde 14:40 Coffee/tea Break 15:00 Dr Jonathan Kerr Professor Malcolm Hooper Biochemical Underpinnings of ME/CFS Pathology of ME/CFS Vascular aspects of ME/CFS Treatments and Diagnosis – A GP’s Perspective Treatments – A ME Clinical Research Perspective Medical Research and Treatment Updates Paediatrics and ME The epidemiology, definitions and techniques of investigation of the ME and CFS patient and the resulting pathological findings or Case Studies / Thyroid Problems Research: A Year On: Viral and Human Gene Expression, development of diagnostic test, news of clinical trials 15:30 Dr. Daniel Peterson Biomedical Research 16:05 16:35 All Speakers 17:30 Adjourn Summary - Future Strategy for ME Research, Diagnosis and Treatment Open forum / Questions 51 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 52 ME Conference 2006 DVD Still available – the IiME ME Conference 2006. Sold in over 20 countries this is now available as an educational tool – useful for healthcare staff (GPs, paediatricians, occupational therapists and others connected with the treatment of ME), researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Comprising 3 DVDs and a data CD the conference has the full lectures from the conference from Dr. Ian Gibson, Professor Malcolm Hooper, Dr. Byron Hyde, Dr. Jonathan Kerr, Jane Colby, Dr. Bruce Carruthers and Professor Basant Puri. Also included are TV programmes from ITV Meridian and Norsk Puls programme about severe ME. Price £13 plus p&p (£2 UK/£3 Europe and USA/Canada/Australia/New Zealand). To order send an email to meconference2006@investinme.org entitled DVD or go to http:///www.investinme.org/tinyurl to order online. Order the 2007 Conference DVD The DVD of the May 2007 conference should be available in early June. To order please email meconference@investinme.org and include your name and contact details plus the number of copies wanted and preferred mode of payment. Available only from Quotable Quotes on ME/CFS IiME. This 42 page booklet has been researched by Maragaret Williams and contains a plethora of quotes from ME experts and from others relating to ME, ME/CFS, CFS/ME and CFS. This is an invaluable document for researchers, healthcare staff, politicians, media, ME support groups and people with ME. Price £3.50 + £1 postage/packing for UK delivery. Apply to info@investinme.org or contact the numbers below. Tel: 02392 252365 or 01603 701980 Invest in ME Charity Nr 1114035 www.investinme.org

V VOO LLUUMMEE 11 II SSSSUUEE 22 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 2 www.investinme.org Autumn 2007 Facts About ME In the World Health Organisation International Classification of Diseases -to which the UK is a signatory and is therefore bound by it – myalgic encephalomyelitis (ME) has been classified as a neurological disorder since 1969. In the 1992 revision (ICD-10) chronic fatigue syndrome (CFS) is listed as a synonymous term for ME and both terms are listed in the neurological diseases section at G93.3, hence the disorder is referred to as ME/CFS. ME Story This is not the life I want, to be 31 with no job, living with my parents and other people's ignorant attitudes , "everyone gets tired", "you just need to sleep less" makes me mad. The government’s lack of funding into research appalls me and the doctors I have seen know less about M.E than I do - Vikki This issue of the Journal continues with the objectives from the first issue – to provide a platform for serious research, appraisal and awareness of the neurological illness Myalgic Encephalomyelitis (ME). In this issue we have research provided by Dr. Tae H. Park from South Korea. Dr. Park has been involved in treating ME for 10 years and his practice in South Korea has treated thousands of patients. We also welcome Professor Sakudo from Japan who publishes for the first time his paper on the potential of visible and near-infrared (Vis-NIR) spectroscopy for the diagnosis of CFS using serum samples. Possible diagnostic testing has never been far from the demands of the ME patient community and Dr. Estibaliz Olano from Spain also presents news of another possible diagnostic test. Invest in ME recently noticed news of mitochondrial research by Dr. Marisol Corral-Debrinski which asked ‘Can "molecular addressing" correct mitochondrial diseases?’ This seemed of interest, when one considers past research on ME and mitochondrial abnormalities. We asked Dr. Corral-Debrinski to publish articles on her work and she has written a detailed overview of her research. We hope it will provide awareness of wider possibilities relating to ME research. We also have a paper on links between Q-fever and ME by Dr. Dragan Ledina from the University of Croatia. Dr. Nigel Speight gave an excellent presentation at the IiME conference in London in May and in this Journal he presents a personal view of ME and Children over the last twenty years. All of these papers reflect the outcome of the IiME conference in May – that there is an abundance of science available to encourage biomedical research into ME – something IiME and others have been pressing the government to acknowledge and yet something NICE have failed to recognise in their recently published guidelines on CFS/ME. Both biomedical conferences of ME Awareness Month 2007, in which IiME and MER UK worked together to promote biomedical research, also demonstrated what an exciting field ME can be for potential researchers. The need for urgent funding of biomedical research into ME is highlighted even further by Margaret Williams’ article on the PACE trials – controversial trials claimed by the Medical Research Council to be worthwhile - but denounced by the ME community as being worthless and a waste of scarce funding. Finally, with most of the ME community objecting to the prominent role psychiatry plays in the diagnosis and treatment of ME we reference a paper from Dr. Marek Marzanski detailing his research on how psychiatry and the Hippocratic Oath co-exist. The science and the advocacy available for all to see seemingly makes the plight of people with ME, and their families, even more tragic and we continue with stories from patients and carers on their experiences with dealing with this illness – including a harrowing account from one family who have had to deal with their severely ill daughter being apportioned yet another psychiatric diagnostic term – Pervasive Refusal Syndrome. We believe this further endorses the need for Journal of IiME – a blend of research, science, facts, politics and real life experiences. Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME Charity Nr 1114035 Page 2/72 Journal of IiME Volume 1 Issue 2 Inside This Issue 3 From the Chairman 5 Comprehensive Treatments of CFS/ME with IVIG 7 CFS as Major Cause of CKD 8 Introduction and Perspectives for Diagnosis of CFS 19 Identification of Differential Genetic Profiles in Severe Forms of FM and CFS in the UK population 21 Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface 30 Chronic fatigue Syndrome after Q fever 35 The reality and nature of ME/CFS 38 Children and Young people with ME – A Personal Overview of the Last 20 Years 42 ME Story 44 IiME Comment: NICE Guidelines 48 The PACE Trial 68 Attitudes of Mental health Practitioners to the Hippocratoc Oath 69 The IiME International ME/CFS Conference 2008 71 Educational Material from IiME www.investinme.org From the Chairman of Invest in ME Welcome to the second Journal of Invest in ME – a combination of research, information, news, stories and other articles relating to myalgic encephalomyelitis. Our first version of the Journal appeared in the delegates’ conference pack at our International conference in London in May 2007. The conference brought together some of the foremost experts on ME and representatives from ME patient groups from all over the UK and Europe. We believe that everyone left not only with an enhanced knowledge gained from the conference but also with renewed hope for the future treatment and possible cure for myalgic encephalomyelitis. As Professor Malcolm Hooper commented in his introduction to the Issue 1 of the Journal - “achievements, hope, and future actions were brought together in this conference”. The breadth of knowledge, science and experience regarding ME, as discussed and presented at the conference, was not only impressive but also exciting. There are grounds for hope that a treatment and cure are on their way. We are glad to see that the many contacts which were established at the conference have continued. To see renowned experts on ME discussing with each other and forming or re-enforcing collaborative efforts was reward enough for hosting the conference. To turn into reality our efforts to form a world alliance of campaigning ME Support organisations was also justification for the conference. The presentations from our distinguished speakers displayed an amazing amount of knowledge regarding the organic nature of myalgic encephalomyelitis. Invest in ME made the decision to fund the DVD of the conference in order that we had a permanent record of the events of that day and of the impressive science which exists already. The conference DVDs have been sold in twenty countries and testify to the need for education about ME. They are an educational tool for physicians to learn about ME. As with many illnesses to which the government gives insufficient attention, and where some existing organisations seemingly fail to represent patients properly, the patients and carers are those who learn most about the illness, out of necessity. It is they who are forced into lobbying for proper attention. Invest in ME was created through such a state of affairs. Our aim is, where possible, to provide information and educational material either free or at cost price - our recent London conference being an example of that where pwme and their carers could attend for a basic price which covered just food and refreshments. Lobbying can work. The recent case of the GMC attempting to discipline Dr. Sarah Myhill is, perhaps, a case in point. Lobbying by patient groups and patients has perhaps forced the GMC to rethink their strange tactics. Dr. Myhill’s case proves how out of touch an established organisation can be with the needs and welfare of patients and their families. Email: info@investinme.org Similarly NICE has shown itself to be an organisation unwilling to progress the treatment and perception of ME. Invest in ME have written to the current minister responsible for ME at the DoH, Mrs. Ann Keen, requesting a meeting with representatives from ME patient groups. The reply was the standard template from the DoH showing both ignorance and apathy to the plight of ME patients and Invest in ME Charity Nr 1114035 Page 3/72

