Journal of IiMER Volume 16 Issue 1 May 2026 UK Charity Invest in ME Research

Contents From the Chair Our Conference Week Partners Fellowship Update: Ian Gibson & LunaNova Light ME Up: Red Light Therapy for ME LunaNova Fellowship: Ancient Viruses, Modern Disease COMPASS-ME SEE ME RESTORE-ME Clinical Trial The Centre of Excellence for ME – A Case for Investment Dutch Research Award Summer Student Bursaries 2026 Young EMERG: Supporting Young Researchers Mike's European Marathons How to Support the Charity Germany Takes Action The BRMEC Colloquia - Fifteen Years of Building ME Research BRMEC15 Day 1 Programme BRMEC15 Day 2 Programme BRMEC15 Day 3 / IIMEC18 Conference 2 5 6 7 9 10 11 11 12 13 14 15 18 19 20 22 33 34 35 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. Published by Invest in ME Research, May 2026 Invest in ME Research Registered Charity No. 1153730 PO Box 561 Eastleigh SO50 0GQ Hampshire, UK investinme.org © Invest in ME Research 2026. All rights reserved. No part of this publication may be reproduced without the prior permission of the publisher. JOURNAL OF IIMER May 2026 CHAIRMAN’S MESSAGE Dear Friends and Supporters, Welcome to International ME Conference Week 2026 - a milestone year in every sense as we mark twenty years of Invest in ME Research and reflect on what two decades of dedication, collaboration, and principled advocacy have made possible. Over twenty years, this charity has remained focused on one unwavering objective: meaningful progress in the understanding and treatment of ME. Our efforts have ranged from direct advocacy and raising educational standards through influential international conferences, to establishing research fellowships, funding the UK's only clinical trial for ME, and initiating and sustaining European networks of researchers, clinicians, and patient groups. These efforts have made a difference - and we have achieved them thanks to the extraordinary support of our supporters and the collaboration of this community of researchers, clinicians, patients, carers, and supporters. This year's conference week spans five days - uniquely the only such 5-day event for ME in the world - and brings together a wonderful combination of events: the seventh early-career workshop led by Young EMERG; the European ME Research Group Annual Meeting, which this year discusses an EMERG-led panEuropean research project for ME; our fifteenth Biomedical Research into ME Colloquium; the eighteenth International ME Conference, now integrated into the final day of the colloquium, bringing researchers, clinicians, and patients together in a shared forum; and a planning meeting organised for a future critical clinical platform project. The theme of the events this year - "20 Years of Investing in ME Research to Discover ME" - reflects both where we have come from and where we now proceed. Our research colloquium focuses on systems biology, immunology, metabolism, neurology, microbiome research, AI and bioinformatics, and future pathways for treatment - representing the breadth and depth of international scientific engagement that our annual gatherings have helped to foster. We are delighted to welcome Professor Sarah Teichmann as keynote speaker at BRMEC15, and to host delegates and speakers from institutions across more than twenty countries - including the NIH, Karolinska Institutet, Columbia University, Imperial College London, the Quadram Institute, Cornell University, the University of Cambridge, Med. University of Vienna, Catholic University of Valencia and many more. This is, quietly but significantly, a landmark year. Though formal announcements must wait a little longer, two major developments - one representing the first substantial pan-European research initiative of its kind for ME, the other a meaningful advance in clinical research capacity - are the direct result of work built patiently over two decades by this charity, its collaborators, and its supporters. Both are landmarks for European ME research. Both are the direct consequence of sustained network-building, collaboration, and long-term investment in research infrastructure. The groundwork laid through EMERG, through our annual colloquia, through investment in early-career researchers, and through European partnership is bearing fruit in ways that will become clear in due course. We look forward to sharing the full story when the time is right. Invest in ME Research Page 2 of 35