Journal of IiME Volume 1 Issue 2 www.investinme.org From the Chairman of Invest in ME (continued) families in this country. IiME was also recently asked by the BBC Radio 4 Programme “You and Yours” to supply information for their series of programs on ME. So education is still a huge priority and Invest in ME, and other groups, continue to perform work in this area - much of it unpublished - but with the intention of making ME a mainstream illness and deserving of educated and sufficient debate. We are determined that what happened to Sophia Mirza, who died, “… as a result of acute renal failure due to dehydration arising as a result of Chronic Fatigue Syndrome (M.E.)” must never be allowed to happen again. We shall endeavour to continue the campaign to educate and lobby and improve the lives of people with ME and their carers. Invest in ME has taken over the distribution of the Canadian Guidelines in the UK. Together with both 2007 and 2006 conference DVD sets, and the Quotable Quotes on ME booklet, we have a useful range of educational material for healthcare staff, politicians, media and, of course, ME patient groups and pwme and their carers. Our 52-page response to the NICE guidelines has also been added to our web site. We hope the Journal of IiME will also continue to assist in this area by providing a platform, as does the IiME conference, for biomedical researchers and clinicians to provide details of their research and work. It will also continue to offer real life experiences from those who have to deal with this illness on a daily basis – a fact to which too many politicians and organisations still remain indifferent. As IiME plan for the May 2008 conference we look forward to working together with those interested in campaigning for funding of biomedical research into ME – the only sure way to provide a cure for this neurological illness. We wish everyone a pleasant autumn and hope and believe that progress will continue in providing a future treatment/cure for ME. Best Wishes Kathleen McCall A Arr tt ii cc ll eess ffoorr tthhee JJoouurrnnaa ll oo ff II iiMMEE Invest in ME welcomes articles for inclusion in the Journal, especially research papers on ME. Our aim is to provide as much information, fact and science regarding myalgic encephalomyelitis in the hope that it will encourage research, funding and discussion of ME and provide more accurate perception on this illness. Articles for consideration should preferably be in MS Word. Please send any articles to jiime@investinme.org and provide a contact number and full address details. Invest in ME Charity Nr 1114035 The NICE Guidelines “By pre-determining the result based on its requirements to view this illness as a broad chronic fatigue illness NICE has failed to grasp the reality, failed to analyse and use proper research, failed to respond to patients’ demands and requirements and produced a document that will continue to allow this illness to be blended into a nebulous fatigue syndrome which only benefits psychiatrists interested in funding of their projects and other organisations who depend for their existence on paying members.” - IiME Comment on the NICE Guidelines for CFS/ME (Page 44) Facts About ME The textbook used to train NHS clinicians (and which is likely to be on the desk of every GP in the UK - Clinical Medicine: Kumar and Clark) categorises CFS/ME in the mental health section under ”Functional or Psychosomatic Disorders” - despite the fact that the World Health Organisation has recognised ME as a neurological illness and that this recognition is also officially supported by the British government. Facts About IiME The IiME website was set up in late 2005. The aim is to provide news, educational material, research information and stories of ME. The IiME website usage has steadily grown with up to 60,000 visits per month from around the world. www.investinme.org Page 4/72 Journal of IiME Volume 1 Issue 2 COMPREHENSIVE TREATMENTS of CFS/ME WITH IVIG By Dr. Tae H. Park CFS/ME Clinic of Seoul, South Korea PURPOSE OF STUDY: To see the effectiveness of low dose gammaglobuline treatment in CFS/ME patients with strict control of diet, activities and sleep. As is commonly known the research into CFS/ME patients is progressing rapidly, but treatments of CFS/ME patients in the clinical frontline is very limited, and most of the treatments are aimed toward the symptomatic relief of CFS/ME. Here (in South Korea), we have 10 years experience of treating CFS/ME with IVIG, strict diet control, ample hydration and activity or exercise control. Overall the response rate is 90% with these regimens. Those who responded had returned to work and resumed normal activities. Contrary to the CDC report that initial symptoms are important for the prognosis of CFS/ME, our study showed that the severity and duration of sx of CFS/ME are not major determinants of prognosis (J.Reeves CDC). There have been several reports about IV gammaglobuline therapy (K.S.Row, Lloyd) but the cost and adverse effect of IVIG treatments prevent CFS/ME patients to have IVIG tx. Further more, the results of IVIG tx are not significant enough to recommend for general use for CFS/ME patients Except Dr.Row’s report that 75-80% of children return to normal school activities and 5-6 yr follow-up also showed the significant improvements. Selection of patients Among our clinic’s 5378 patients, we selected 50 patients who met the 1994 Fukuda criteria in random fashion. Duration of illness: from 2 years to 15 years Ages of patients: Gender: Method of treatments Sleep control: Sleep before midnight and at least 7 hours sleep. If there is DIMS (difficulties in initiating and maintaining sleep), used klonopine and (or) prozac (10-20mg) at night. 18 to 50 male: 28 female:22 Dr Tae Park M.D. Dr.Park runs his own CFS clinic in Seoul, Korea. Dr. Park attended the Invest in ME International ME/CFS Conference in London in May 2007 and has subsequently supplied this and the following articles. Diet control Organic foods: rice and vegetables Avoidance of certain foods: bread, canned food, coffee, chocolate, monosodium glutamate, aspartame and hot peppers, orange juice, carbonated beverages. A high protein diet (but avoidance of pork). Ample hydration 2-3 litres of water with 2 tsp of salt. Strict control of exercise and activities. No heavy lifting (anything using upper extremities – such as house cleaning) is prohibited. Walking is allowed if patient improves. If the patient feels any post-exertional malaise, then reduce the exercise. IV Gammaglobuline One gram per week in 500cc of 0.9% normal saline infused over one hour. Avoid NSAID (non-steroidal anti-inflammatory drugs) medication, and avoid tests using contrast media (like CT-scan, or IVP) How to have rest Rest (like monks meditate), No loud music and no reading books. In acute stages, absolutely no exercise. If anyone does exercise they may develop cardiomyopathy or severe cardiac arrhythmia - even death. Results of treatment 90% of patients who were treated with the above regimens recovered and returned to work, or returned to school. Showed KS score from 40 to 90. The fatigue impact scale improved from 120 to 20-40. Especially, we found improvements in the cognitive functions. We found improvements in concentration and comprehension, but short-term memory is the last to recover. Most of our CFS/ME patients showed impaired renal functions. They showed reduced GFR (glomerular filtration rate) and when compared with normal controls (Park, presented at Japan CFS/ME conference 2007). (continued on page 6) Invest in ME Charity Nr 1114035 Page 5/72 www.investinme.org

Journal of IiME Volume 1 Issue 2 www.investinme.org COMPREHENSIVE TREATMENTS of CFS/ME WITH IVIG (continued) In CFS/ME patients, 88% of patients showed GFR below 80ml/min (compared with non-diabetic general populations: 39%), 46% of CFS/ME patients showed GFR below 60ml/min (compared with 19% of general nondiabetic population). Due to the low GFR nearly all of CFS/ME patients we need to be careful to monitor their renal function on a regular basis (every 3 months to check s-creatinine). Method of follow up of patients 1. Check quality of sleep: dreams, DIMS, snoring with apnea, refreshing sleep. 2. Check BP: each time of visit, manually checking BP and record correctly. patient’s fatigue sx is getting better. If BP is still low with hydration of 2 litres of water with 2 tsp of salts, then add florinef. 3. Nocturia: check how frequently patients experience nocturia. If nocturia reduces, then patient’s sx of CFS/ME improves. 5. DIMS (difficulties in initiating and maintaining sleep). If DIMS diminishes then the patient’s sx improves. 6. Strict control of exercise and activity. No heavy lifting (anything using upper extremities such as house cleaning is prohibited). Walking is allowed if patient improves. If patient feels post-exertional malaise then reduce the amount of exercise. 7. Check GFR in all CFS/ME patients (nearly 50% of CFS/ME patient’s GFR is close to chronic kidney disease range (near GFR of 60 ml/min). 8. Avoid the use of NSAID and contrast media using tests such as CT or IVP. 8. Hunger discomfort (such as sudden weakness, sweating) indicates the patient’s liver is enlarged. That means that the patient’s activity level is too high or the patient’s level of exercise is too great. 10. Check liver and spleen at each consultation. If the liver and (or) spleen became smaller then the patient sx improves. If a patient’s liver and (or) spleen are enlarged that means patient’s activity level is too high or patient’s diet control is poor. If BP is rising from low BP, then ME Patient’s Carer’s Story Some time around May or June I got a letter from social services asking me to contact them. In my innocence I thought it was a follow up to our claim for DLA (Disability Living Allowance), so from the disability team offering support. Not a bit of it, my sister had reported me for suspected Munchausen's by Proxy. The fact that she hadn't seen us for two years hadn't held her back. So to add to the difficulties of dealing with the school, the benefits system, a paediatrician from hell and a sick child, I now had to deal with a social services investigation. - Parents of Emma Facts About ME The UK Medical Research Council has a secret file on Myalgic Encephalomyelitis (ME) that contains records and correspondence since at least 1988; The file is held in the UK Government Archive at Kew and cannot be opened until 2023. ME Petition to the Prime Minister The E-petition to the Prime Minister, created by Konstanze Allsopp, to enforce the acceptance of ME as a neurological illness is still open for new signatures. In fact this petition (at http://www.investinme.org/E-Petition%202007.htm) has a closing date of January 2008. One can lend support for this petition, which states - "We the undersigned petition the Prime Minister to get the Health Service and medical profession to accept the WHO classification of ME/CFS as an organic neurological disorder and not as a psychosocial syndrome." Invest in ME Charity Nr 1114035 Page 6/72 Journal of IiME Volume 1 Issue 2 www.investinme.org CFS/ME MAY BE MAJOR CAUSE of CHRONIC KIDNEY DISEASE IN NON-DIABETIC POPULATIONS By Dr. Tae H. Park OBJECTIVE OF STUDY: To prove that CFS/ME is a major cause of chronic kidney disease (CKD) in the general population. DESIGN: Cross-sectional study PATIENTS: Participants are 20 years of age and older 400 CFS/ME patients There is a sudden increase in occurrence of non-diabetic, chronic kidney disease patients in the last 3-4 years. In one report (Class et al), 39% of the non-diabetic population showed GFR below 80ml/min. Among them 14% showed GFR below 60ml/min. We collected data from our 400 CFS/ME patients who meet the Fukuda criteria of 1994 and calculated the GFR using the Cockcroft-Gauld formula. The results which we found in our study are striking. Among our 400 CFS/ME patients we found 88% of the patients showed GFR below 80ml/in and 46% GFR below 60ml/min. If we subdivided stage 3 CKD patients (GFR below I60ml/min) then 38.4% showed GFR between 55-60, 33.6% showed GFR 50-54, 29% showed GFR 45-49. In stage 2 CKD classification (GFR below 90) our study showed 84.7% of CFS/ME patient met stage 2 criteria. Among stage 2 patients we further subdivided patients. The result is as follows - GFR 60-65 is 43%, 65-70 is 45%. Even in stage 2 classification we found 88% of CFS/ME patients were close to CKD. What this means is that these CFS/ME patients will be CKD patients in the near future without any diabetes or hypertension. A recent report showed 80% of CFS/ME patients are not diagnosed yet, with only 20% being diagnosed. If we bear these facts in mind, and if many of CFS/ME patients are misdiagnosed as having a psychiatric disease or as having HIV, then these non-diagnosed CFS/ME patients would contribute to a major risk factor of CKD in general populations. We suggest that every CFS/ME patient is checked for s-creatinine based GFR and that this is recorded. Furthermore, one should avoid medication like Nonsteroidal anti-inflammatory drugs (NSAIDs) to control pain and most importantly to avoid many tests using contrast media - CT scan, intravenous pyelogram (IVP) especially coronary angiography, even if they have non-specific chest pains. Facts About ME “Psychogenesis of these illnesses is based on the shaky foundation of somatoform disorders and somatisation. It is based on emotion-laden phrases, transparent falsehoods, logical flaws, overstated claims, and unsupported or poorly supported opinion”. “It is based on ignoring the existence of a genetic role in these illnesses. It is based on ignoring the long history of false psychogenic attributions of other illnesses” “It is based on ignoring hundreds of studies documenting real physiological changes in multi-system illnesses”. “It is based on a deliberate ignorance, flaws and quicksand. I do not know how long it will take for the scientific community to realise the demise of the psychogenic view of multi-system illnesses, but it will happen”. “My critique of psychogenesis of multi-system illnesses should not be considered as a critique of psychiatry. It is rather a critique of those who either lack wisdom or who have sold their integrity”. “Whilst the most severe long-term damage created by psychogenic advocates has been to the research prospect for these illnesses, the most severe short-term impact has clearly been to sufferers of these illnesses and their families”. Professor Martin L Pall Professor of Biochemistry and Basic Medical Sciences at Washington State University, (Explaining ‘Unexplained Illnesses’:; Haworth Press, 2007) http://www.investinme.org/Documents/PDFdocuments/Martin%20Pall%20Book.pdf Invest in ME Charity Nr 1114035 Page 7/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of Chronic Fatigue Syndrome By Akikazu Sakudo1* Yukiko Hakariya1, Takanori Kobayashi1, and Kazuyoshi Ikuta1 1 Department of Virology, Center for Infectious Disease Control, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan *To whom correspondence should be addressed: Akikazu Sakudo, Department of Virology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan Tel.: ++81-6-6879-8307 Fax: ++81-6-6879-8310 E-mail: sakudo@biken.osaka-u.ac.jp Summary Currently, chronic fatigue syndrome (CFS) is diagnosed based on clinical symptoms. Although various information on psychological, endocrinological, and immunological abnormalities in CFS patients has been reported, there is no clear consensus, possibly due to the absence of an objective diagnostic method. One experimental approach is the use of instrumentation for diagnosis. Recently, our research group has shown the potential of visible and near-infrared (VisNIR) spectroscopy for the diagnosis of CFS using serum samples. This review will introduce the method and the future perspectives made possible by it. Keywords: Chronic fatigue syndrome; myalgia encephalomyelitis; visible and near-infrared spectroscopy; diagnosis Introduction Chronic fatigue syndrome (CFS) is a debilitating disorder involving persistent fatigue lasting for more than six months [1]. However, the difference between CFS and CFS-like diseases such as myalgia encephalomyelitis (ME), postviral fatigue syndrome (PVFS), chronic fatigue/immune dysfunction syndrome (CFIDS), and ‘Yuppie flu’ remains unclear. The symptoms of CFS include fatigue, pain, breathing problems, depression leading to digestive disturbances, low grade fever, difficulty in concentrating, and weakness of the immune system and muscles [1]. The symptoms are not resolved by sufficient rest [1]. The incidence of CFS is 0.4% in the United States and other countries [2] and 0.26% in Japan [3]. Economic losses caused by the disease are estimated at as high as 9.1 billion dollars per year in the United States [4] and 408 billion yen per year in Japan [3]. However, research conducted by the Centers for Disease Control and Prevention (CDC) estimates that less than 20% of CFS patients in the United States have been successfully diagnosed [2, 5], indicating that the number of patients will increase if more reliable diagnostic methods are established. The main barriers to identifying CFS patients are an absence of biophysical and biochemical signs that identify the disease and lack of diagnostic laboratory tests [6]. This may be at least in part due to the heterogeneity of the symptoms of CFS patients [6]. At present, CFS diagnosed based on the presentation of symptoms and exclusion of other medical entities. Therefore, it relies on symptometology. Most published studies have diagnosed CFS on the basis of CDC criteria [1]. As psychiatric diseases and other treatable conditions are sometimes difficult to distinguish from CFS, the patient’s Invest in ME Charity Nr 1114035 Fig. 1. Our research group Medical spectroscopy group at Department of Virology, Research Institute for Microbial Diseases, Osaka University was composed of a virologist (Kazuyoshi Ikuta), spectroscopist (Akikazu Sakudo), physician (Yukiko Hakariya), and clinical laboratory technologist (Takanori Kobayashi). Researchers with different backgrounds are studying CFS. (continued on page 9) Page 8/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS symptoms should carefully be examined. Physicians should, through a careful investigation of the patient’s medical history and appropriate testing, rule out other diseases including mononucleosis, Lyme disease, thyroid conditions, diabetes, multiple sclerosis, various cancers, depression and bipolar disorder. We feel that the main problems in CFS studies can be attributed to the objectivity of diagnosis and absence of biomarkers. Our research group, composed of a virologist, spectroscopist, physician, and clinical laboratory technologist, has been studying visible and near-infrared (Vis-NIR) spectroscopy (Fig. 1). We decided to apply Vis-NIR spectroscopy to the study of CFS. In this review, we introduce the method and its possible uses for CFS research. Vis-NIR spectroscopy and multivariate analysis The short wavelength (SW)-NIR region and the red region, the so called “optical window” from 600 to 1,100 nm, are together the most useful region for measuring biological samples [7]. The absorption of hemoglobin and water is extensive in the region below 600 nm and above 1,100 nm, respectively, which limits spectroscopic and microscopic studies [8]. Absorption in the SW-NIR region is due to combinations and overtones of vibration such as the stretching and bending of hydrogen-bearing functional groups including –CH, -OH and –NH [9]. Water, melanin, and bilirubin in animals were absorbed by the radiation of this region [8]. In addition, oxyhemoglobin, deoxyhemoglobin, and oxidized cytochrome c oxidase have characteristic absorption spectra in the SW-NIR region [10]. Recently, biologically important molecules such as albumin [11-13], cholesterol [14, 15], globulin [11-13], glucose [13, 16-24], protein [12, 15, 25-28], urea [12, 13, 27], lipid [15], linoleic acid [15], collagen [15], DNA [15], and α-elastin [15] have also been investigated by Vis-NIR spectroscopy. However, there has been considerable debate as to whether the accuracy and stability of Vis-NIR calibration models for non-invasive transcutaneous monitoring of blood glucose levels in patients with diabetes met criteria for clinical diagnosis [18, 29, 30]. Creatine [27], lactate [22, 31], triacetin [20], triglyceride [13], βlipoprotein [25], Vibrio cholerae [32], Escherichia coli [33, 34], Yeast [35, 36], Ethanol [36, 37], RNA [28], Acetate [34], Ammonia [22, 34], Glycerol [34], and Glutamine [22] have also been quantitatively determined by VisNIR spectroscopy. Representative biomolecules studied by Vis-NIR spectroscopy are listed in Table 1. Vis-NIR spectroscopy has been recognized as having diagnostic potential ever since Jöbsis first used it to demonstrate oxygenation in cats [38]. Vis-NIR spectroscopy has also been applied in the clinical setting to aging [39, 40], Alzheimer’s disease [41], cancer [42-50], chronic fatigue syndrome [51-54], dermatological conditions [43], diabetes [18, 21, 55], epilepsy [56], human immunodeficiency virus (HIV) infection [57], seizure types [58], migraine [59], cervical Invest in ME Charity Nr 1114035 dysplasia [60], atherosclerotic plaques [61], rheumatoid arthritis [62], hemodynamics [63], glioma [64], intraocular pressure [65], hemorrhagic shock [66], skin moisture [67], brain edema [68], optic neuritis [69], and maternal hypotension [70] (Table 2). The number of diseases studied by Vis-NIR spectroscopy has been increasing, although most studies have focused on the monitoring of oxyhemoglobin and deoxyhemoglobin. At present, the diagnostic application of this method in the medical field is rare. The development of laboratory instrumentation for Vis-NIR spectroscopy has been well reviewed [71]. Manufacturers and commercially available instrumentation has also been listed [72], and the number of manufacturers has shown further dramatic increase. The range of wavelengths and modes of measurement available must be paid greater attention to select a suitable instrument for analysis. Cuvettes are sometimes used for measurements. Quartz and polystyrene cuvettes are preferable because much Vis-NIR spectral information on quartz and polystyrene has been reported. The methods of measurement are divided into four types: transmission, reflection, transflection, and interactance in spectroscopy [73]. In transmission spectroscopy, radiation transmitted through sample is measured. In reflection spectroscopy, radiation reflected on the surface is measured. In transflection spectroscopy, which is a combination of the transmission and reflection methods, radiation is transmitted through the sample and scattered back from a reflector on the opposite side. In interactance spectroscopy, radiation transmitted through the sample is collected in contact with the surface of the sample with the end of a fibre optic probe, which has both a radiator and a detector [74]. The availability of fibre optic probes is one advantage of Vis-NIR spectroscopy. Vis-NIR spectroscopy enables the rapid, non-destructive, accurate, and simultaneous determination of multiple components in both liquid and solid samples [75]. However, it also has disadvantages. (continued on page 10) Fig. 2. Characteristics of near-infrared radiation. Ultraviolet (UV), visible (Vis), and infrared (IR) radiation is highly absorbed, whereas near-infrared (NIR) radiation is relatively little absorbed, by water and haemoglobin. Notably, 600-1,100 nm including the red region and short wavelength region of near-infrared (SW-NIR) radiation is called the “optical window”, because this region is suitable for biological analysis. Modified from Fig. 1 in Sakudo et al. [103] with permission from Nippon Rinsho Co. Page 9/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS HIV: human immunodeficiency virus principal component analysis PCA: PLS: Table 1. Representative biomolecules studied by Vis-NIR spectroscopy MLR: multiple linear regression analysis PCRA: principal component regression analysis partial least squares regression analysis Vis-NIR spectroscopy is not very sensitive: the limit is only about 0.15% (w/w) for most constituents, and the signal to noise ratio of the instrument is low [less than 10-4 optical density (OD)] [76], but is dependent on several factors such as the measurement accessory, spectrometer including detectors, and acquisition time. A large amount of sample is needed for Vis-NIR spectroscopy compared to other methods of chemical analysis [76]. The direct interpretation of spectral absorbance is very difficult for complex mixtures because of broad overlapping and interacting absorption bands [76]. Vis-NIR spectroscopy thus relies on a multivariate analysis to quantify properties or constituents of interest. A multivariate analysis is an analysis of data with many variables based on statistics and mathematics. It can simplify complicated data and uncover hidden information. The analysis can be qualitative or quantitative. It is based on chemometrics algorithms. Methods of quantitative analysis include the partial least Invest in ME Charity Nr 1114035 SIMCA: software-independent modeling by class analogy squares regression analysis (PLS) and the principal component regression analysis (PCRA), which are used to develop the regression model for the prediction of the reference value [77, 78]. Methods of qualitative analysis include the principal component analysis (PCA) [79] and the software-independent modeling by class analogy (SIMCA) [80]. PCA is a method for transforming an original variable such as absorbance at various wavelengths into new variables called principal components (PCs). By plotting the data defined by PCs, important relationships in the data (e.g., similarities and differences among objects) can be clearly identified. SIMCA is a recently developed method based on PCA [81]. PCA reduces the amount of data, and SIMCA further extracts discriminant rules among different groups. PCRA is a method for performing PCA on x variables such as wavelength and then regressing y variables on the principal components, whereas PLS (continued on page 11) Page 10/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS Hb: deoxyhemoglobin Table 2. Representative clinical applications of Vis-NIR spectroscopy HbO2: oxyhemoglobin HIV: Human immunodeficiency virus PCA: principal component analysis PLS: partial least squares regression analysis gives extra weight to variables that show a high correlation with y variables. Therefore, PLS is usually more effective for predictions than PCR. Further detailed illustrations and mathematical formulas of algorithms are available in many reports about chemometrics [82, 83]. In a multivariate analysis, the number of PCs is important, because too few or too many PCs distort signals or diminish the signal-to-noise ratio, respectively. To choose the correct number of PCs, a validation step is usually included in the process of modeling [9]. For validation steps, internal validation or external validation is used. Most chemometrics software programs include internal cross validation. In internal cross validation, the sample set is repeatedly divided into two groups. One group is reserved for validation and the other, for calibration. This process is repeated until all groups have been used for validation once. In external validation, sample sets are first separated into calibration samples and test samples, which are subjected to validation and used for assessment of the calibration model. By finding the number of PCs when the model shows a minimum standard error of validation (SECV), the number of PCs can be used to describe the signal in the data. Invest in ME Charity Nr 1114035 These results suggest that combining Vis-NIR spectroscopy with chemometrics is a promising way to objectively diagnose CFS. They also suggest that an unknown factor or factors present in the serum of all CFS patients could provide important clues as to the agent causing this debilitating disease. Recently, commercially available chemometrics software programs such as Pirouette (Infometrics, Woodinville, Washington, USA) and Unscrambler (CAMO Inc., Woodbridge, New Jersey, USA) have been used for Vis-NIR analyse. The number of manufacturers of these software programs is increasing. The programs and their manufacturers are listed in Table 3. The software programs are designed to analyze spectral data, and because preprocessing such as standard normal variate (SNV) [84] and smoothing [85], which minimize differences between spectra caused by baseline shifts and noise, is carried out during the analysis, pre-processing handling, which is time(continued on page 12) Page 11/72 LDA: linear discriminant analysis MELAS: myopathy, encephalopathy, lactic acidosis, MERRF: myoclonic epilepsy with ragged red fibers and stroke-like episodes PCRA: principal component regression analysis

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Table 3. Reprentative chemometrics software and statistical analysis used in Vis-NIR spectroscopy studies MLR: Mutilinear regression PCR: Principal component regression PLS: PCA: Partial least squares regression Principal component analysis KNN: K-nearest neighbors SIMCA: Soft independent modeling of class analogy HCA: Hierarchical cluster analysis Class least squares CLS: consuming, is not required. Furthermore, cross validation steps are also included, and these reduce the overall handling and risk of error during analysis. Application of Vis-NIR spectroscopy for CFS research Several biochemical changes are reported in CFS patients, but there is no clear consensus for any of them. Therefore, the diagnosis of CFS is currently based on clinical symptoms. As this approach relies on experience and skill, CFS can be diagnosed only by limited numbers of medical doctors. To overcome these problems, an additional method using instrumentation to achieve an objective diagnosis is needed. We reasoned that Vis-NIR spectroscopy might provide new insights if patients could be compared with individuals without the disorder. Here, we describe the results obtained when sera from CFS patients as well as healthy volunteers were subjected to Vis-NIR spectroscopy [86]. At the Medical Hospital of Osaka City University, serum samples from 77 CFS patients (33.0 ± 8.8 years old; Male/Female: 29/48), diagnosed on the basis of clinical criteria proposed by CDC were examined [1]. Samples from 71healthy volunteers (41.7 ± 10.4 years old; Male/Female: 33/38) were also used. The sera of the 77 CFS patients and 71 healthy volunteers served as test samples to develop calibration models for PCA and SIMCA. Another 99 determinations [54 in the healthy group (35.9 ± 9.1 years old; Male/Female: 11/7) and 45 in CFS patients (34.9 ± 7.0 years old; Male/Female: 8/7)] were masked and used for predictions. All samples were diluted 10-fold with phosphate-buffered saline and adjusted to a constant volume (2 ml) in a polystyrene cuvette before the Vis-NIR spectroscopic measurements. Three consecutive Vis-NIR spectra were measured at a resolution of 2 nm with an NIRGUN (Japan Fantec Research Institute, Shizuoka, Japan) at 37°C. The spectral data were collected as absorbance values [log(1/T)], where T= transmittance in the wavelength range from 600 to 1,100 nm. Pirouette software (ver. 3.11; Invest in ME Charity Nr 1114035 Infometrics) was employed for all data processing. To minimize differences between spectra caused by baseline shifts and noise, prior to calibration, spectral data were mean-centered and transformed by SNV [84] and smoothing based on the Savitsky-Golay algorithm [85]. To identify the predominant absorbance peaks in the spectra, PCA and SIMCA methods were further applied to develop PCA and SIMCA models for CFS diagnosis. A clear difference in the sera of CFS patients from those of healthy donors was seen in PCA scores using the first principal component (PC1) and second principal component (PC2) (Fig. 3A, B). The SIMCA model allowed correct separation of the Vis-NIR spectra of 209 of 213 (98.1%) healthy volunteers and 220 of 231 (95.2%) CFS patients. SIMCA using Coomans plots demonstrated that classes of sera from the volunteers and patients did not share multivariate space, providing validation for the separation (Fig. 4A, C). Furthermore, masked samples were subjected to Vis-NIR spectroscopy, and predictions made with the PCA and SIMCA models. PCA clearly distinguished the masked samples of the healthy volunteers from those of the CFS patients (Fig. 3C). SIMCA correctly predicted 54 of 54 (100%) volunteers and 42 of 45 (93.3%) patients (Fig. 4B, D). These results suggest that combining Vis-NIR spectroscopy with chemometrics is a promising way to objectively diagnose CFS. They also suggest that an unknown factor or factors present in the serum of all CFS patients could provide important clues as to the agent causing this debilitating disease. We concede that statistically, the results are not robust enough for clinical use at this time. The PCA and SIMCA model was developed from Vis-NIR (continued on page 13) Page 12/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Fig. 3. PCA of Vis-NIR spectra of serum samples for CFS diagnosis (A-B) Vis-NIR spectra of serum samples from healthy donors (Blue) and CFS patients (Red) were subjected to PCA and the results plotted as PC1 versus PC2 to establish a PCA model (A). Loadings show the importance of each wavelength for the PCs indicated by peaks (B). (C) Masked samples, which were not used for development of the model, were subjected to PCA and the results plotted as PC1 versus PC2. Modified from Fig. 1 in Sakudo et al. [86] with permission from Elsevier. spectra of 148 individuals including 77 CFS patients and 71 healthy donors, not a sufficient number for practical use in the clinic. The influences of sex and race, etc. on the results of this diagnostic method remain unclear. To obtain more Vis-NIR spectra, samples for the calibration set should be obtained in a similar way to those that will be analyzed for diagnosis. Furthermore, uniformity of the solvent among samples is very important. For example, in blood samples, identical methods of preparation of serum are necessary. Stable humidity and temperature should be maintained during the scanning event, because humidity and temperature may affect water absorption in the NIR region. In this study, we used serum samples for Vis-NIR spectroscopy. Therefore, the method is invasive but nondestructive. Vis-NIR spectroscopy can also be applied to non-invasive analyse and we are now approaching the Invest in ME Charity Nr 1114035 non- invasive diagnosis of CFS (Fig. 5).Hopefully, after these issues are addressed, this diagnostic method might be adopted in the clinic (Fig 6). The next step in terms of research into the disease, as opposed to diagnosis, is to use this approach together with other evidence to try and identify specific biochemical markers common to CFS. This is the best way to understand the cause of CFS. Our experimental system coupling Vis-NIR spectroscopy with chemometrics may also contribute to this issue. Finally, we would like to emphasize that international collaboration is important in the development of this method, because CFS is heterogeneous and diagnostic criteria differ slightly among countries. Differences and similarities between CFS and CFS-like diseases such as ME, PVFS, CFIDS, and ‘Yuppie flu’ would also be made clear by this method. (continued on page 14) Page 13/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Fig. 4. SIMCA analysis of Vis-NIR spectra of serum samples for CFS diagnosis (A-B) Vis-NIR spectra of serum samples from healthy donors (Blue) and CFS patients (Red) were subjected to SIMCA. Coomans plots show distances to model of healthy donors versus CFS patients to establish a SIMCA model (A). Discriminating power shows the importance of each wavelength for distinguishing healthy donors from CFS patients (B). (C) Masked samples, which were not used for development of the model, were subjected to SIMCA. Coomans plots show distances to model of healthy donors versus CFS patients. Modified from Fig. 2 in Sakudo et al. [86] with permission from Elsevier. References [1] K. Fukuda, S.E. Straus, I. Hickie, M.C. Sharpe, J.G. Dobbins, and A. 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Whistler, E. Aslakson, M. Rajeevan, and W.C. Reeves, Challenges for molecular profiling of chronic fatigue syndrome. Pharmacogenomics 7 (2006) 211-8. (continued on page 15) Page 14/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) [7] S. Nioka, and B. Chance, NIR spectroscopic detection of breast cancer. Technol Cancer Res Treat 4 (2005) 497512. [8] K. Konig, Multiphoton microscopy in life sciences. J Microsc 200 (2000) 83-104. [9] I. Murray, Forage analysis by near infra-red spectroscopy, in: A. Davies, R.D. Baker, S.A. Grant (Eds.), Sward Management Handbook, British Grassland Society, UK, 1993, pp. 285-312. [10] B.L. Horecker, The absorbance spectra of hemoglobin and its derivatives in the visible and near infra-red regions. J Biol Chem 148 (1973) 173-83. [11] K. Murayama, K. Yamada, R. Tsenkova, Y. Wang, Y. 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Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Fig. 6. Comparison of current CFS diagnosis and future Vis-NIR CFS diagnosis Currently, CFS can only be diagnosed by skilled doctors. The diagnosis requires experience and sophisticated techniques. Furthermore, even with a skilled doctor, it takes long time to reach a final clinical diagnosis. Vis-NIR spectroscopy would enable an objective and rapid diagnosis. Moreover, it would not require experience and skill. Modified from Fig. 2 in Sakudo et al. [103] with permission from Nippon Rinsho Co. [30] H.M. Heise, Applications of near-infrared spectroscopy in medical sciences, in: H.W. Siesler, Y. Ozaki, S. Kawata (Eds.), Near-infrared spectroscopy (Principles, instruments, applications), Wiley-VCH, Weinheim, 2002, pp. 289-333. [31] D. Lafrance, L. Lands, D. 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Tamura, Impaired interhemispheric integration in brain oxygenation and hemodynamics in schizophrenia. Eur Arch Psychiatry Clin Neurosci 244 (1994) 17-25. [102] A. Koike, H. Itoh, R. Oohara, M. Hoshimoto, A. Tajima, T. Aizawa, and L.T. Fu, Cerebral oxygenation during exercise in cardiac patients. Chest 125 (2004) 18290. [103] A. Sakudo, H. Kuratsune, Y. Hakariya, T. Kobayashi, and K. Ikuta, Spectroscopic diagnosis of chronic fatigue syndrome by multivariate analysis of visible and nearinfrared spectra. Nippon Rinsho 65 (2007) 1051-6. Page 18/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Identification of Differential Genetic Profiles in Severe Forms of Fibromyalgia and Chronic Fatigue Syndrome in the UK population by Estibaliz Olano Fibromyalgia (FMS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) are two controversial diseases with overlapping symptoms, difficult to distinguish and diagnose properly with clinical criteria. To date there are no biological markers for either condition and are diagnosed using separate but overlapping clinical criteria. All too often the patients concerns are dismissed as imaginary or unimportant and only recently they have started to be recognized and accepted by physicians. Since recent studies have started to point out the genetic background of these diseases, Progenika Biopharma, S.A. has developed a new system of DNA testing for the diagnosis and prognosis in Fibromyalgia and Chronic Fatigue Syndrome. A multidisciplinary group led by Dr. Ferrán García, Head of Rheumatology (Clínica CIMA, Barcelona), Dr. Joaquim Fernández Solá, Unit of Chronic Fatigue Syndrome (Hospital Clínic, Barcelona) and Dr. Jose Ignacio Lao, Unit of Molecular Genetics (Echevarne Laboratorie) started this research five years ago, by looking at different mutations (SNPs) associated with FM and CFS/ME. 99.8% of the genetic information is homogenous among humans, and only 0.2% is variable. These differences in our DNA can be due insertions or deletions (e.g. familial hypercholesterolemia), repeat sequences (e.g. Huntington disease CAG repeats) or Single nucleotide polymorphisms – SNPs. These SNPs are changes (mutations) of only one of the nucleotides (“building blocks”) that forms the DNA, and they account of up to 90% of the variability encountered between humans. Variations in these DNA sequences of humans can affect how we develop diseases, respond to pathogens, chemicals, drugs, etc. Therefore, SNP analysis has the potential for identification of markers for genetic predisposition to disease or even define subtypes within diseases with different prognosis, severity, drug response ..... Some of the results of this ongoing study have been presented in the 8th International IACFS Conference on Chronic Fatigue Syndrome, Fibromyalgia and other Related Illnesses held in Florida and in the ME Research conference held in Edinburgh and are summarised here: Among the individuals register in the “Fibromyalgia and/or Chronic Fatigue Syndrome patients Record” (www.fundacionfatiga.org/registro_pacientes.htm) 1500 subjects diagnosed with FM, CFS/ME or both were randomly selected and invited to participate in the study. From these, 1371 gave written consent to take part and filled in a questionnaire which included details about their diagnosis, familiar diagnosis of FM or CFS/ME and presence of mental disorders. In addition, those patients were also asked to answer the Fibromyalgia Impact Questionnaire (FIQ) for FM (Burckhardt et al., 1991; Bennett, 2005) and the CDC Invest in ME Charity Nr 1114035 Dr. Estibaliz Olano Dr. Olano is a senior scientist at Progenika Biopharma (a biotech company based in Bilbao, Spain). She is responsible for investigating the genetic profiling via SNP analysis by using it as an effective tool to discriminate between the more severe forms of fibromyalgia and chronic fatigue syndrome. Symptom Inventory (CSI) for CFS/ME (Wagner et al., 2005) and to provide a blood sample for DNA extraction. Taking into account that there is a recognized gender bias in FIQ (Bennett, 2005), eventually only women were included in the study. Previous treatment for psychiatric disorders was also considered an exclusion criterion. At the end of the selection process the number of recruited subjects was reduced to 403 patients (186 FM patients aged 45-54 years and 217 CFS patients aged 30-39 years). These cases were clinically diagnosed according to the 1990 American College of Rheumatology (ACR) classification for FM (Wolfe et al., 1990) or the US Centres for Disease Control criteria for CFS developed by Fukuda et al.1994 at the Hospital Clinic and Clinica CIMA (Barcelona, Spain). For each sample one hundred and seven SNPs were genotyped by SNPlexTM. An independent second association study with 282 women (126 FM / 156 CFS) was used to validate the results. We identified 15 SNPs able to discriminate between FM and CFS patients with a 11·5 Likelihood Ratio (LR+, 95% specificity). The analysis of further SNPs allowed differential genetic profiling between the most aggressive FM phenotype and the mild forms (12·4 LR+) and between a severe CFS phenotype and a milder one (12·4 LR+). (continued on page 20 Page 19/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Identification of Differential Genetic Profiles in Severe Forms of Fibromyalgia and Chronic Fatigue Syndrome in the UK population (continued) In this study we prove that genetic profiling via SNP analysis can be a very effective tool to discriminate between the more severe FM and CFS cases. In addition we claim that FM and CFS are two separate diseases with an important genetic component, and we suggest that the severe cases might be different disease subtypes with distinctive genetic profiles. However this methodology is still dependable of a preliminary reliable diagnose that fulfils all the disease inclusion and exclusion criteria. These first results of the research carried out so far has lead to the design of “FIBROchip”, a DNAchip for the identification of the patient’s genetic predisposition to develop the most aggressive forms of Fibromyalgia and Chronic Fatigue Syndrome / Myalgic Encephalomyelitis. On the genetic profile base, FIBROchip is able to differentiate between the patients with Fibromyalgia and Chronic Fatigue Syndrome. Additionally, being based on the information provided by FIBROchip, the doctor will be able to know if his patient can develop a Fibromyalgia and Chronic Fatigue Syndrome very severe. The main target of the DNA chip is to identify those patients who have a greater possibility of developing the most aggressive forms of the diseases and this way to apply the most suitable treatment to each patient. The investigation project is in the last phase of clinical validation, and is predicted that their exit to the market is at the end of this year. ME Story Now at 35 I'm 99% bedridden, I am paralysed down the right hand side and in both legs. I am incontinent and have a supapubic catheter fitted through my stomach into my bladder. Four years ago, I was forced to go into an old people's Nursing home as we didn't have enough room downstairs for me to have a bedroom where I could be hoisted. Therefore my O.T. involved a man from disability grants who agreed to fund the building of an extension in which I have a ceiling track hoist, as I can't transfer myself at all, that takes me from my small bedroom into an en-suite shower room & Closomat toilet. I spent 2 years in the nursing home while this was being completed where I deteriorated further, I have between 35-40 symptoms related to M.E including an immune deficiency. Chemical sensitivity disorder, brain fog etc... I am a member of the 25% M.E group who are the only support group for the one Facts About IiME IiME’s May conferences in London have attracted speakers and delegates from all parts of the world. The conference DVDs have sold in twenty countries worldwide. quarter of all M.E sufferers who have severe M.E Some days I feel so ill that I want to go to sleep and never wake up !!! -Mattie Petition to Retain GPs’ Rights to Issue Sickness Notes This E-petition to the Prime Minister, seeks to prevent the application of the return to work legislation that will be overseen by work advisors in surgeries. It will adversely affect chronically ill people like sick Gulf War veterans, ME-CFS sufferers, pesticide poisoned people and MCS sufferers. Text from the petition creator – The administration is seeking to cut the number of people claiming incapacity benefit but penalising poorly people in need of a sick note is not ethical. Making sick people have to mess around even more is counterproductive. GP's have not complained about issuing sick notes all these years, they are professionally trained, well paid, and should be able to deal with this. I see no reason to change what is a decent scheme. "We the undersigned petition the Prime Minister to carry on allowing all GPs to issue sick notes to patients and not alter legislation concerning GP's issuing sick notes themselves.." http://petitions.pm.gov.uk/SickNotesGPs Invest in ME Charity Nr 1114035 Page 20/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Can "molecular addressing" correct mitochondrial diseases? Mitochondria are the power plants of the cell and perform most of the chemical reactions that transform sugars into usable energy. Mitochondrial diseases are estimated to affect at least 1 in 5000 people and can lead to a variety of serious diseases. Many of the genes responsible for energy production are made up of mitochondrial DNA, rather than DNA in the cell's nucleus - and an obvious solution to mitochondrial errors would be to introduce a normal copy of the defective gene into the mitochondrial DNA. Dr. Marisol Corral-Debrinski and her colleagues at the Pierre and Marie Curie University in Paris, France, picked two mitochondrial gene mutations. The team tagged normal versions of these genes with two separate cellular "address codes" and inserted them into the cytoplasm of cells grown in a lab dish. The first code directs the messenger RNA - the molecule that carries the instructions for making a protein - to the surface of the mitochondria, ensuring that the protein gets made at the mitochondrial membrane. The second address code, known as the mitochondrial targeting sequence, tells the protein to enter the mitochondria. These double-tagged genes were able to reverse the effect of both mitochondrial mutations in cell cultures for up to a year. Corral-Debrinski is now planning to test the gene therapy on laboratory mice. Although not directly affecting ME we felt that Marisol’s work on mitochondria might be of interest. Marisol allowed IiME to publish three of her research papers in the Journal but, unfortunately, we have been unable to get the permission to from the publishers to include them here. So instead Marisol has kindly produced the following article describing her work. Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface By Marisol Corral-Debrinski1 1 Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U592, Université Pierre et Marie Curie (UPMC-Paris6), Hôpital St. Antoine–Bât. Kourilsky, Paris, France. 2 INSERM U676, Hôpital Robert Debré 48, Paris, France. Mitochondrial diseases encompass an extraordinary assemblage of clinical problems, commonly involving tissues that have high energy requirements, such as retina, brain, heart, muscle, and endocrine systems. The clinical presentations range from fatal infantile disease to muscle weakness and most of them are characterized by inexorable progression. Recent epidemiological studies have shown that mitochondrial disorders have a prevalence of at least one in 5000, making them probably the most common form of metabolic disorders. 300 mitochondrial DNA (mtDNA) alterations have been identified as the genetic cause of approximately 30 % of these diseases. Moreover, the spectrum of mitochondrial diseases has been expanded by the recognition that mutations in the genes for nuclear-encoded mitochondrial proteins cause not only a number of neurodegenerative diseases but also haematological and ophthalmological disorders. Hence, finding ways to fight these devastating disorders especially in the case of neuromuscular degeneration is the main objective of many laboratories worldwide. Since almost four years we are using the phenomenon of mRNA localization to the mitochondrial surface aimed at developing a therapeutic strategy for replacing inactive proteins inside the mitochondria. Hence, we have optimized the nuclear expression of ATP6, ND1 and ND4 genes, originally located in the organelle, by the addition of cis-acting elements which ensures the transport of their transcripts to the mitochondrial surface. The optimization of this approach, known as "allotopic expression" have led to the complete and long-lasting rescue of mitochondrial dysfunction in fibroblasts from patients harboring a deleterious mutation in either ATP6, ND1 or ND4 genes. Because of their highly sophisticated function in the visual process retinal cells contain a large number of mitochondria. Therefore, any impairment in mitochondrial function leads to retinal cell degeneration that arises from mutations in genes encoding mitochondrial proteins located in either nuclear or mitochondrial genomes, such as neurogenic muscle weakness Ataxia Retinitis Pigmentosa (NARP), Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA). As for the other mitochondrial disorders, no cure is available. Since, the eye is an excellent target organ for gene therapy, given its small size, its relative anatomical isolation and the ease with which vectors can be delivered to retinal cells we have decided to apply our optimized approach as a first step for treating neuromuscular diseases dues to mitochondrial dysfunction. Ultimately, our most important goal is to provide a gene therapy that will impede blindness of adults brutally affected by LHON or DOA, this therapy will subsequently become available for an array of neuromuscular degenerations caused by mutations in both nuclear and mitochondrial DNA genes encoding mitochondrial proteins. Invest in ME Charity Nr 1114035 (continued on page 22) Page 21/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) A. Introduction Mitochondria play a central role in intermediary metabolism, energy production, ion homeostasis and apoptosis 1. Impairment of mitochondrial function is the key pathogenic factor in a growing number of human diseases. Indeed, primary defects in mitochondrial oxidative phosphorylation (OXPHOS) function are implicated in over 130 diseases 2. Their clinical presentations range from fatal infantile disease to adult muscle weakness and/or nervous system dysfunction. Moreover, mitochondrial impairment can lead to tumor formation and probably play a role in the aging process 3 . Mitochondrial OXPHOS disorders are far more common than was previously anticipated. Recent epidemiological studies have shown that their prevalence is at least one in 5000, making this group of diseases probably the most frequent form of metabolic disorders 4. Approximately 300 mitochondrial DNA (mtDNA) alterations have been identified as the genetic cause of mitochondrial diseases, one-third of which are located in coding genes for OXPHOS proteins 5. Despite, more than 70% of human degenerative diseases involving mitochondrial deficiencies remain unravelled at the molecular level; since they are caused by mutations in nuclear-encoded mitochondrial proteins. Hence, only 56 nuclear genes encoding mitochondrial proteins underly clinical mitochondrial disorders 6. The main obstacle encountered for the identification of disease causing genes is that at least half of the 1500 estimated mitochondrial proteins 7 is not yet discovered; indeed, up until today only 807 are ascribed to the most extensive database of human mitochondrial proteins (http://www.mitop.de:8080/mitop2 ), 8. The understanding of the pathogenesis of mitochondrial diseases has improved considerably in the last decade. Nevertheless, the most disappointing area is the lack of efficient treatment for patients with mitochondrial diseases. Indeed, they are still treated with vitamin and cofactor mixtures, harmless but largely inadequate and inefficient. Ocular involvement is a prevalent feature in mitochondrial diseases, indeed retina cells contain a large number of mitochondria, reflecting their high requirements for OXPHOS 9. Moreover, mitochondrial impairment may contribute to changes in macular function observed in aging and age-related macular dystrophy 10. Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) are both non-syndromic optic neuropathies with a mitochondrial etiology. LHON is associated with point mutations in the mitochondrial genome. The majority of DOA patients harbor mutations in the nuclear-encoded protein OPA1 which is targeted to mitochondria. In both disorders the retinal ganglion cells (RGCs) are specific cellular targets of the degenerative process 11. Neurogenic muscle weakness, Ataxia, Retinitis Pigmentosa (NARP) syndrome is due to a point mutation in the mitochondrial ATP6 gene. The most common ocular feature associated with the mutation is retinal Invest in ME Charity Nr 1114035 dystrophy, with a substantial variability in rod and cone photoreceptor manifestations 9. As for other visual impairments or mitochondrial disorders, no efficient therapies are available at the present time and current understanding of the cellular and molecular mechanisms underlying retinal cell death due to mitochondrial dysfunction is still quite limited. Remarkably, the eye has a combination of features that make it ideally suited as a target organ for gene therapy. The highly compartmentalized anatomy of the eye facilitates accurate delivery of vectors at target sites within the globe especially at the vicinity of retinal cells, which minimizes systemic dissemination and unwanted systemic effects. The blood retinal barrier and the retinal pigment epithelium (RPE), anatomically protect a wide-spread diffusion of the vectors to the systemic circulation. These barriers also provide a beneficial effect in protecting the retina from the immune response 12. Retinal function can be easily monitored with non-invasive and quantitative tests such as ophthalmoscopy, electroretinogram (ERG), optical coherence tomography (OCT), and visual evoked potentials (VEP). Moreover, appropriate animal models resembling human retinal abnormalities are available for the development of experimental therapies. Notable successes have been achieved by gene replacement strategies in some of these models. For instance, the Swedish Briand dog is a model for a null mutation in the RPE65 gene. This gene encodes an RPE-specific visual cycle isomerase involved in the synthesis of 11-cis retinal. Mutations in the RPE65 gene are responsible of Leber’s Congenital Amaurosis (LCA), representing a group of severe earlyonset retinal dystrophies 13. The fact that there are close similarities between human and Briand dogs, in terms of the clinical characteristics of the disease allowed the evaluation of gene replacement therapy. Thus, three independents groups have now reported the restoration of vision in these dogs by the use of recombinant AAV vector-mediated delivery of the RPE65 gene 14, 15, 16. These recent advances have enabled the development of proposals for clinical trials of gene therapy for ocular diseases. In May 2007, the first patient, out of 12, has been treated with the rAAV2-RPE65 vector (Dr. R. Ali, College University, London) at the ophthalmologic hospital of Moorfields in London. This is the first step of phase I/II doseescalation clinical trial for this severe early-onset retinal degeneration. Dr. F. Rolling (INSERM U 649, Nantes) will conduct a clinical trial in 2009. Our main objective is to develop in the near future a gene therapy that could be both preventive and curative for retinal dystrophies due to mitochondrial dysfunctions. In this purpose we were mostly interested in the LHON disease. LHON was the first maternally inherited disease to be associated with point mutations in mtDNA and is now considered the most (continued on page 23) Page 22/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) common mitochondrial disorder with an estimated prevalence of 1 in 25,000 in north-east England. The pathology is characterized by selective death of RGCs leading to central vision loss and optic nerve atrophy, prevalently in young males. The age of onset of visual loss ranges from 8 to 60, typically occurs between ages of 15 and 35 years. The course of visual loss is generally acute or subacute, both eyes are involved sequentially. The average time interval between affected eyes is approximately two months, the duration of progression of visual loss in each eye averaged approximately four months 17. LHON is a devastating disorder with the majority of patients showing no functional improvement and remaining within the legal requirement for blind registration. The three most common pathogenic mutations found in about 95% of LHON’s patients are located in ND1 (G3460A), ND4 (G11778A) or ND6 (T14484C) genes. They encoded subunits of the respiratory chain complex I and the mutations have the double effect of lowering ATP synthesis and increasing oxidative stress chronically 17. Although, extensive studies were conducted since more than 15 years, the pathogenesis of LHON is poorly understood. One recent hypothesis suggests that the pathophysiology of optic neuropathies does not just involve the disorder of ATP production by mitochondria but that the non-maintenance of the sharp mitochondrial gradient at the optic nerve head constitutes the first step in a vicious event cycle that further compromises neuronal respiration and that would eventually lead to profound energy depletion, the increased production of toxic free radicals and neuronal cell death through apoptosis 18, 19. LHON, as the other mitochondrial diseases, is resistant to treatments with quinone analogs, vitamines or oxygen radical scavengers, which were harmless but very inefficient in most of the cases 20. Therefore, the allotopic expression (expression of mitochondrial genes transferred to the nucleus) of some of mtDNA genes has been tried in cybrid cells as a possible therapeutic option to cure mitochondrial diseases. However, several attempts failed to obtain a complete and long-lasting rescue of the mitochondrial defect in cells harboring mutations of mtDNA genes 21, 22, 23. Probably, the highly hydrophobic nature of proteins encoded by the mitochondrial genome represents a physical impediment to mitochondrial import. Therefore, up until today important limitations are found to the allotopic expression as a therapeutic approach for mtDNA-related diseases 24. In previous studies, we demonstrated that in the yeast Saccharomyces cerevisiae, 47% of mRNAs encoding mitochondrialproteins are transported to the organelle surface 25. This phenomenon represents a key step to ensure the proper import and functionality of the corresponding polypeptides inside the organelle 26 and is conserved in human cells 27. The delivery of mRNAs to the organelle surface depends on two sequences: the region coding for the mitochondrial targeting sequence (MTS) and the 3’ untranslated region (3’UTR) 28. Invest in ME Charity Nr 1114035 Thus, we decided to optimize the allotopic expression for mtDNA genes by ensuring the delivery of corresponding mRNAs to the organelle surface. This optimization will prepare the development of an effective treatment for mitochondrial disorders due to mtDNA mutations. The research project of our team is conducted since 2004 along the following complementary axes: Optimize the allotopic expression of mtDNA genes. Rescue of respiratory chain defects in cells harboring different mutations in mtDNA encoded genes. B. Previous activities of our team: 2004-2007 I. Optimization of the allotopic expression of mtDNA genes (Kaltimbacher et al., RNA : 12, 1408-1417 ; 2006) Recently, we have shown that a protein which is normally encoded by mtDNA was efficiently translocated into the mitochondria of HeLa cells by the use of signals that force its mRNA, transcribed in the nucleus, to localize to the organelle surface. We constructed a nuclear version of the mtDNA-encoded ATP6 gene flanked by cis-acting elements of either COX10 or SOD2 mRNAs, which localizes to the mitochondrial surface in HeLa cells 27, 29. The rationale behind this was that mRNA targeting to the mitochondrial surface will lead to a tight coupling between both translation and translocation processes, which should be required for highly hydrophobic proteins, such as ATP6. Noteworthy, when both the MTS and the 3’UTR of SOD2 or COX10 a highly efficient mitochondrial translocation of the ATP6 was observed (Fig.1). Notably, ATP6 protein was insensitive to proteolysis in the presence of detergent, suggesting that it probably was assembled in the complex V of the respiratory chain 30. (continued on page 24) ME Facts Mitochondrial dysfunction provides a physiological basis for the debilitating and overwhelming fatigue suffered by ME/CFS patients whilst the changes in the NTE (neuropathy target esterase) gene provide an intriguing link with OP poisoning and nerve agent exposure found in GWS. - Group for Scientific Research into ME 2006 (http://www.erythos.com/gibsonenquiry/Repor t.html) Page 23/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Figure 1: Enrichment at the mitochondrial surface of the nATP6 mRNA led to an efficient mitochondrial import of the corresponding protein A. The amount hybrid nATP6 mRNA was determined by RTPCR in RNA purifications obtained from free polysomes (FP) and mitochondrion-bound polysomes (MP). The distribution of the endogenous mRNAs SOD2 and ATP6 were also examined in both polysome fractions. Four independent experiments were compared, the results obtained are illustrated as bar graphs. The presence of the SOD2 MTS in the nATP6 mRNA allowed its enrichment in the MP fraction. Nevertheless, both the MTS and 3’UTR were required in the hybrid mRNA for allowing its exclusively sorting to the mitochondrial surface. B. The amount of the chimeric ATP6 protein was evaluated in six independent mitochondrial purifications subjected to Proteinase K (PK) digestion. This amount was compared to the quantity of ATPα protein insensitive to PK proteolysis. When the synthesis of ATP6 was directed by the gene in which both the MTS and 3’UTR of SOD2 were present, the amount of fully translocated ATP6 protein was not significantly different to the ATPα protein (bar graphs). (continued on page 25) Invest in ME Charity Nr 1114035 Page 24/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) II. Rescue of respiratory chain defects in fibroblasts harboring mutations in ATP6 and ND4 genes (Bonnet et al., Rejuvenation Research : 10, 128-144 ; 2007) With the aim of determining whether allotopically expressed mtDNA-encoded genes could rescue mitochondrial dysfunction, we examined human cultured skin fibroblasts harboring either the NARP T8993G ATP6 mutation or the LHON G11778A ND4 mutation, allotopically expressing the recoded ATP6 or ND4 wild-type genes. Mitochondrial function was evaluated by the measurement of (i) cell ability to grow in galactose medium, which force them to rely on OXPHOS; (ii) in vitro ATP synthesis using respiratory chain substrates; (iii) enzymatic activity of respiratory chain complexes I and V 31. We were able to demonstrate that the allotopic expression of engineered ATP6 and ND4 genes in human fibroblasts harboring either of these genes mutated leads to a complete and long-lasting restoration of respiratory chain function 32 (Tables 1 and 2). Notably, we examined a second LHON patient harboring the G3460A substitution in the ND1 gene. Our optimized allotopic approach significantly rescued respiratory chain I deficiency in these cells. Therefore, our approach for ND1, ND4 and ATP6 genes ensures the efficient mitochondrial translocation of the corresponding precursors, probably via a co-translational pathway. The rescue of mitochondrial dysfunction indicated that the processed polypeptides were fully functional within their respective respiratory chain complexes and, therefore, able to compensate for the endogenous inactive proteins 32, and C.Bonnet, S. Augustin et al. (manuscript submitted, 2007) . (continued on page 26) Table 1: In vitro ATP synthesis rate µM ATP/min/106 cells Complex I substrats Complex II substratI P value ; n Complex I substrats Complex II substrats Control NARP NARP + nATP6 Control LHON LHON + nND4 2081.9 ± 138.1 805.6 ± 262.4 2045.52 ± 428.7 1962.1 ± 352.1 793.3 ± 493.7 1659.4 ± 245.5 1563.1 ± 214.0 400.7 ± 221.7 1659.6 ± 522.5 1266.3 ± 62.1 658.7 ± 185.2 1929.7 ± 480.2 0.004 ; n = 5 0.0013 ; n = 4 0.0003 ; n = 5 0.0022 ; n = 4 P values shown in the third column were obtained according to the Student’s t test for the pairs NARP/ NARP + nATP6 or LHON/ LHON + nND4 for data collected for either complex I or complex II substrates. "n" indicates the number of independent measurements performed. LHON fibroblasts showed a decreased ATP syhtesis rate when complexe II substrates were uses. This result suggests a general perturbation of the respiratory chain activity. Notably, this activity was fully restored by the allotopic expression of ND4. Invest in ME Charity Nr 1114035 Page 25/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Table 2 : Complexes I and V activity measurements in NARP and LHON fibroblasts after normalisation with the values obtained in control fibroblasts Complexe I Complexe V NARP 1 NARP + nATP6 1 LHON 0.6 ± 0,12 1.05 ± 0,23 0.47 ± 0.009 1 LHON + nND4 0.97 ± 0.24 1 < 0.0001 ; n = 9 P values shown in the fourth column were obtained according to the Student’s t test for the pairs NARP/ NARP + nATP6 or LHON/ LHON + nND4. "n" indicates the number of independent measurements performed. Complex I activity in NARP cells was identical to that measured in control fibroblasts (1). Complex V activiy in LHON fibrolbasts was not different to the one measured in control cells (1). Complex I and V activities were fully restored in LHON and NARP fibroblasts by the optimized allotopic expression of ND4 and ATP6 genes respectively. C. Research Project We are aware that the optimization of allotopic expression represents a real hope for patients suffering from diseases caused by mutations in mtDNA genes. However, all our efforts will remain unfruitful if the biosafety and the beneficial to mitochondrial function of our vectors are not proved in experimental models for mitochondrial diseases. Since, this proof is the mandatory step required before any attempt to the transfer to clinic, it becomes our highest priority. Unfortunately, only one animal model for mtDNA gene invalidation is available. These mice carry a mutation in the mitochondrial COXI gene leading to a decreased cytochome oxydase (COX) activity in several tissues 33. Even though, they do not have any visual impairment, we will try to rescue their muscle COX deficiency using our strategy. Additionally, we decided to use the optimized allotopic expression approach to create an animal model which will mimic LHON disease. First, we performed in vitro mutagenesis of the wild-type engineered human ND4 gene to obtain a nuclear version harboring the G11778A substitution. This mutation, responsible of 60% of LHON cases, converts a highly conserved arginine to histidine at codon 340 17. Each nuclear version of ND4 was combined with the two mRNA targeting sequences of the COX10 gene, which ensures the efficient delivery of the polypeptides inside the organelle 32 . We developed an in vivo electroporation (ELP) method to introduce either the wild-type or the mutated version of ND4 into retinal ganglion cells (RGCs) Invest in ME Charity Nr 1114035 of adult rats, as recently described 34. If we confirm that the animal model generated share an array of similarities with the clinical manifestations of LHON, we will assess the ability of our vector to protect RGCs. If we can demonstrate the proof-of-principle that our approach results in significant quantifiable improvements of RGC function in the experimental model of LHON that we generated we will open the door to gene therapy for retinal degenerations due to mutations in mtDNA. Expected consequences for knowledge in the field of medicine and public health Retinal dystrophies with mitochondrial etiology are inaccessible to curative or pallialtive therapy. Our knowledge on mRNA sorting to mitochondrial surface and its involvement in the organelle biogenesis makes this phenomenon a promising tool to fight these diseases. The transfer to clinic of our gene therapy protocol will undoubtedly represent a major step for the generation of a treatment aimed at improving life conditions of patients suffering for diseases such as LHON or DOA. We can envisage if these trails are successfull that clinical studies on other visual handicaps leading to blindness such as glaucoma 35 and devastating neurodegenerative disorders such as Charcot-Marie Tooth 36 could begin. (continued on page 27) Page 26/72 < 0.0001 ; n = 8 P value ; n Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Our position in the international research field Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions are also playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has almost 20 years of history all over the world. We are involved, as many other laboratories, in the challenge to find ways to fight these diseases. However, our main limitation is the absence of animal models required for both the understanding of the molecular mechanisms underlying the diseases and to evaluate therapeutic strategies. This is especially true for diseases due to mtDNA mutations, an American team has recently described a strategy similar to the one we have developed, to induce retinal ganglion cell degeneration in mice 37. Nevertheless, their strategy encounters the limitation of the inefficient mitochondrial import of the protein and will not generate a robust experimental model to evaluate putative treatments. If we succeed in creating a long-term animal model for the mitochondrial ND4 mutation and in confirming that it shares similarities with LHON, it will certainly allow the rapid development of new model systems for studying mtDNA mutations which are to date extremely rare. Most importantly, our protocol of gene replacement therapy for both the rat model and the Harlequin mouse strain will permit the development of clinical trials to treat patients suffering for visual impairment due to mitochondrial dysfunction. These clinical studies will be performed in the Vision Institute, a guarantee of expertise, rigour and thorough. Therefore, we are convinced that we possess a significant advance in comparison to laboratories working in the field worldwide. Bibliography 1. Orrenius S GV, Zhivotovsky. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007;47:143-183. 2. McFarland R TR, Turnbull DM. Mitochondrial disease-its impact, etiology, and pathology. Curr Top Dev Biol. 2007;77:113-155. 3. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann. N. Y. Acad. Sci. 2006;1067:182-190. 4. Schaefer A.M, Taylor R. W., Turnbull D. M., P.F C. The epidemiology of mitochondrial disorders -past, present and future. Biochem. Biophys. Acta 2004;1659:115-120. 5. Shapira AHV. Mitochondrial disease. Lancet 2006;368:70-82. Invest in ME Charity Nr 1114035 (continued on page 28) Page 27/72 Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions are also playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. 6. Calvo S JM, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat. Genet. 2006;38:576-582 7. Taylor SW, Fahy E, Ghosh SS. Global organellar proteomics. Trends in Biotech. 2003;21(2):82-88. 8. Prokisch H AC, Ahting U, Heiss K, Ruepp A, Scharfe C, Meitinger T. MitoP2: the mitochondrial proteome database--now including mouse data. Nucleic Acids Res. 2006;34 (Database issue):D705-711. 9. Perkins GA EM, Fox DA. The structure-function correlates of mammalian rod and cone photoreceptor mitochondria: observations and unanswered questions. Mitochondrion 2004;4:695-703. 10. Feher J KI, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging 2006;27:983-993. 11. Votruba M. Molecular genetic basis of primary inherited optic neuropathies. Eye 2004;18:1126-1132. 12. Bainbridge J, Tan M, Ali R. Gene therapy progress and prospects: the eye. Gene Ther. 2006;13:1191-1197. 13. Hanein S, Perrault, J., Gerber, S., Tanguy, G., Rozet, J.M. and Kaplan, J. Leber congenital amaurosis: survey of the genetic heterogeneity, refinement of the clinical definition and phenotype-genotype correlations as a strategy for molecular diagnosis. Clinical and molecular survey in LCA. Adv. Exp. Med. Biol. 2006;572:15-20.

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) 14. Acland G, Aguirre G, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 2001;28:92-95. 15. Narfstrom K, Vaegan M, Katz M, Bragadottir R, Rakoczy E, Seeliger M. Assessment of structure and function over a 3-year period after gene transfer in RPE65-/- dogs. Doc. Ophthalmol. 2005;111:39-48. 16. LeMeur G KS, AJ Smith, M Weber, JY Deschamps, D Nivard, A Mendes-Madeira, N Provost, Y Pereon, Y Cherel, RR Ali, C Hamel, P Moullier, F Rolling. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther. 2007;14:292-303. 17. Yen M-Y, Wang A-G, Wei Y-H. Leber's hereditary optici neuropathy: A multifactorial disease. Prog. in Retina Eye Res. 2006;25:381-396. 18. Yu Wai Man CY CP, Griffiths PG. Optic neuropathies-importance of spatial distribution of mitochondria as well as function. Med Hypotheses 2005;65(6):1038-1042. 19. Carelli V LMC, Iommarini L, Carroccia R, Mattiazzi M, Sangiorgi S, Farne' S, Maresca A, Foscarini B, Lanzi L, Amadori M, Bellan M, Valentino ML. Mitochondrial optic neuropathies: how two genomes may kill the same cell type? Biosci. Rep. 2007;27:173-184. * Tel.: +33 1 40 01 13 66 fax: +33 1 49 28 66 63. 20. DiMauro S MM. Mitochondrial diseases: therapeutic approaches. Biosci. Rep. 2007;27:125-137. 21. Manfredi G., Fu J., Ojaimi J., et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene to the nucleus. Nature Genet. 2002;30:394-399. 22. Oca-Cossio J., KenyonL., Hao H., T MC. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics 2003;165:707-720. 23. Bokori-Brown M, Holt IJ. Expression of Alga1 nuclear ATP synthase subunit 6 in human cells results in protein targeting to mitochondria but no assembly into ATP synthase. Rejuvenation Res. 2006;9(4):455-469. 24. Smith PM, Ross GF, Taylor RW, Turnbull DM, Lightowlers RN. Strategies for treating disorders of the mitochondrial genome. Biochem. Biophys. Acta 2004;1659:232-239. 25. Sylvestre J., Vialette S., Corral-Debrinski M., C. J. Long mRNAs coding for yeast mitochondrial proteins of prokaryotic origin localize to the vicinity of mitochondria. Genome Biology 2003;4(7):R44.1-R44.9. (continued on page 29) E-mail address: corral@st-antoine.inserm.fr Additional articles from Marisol’s team can be found at the following sites: - ScienceDirect RNA Journal http://www.sciencedirect.com/science/journal/01674889 http://www.rnajournal.org/cgi/content/full/12/7/1408 Rejuvenation research http://www.liebertonline.com/doi/abs/10.1089/rej.2006.0526 Invest in ME Charity Nr 1114035 Page 28/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) 26. Margeot A, Blugeon C, J. Sylvestre, Jacq C, CorralDebrinski M. In Saccharomyces cerevisiae, ATP2 mRNA sorting to the vicinity of mitochondria is essential for respiratory function. EMBO J. 2002;21(24):6893-6904. 27. Sylvestre J, Margeot A, Jacq C, Dujardin G, CorralDebrinski M. The role of the 3'UTR in mRNA sorting to the vicinity of mitochondria is conserved from yeast to human cells. Mol. Biol. Cell 2003;14:3848-3856. 28. Corral-Debrinski M, Blugeon C, Jacq C. In yeast, the 3' Untranslated Region or the presequence of ATM1 is required for the exclusive localization of its mRNA to the vicinity of mitochondria. Mol. Cell Biol. 2000;20(21):78817892. 29. Ginsberg MD, Feliciello A, Jones JK, Avvedimento EV, Gottesman ME. PKA-dependent binding of mRNA to the mitochondrial AKAP121 protein. J. Mol. Biol. 2003;327(4):885-897. 30. Kaltimbacher V, C.Bonnet, Lecoeuvre G, Forster V, Sahel J-A, Corral-Debrinski M. mRNA localization to the mitochondrial surface allows the efficient translocation inside the organelle of a nuclear recoded ATP6 protein. RNA 2006;12(7):1408-1417. 31. Benit P., Goncalves S., Dassa E. P., Briere J.J., Martin G., Rustin. Three spectrophotometric assays for the measurement of the five respiratory chain complexes in minuscule biological samples. Clin Chim Acta. 2006;374(1-2):81-86. 32. Bonnet C, Kaltimbacher V, Ellouze S, et al. Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mtDNA mutations affecting complex I or V subunits. Rejuvenation Res. 2007;10:128-144. 33. Kasahara A IK, Yamaoka M, Ito M, Watanabe N, Akimoto M, Sato A, Nakada K, Endo H, Suda Y, Aizawa S, Hayashi J. Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells. Hum Mol Genet 2006;15(6):871-881. 34. Ishikawa H TM, Matsumoto N, Sawada H, Ide C, Mimura O, Dezawa M. Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode. Gene Ther.2005;12(4):289-298. 35. Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog. Retin. Eye Res. 2006;25:490-513. 36. Züchner S MI, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 2004;36:449-451. 37. Qi X SL, Lewin AS, Hauswirth WW, Guy J. The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Invest Ophthalmol Vis Sci 2007;48:1-10. ME Story In a few weeks time it will be the one year anniversary of my gorgeous and funny and talented sister's death. If you knew her before she got ill she was like a force of nature. Talented, funny, generous she had loads of friends and was very much a person who lived her life to the full. She had courage and was original and so much more. M.E. was the cruellest thing to ever happen to Sophia. I will not go on about how much she suffered because it is an unbelievable amount. To top it all her illness was not recognised as a neurological disease and so there was the added burden of trying to get the authorities to understand the true nature of her illness. Unfortunately for us all Sophia suffered even more than was necessary. My amazing sister has paid with her life but she all she wanted was that if only one person was helped by her experience it would all have been worth it for her. From Sophia Mirza's sister - Roisin Mirza (written in 2006) Invest in ME Charity Nr 1114035 Page 29/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Chronic Fatigue Syndrome after Q fever By Dr. Dragan Ledina Department of Infectious Diseases, Split University Hospital Center, Split; Croatia Summary Background: Q fever is a common and acute but rare chronic zoonosis caused by Coxiella burnetii. Its acute form manifests as atypical pneumonia, flu-like syndrome, or hepatitis. Some authors observed symptoms of chronic fatigue in a small number of patients after the acute phase of Q fever; in many cases serological assay confi rmed the activity of Coxiella burnetii infection. The effect of antibiotic therapy on post-Q-fever fatigue syndrome has not been studied in south-east Europe thus far. Case Reports: Three patients are presented with post-Q-fever fatigue syndrome. All fulfilled the CDC criteria for chronic fatigue syndrome. IgA antibodies to phase I of the growth cycle of Coxiella burnetii were positive in two patients and negative in one. Two patients were treated with doxycycline for two weeks in the acute phase of illness and one with a combination of erythromycin and gentamycin. After 4–12 months they developed post-Q-fever fatigue syndrome and were treated with intracellular active antibiotics (fl uoroquinolones and tetracycline) for 3–12 months. Effi cacy of the treatment was observed in two patients, but in one patient the results were not encouraging. Conclusions: These results suggest the possibility of the involvement of Coxiella burnetii infection in the evolution of chronic fatigue syndrome. This is the fi rst report on post-Q-fever fatigue syndrome in Mediterranean countries. Evidence of IgA antibodies to phase I of the growth cycle of Coxiella burnetii is not a prerequisite for establishing a diagnosis of CFS. The recommendation of antibiotic treatment in post-Q-fever fatigue syndrome requires further investigation. keywords: chronic fatigue syndrome • Coxiella burnetii • post-Q fever fatigue syndrome • antibiotic treatment BACKGROUND Q fever is one of the most common anthropozoonoses in southeast Europe. It is caused by Coxiella burnetii, an intracellular pathogen whose classifi cation has been changed from the order of Rickettsiaceae to the order of Legionellales [1]. Human infection develops after inhalation of contaminated aerosol or consumption of unpasteurized milk. It is rarely transmitted by vectors, transfusions of contaminated blood, or transplancentally [2,3]. Recently, a major role in disease spread was attributed to air currents [4]. About 60% of infections caused by Coxiella burnetii are asymptomatic [2]. Acute infection usually presents as a febrile state, pneumonia, or hepatitis, while other organs are less commonly affected. Coxiella burnetii is endemic in rural, coastal, and noncoastal areas of southern Croatia and is associated with stockbreeding. Acute Q fever in Split-Dalmatia County (470,000 inhabitants) is most commonly presented with both pneumonia and hepatitis (60.0%), followed by pneumonia (25.8%), hepatitis (9%), and nonspecific febrile illnesses (5.2%). During the period from 1985 to 2002, 155 acute Q fever cases were hospitalized at the Split University Hospital, with a mean annual incidence of 1.82/100,000/year. All cases were verifi ed by serologic testing with C. burnetii phase II antigen as is routinely done in all patients with clinical syndrome of atypical pneumonia that live in endemic areas [5]. In the northern part of Croatia, Coxiella burnetii causes 6.45% of all interstitial pneumonias that are serologically verified [6]. In its chronic form, Q fever mostly presents as endocarditis, infl ammation of intravascular implants, osteoarthritis, and chronic hepatitis [7]. During a follow-up of convalescent patients after acute Q we noticed that some had symptoms that were consistent with chronic fatigue syndrome (CFS). The diagnostic criteria for CFS include fatigue for six months or more together with at least four of the following symptoms: lack of concentration or/and memory that interferes with normal activities, sore throat, tender cervical or axillary lymph nodes, joint pain without swelling, muscle pain, headache, no refreshing sleep, and malaise lasting longer than 24 hours after exertion [8]. CFS is twice as common in females as in males, and it is most common between 25–45 years of age. The cause of CFS is not fully understood. There are three hypotheses about the cause of this impairment: postinfectious, immunological, and depression [9,10]. Penttila and associates found that in Australia, 20% of patients after acute Q fever develop post-Q-fever fatigue syndrome (QFS). Increased concentrations of IL6 and interferon- as well as lowered concentrations of IL-2 that are found after stimulating peripheral blood mononuclear cells in cultures from these patients are presumed to be implicated in the pathogenesis of QFS [11]. The purpose of this paper is to emphasize the existence of CFS after Q fever in Croatia and its incidence and to show the effects of antimicrobial therapy of patients with QFS. We describe three patients who had QFS. During the period from January 2000 to December 2004, 90 patients with acute Q fever were treated at the Split University Hospital and we observed 3/90 patients with post-Q-fever fatigue syndrome. After the diagnosis of QFS was established, these patients were treated with antibiotics. They were asked to fill out questionnaires assessing their clinical condition before (continued on page 31) Invest in ME Charity Nr 1114035 Page 30/72 Journal of IiME Volume 1 Issue 2 Chronic Fatigue Syndrome after Q fever (continued) and after the treatment. The questionnaire survey included subjective symptoms: fatigue, lack of concentration, no refreshing sleep, sore throat, tender cervical or axillary lymph nodes, joint pain without swelling, muscle pain, headache, and malaise lasting longer than 24 hours after exertion. These symptoms were evaluated according to four grades (0: absent, 1: mild, 2: moderate, 3: severe). If the summed result of the survey was halved after the treatment, the effect of antibiotic therapy was considered favorable (Table 1). CASE REPORTS Case 1 A 34-year-old male shopkeeper with atypical pneumonia caused by Coxiella burnetii was treated at the Department for Pulmonary Diseases in February 2000. He did not have any serious illness before he caught Q fever. He arrived from a rural area where Q fever is endemic. Laboratory results showed an eryth