JOURNAL OF IIMER May 2026 It is worth reflecting on how progress of this kind is made. The networks, research relationships, and institutional infrastructure that now exist were built here - collaboratively, persistently, and without public support - over twenty years. That is not a complaint; it is context. Public funding, when it has materialised, has too often been directed towards familiar recipients and familiar approaches, at times reconstructing what already existed rather than building upon it. The effect has been to introduce delay where there was opportunity for acceleration, and to consume resource that might otherwise have gone directly to research. This may not be unique to ME; it is a pattern well recognised across many fields. But for a condition where patients have waited long enough, the cost is felt particularly keenly. Influence over the research agenda is not the same as advancing it. Administrative overhead is not the same as doing the work. And the structures this community has spent twenty years building do not need to be replicated elsewhere - they need to be resourced. Control is not progress. Administration is not research. The wheel does not need reinventing - it needs funding and support. The Centre at Norwich Research Park stands as one of the clearest expressions of what vision, commitment, and genuine collaboration can produce. The scientific and institutional infrastructure is in place. The missing ingredient has been consistent, adequate funding from those with both the means and the mandate to provide it. Twenty years have shown that persistence, integrity, and collaboration yield results. Yet, as a small, entirely volunteer-run charity - no salaries, every donation directed to biomedical research - we continue to swim against the tide with continuing missed opportunities at the policy level demonstrating that, in the UK at least, rapid progress will come primarily through the efforts of the biomedical research community that has been built here, not through the goodwill of institutions that have repeatedly shown their preference for a status quo or strategic indecision. Our great thanks to conference sponsors the Irish ME Trust, Quadram Institute Bioscience, Terra Biological LLC, PrecisionLife, and Vazyme, and to The Hendrie Foundation and LunaNova for their immense and valued commitment to our research. As we open this conference week, we invite all delegates - researchers, clinicians, patients, early-career scientists, and supporters - to engage fully with the presentations, participate in the discussions, and build the connections that will carry ME research forward into its next chapter. Welcome to International ME Conference Week 2026. Kathleen McCall Chairman, Invest in ME Research Invest in ME Research Page 3 of 35

JOURNAL OF IIMER May 2026 Our 2026 Conference Week Partners This May, Invest in ME Research marks twenty years of funding and facilitating biomedical research into Myalgic Encephalomyelitis - and does so by bringing the global ME research community together for the International ME Conference Week 2026. Five days. Five events. Researchers, clinicians, early-career scientists and patients from more than twenty countries. To our knowledge, the only five-day international conference week dedicated entirely to ME anywhere in the world. That this week exists at all is a reflection of twenty years of determination. That it continues to grow is, in no small part, due to the partners we are proud to acknowledge here. The Irish ME Trust has supported every single conference since 2006 - a partnership spanning the full twenty years of this charity's history. That kind of sustained, unconditional commitment to ME research is rare, and its value cannot be overstated. We extend our sincere thanks also to Quadram Institute Bioscience, Terra Biological LLC, PrecisionLife and Vazyme. Together, these organisations represent something important - not simply financial support, but confidence in the science, in the researchers, and in the work this community is doing. That confidence is what allows this conference week to exist, to grow, and to matter. We are grateful for every part of it. Invest in ME Research Page 5 of 35 JOURNAL OF IIMER May 2026 Advancing ME Research The Fellowships at Norwich Research Park Invest in ME Research, in partnership with the Quadram Institute, has established two postdoctoral fellowships at Norwich Research Park - the Ian Gibson Fellowship and the LunaNova Fellowship - both dedicated to advancing biomedical research into myalgic encephalomyelitis. The Ian Gibson Fellowship, launched in 2022 and named in honour of the late Dr Ian Gibson - scientist, politician and tireless advocate for people with ME - was the first postdoctoral fellowship in the UK dedicated solely to ME research. Held by Dr Katharine Seton, it continues her career in ME research at the Quadram Institute, building on her PhD funded by Invest in ME Research and the University of East Anglia. Dr Seton's research focuses on determining the contribution of the intestinal microbiome to oxidative stress in ME patients, and whether this drives alterations in immune function that accelerate premature immune ageing. She is also investigating the impact of microbiota replacement therapy on intestinal and systemic oxidative stress in ME patients - the first study to directly assess this relationship - with the aim of identifying whether targeting the gut microbiome can restore immune function and alleviate symptoms. The LunaNova Fellowship, funded by technology company LunaNova and introduced in 2023, is held by Dr Krishani Perera, who joined Professor Simon Carding's laboratory at the Quadram Institute of Bioscience in July 2024. Her two-year fellowship centres on the gut-immune-brain axis and the search for biomarkers, with strong links to the European ME Research Group and international partners. Dr Perera's research investigates whether the reactivation of human endogenous retroviruses - genes embedded within our genome that are ordinarily kept inactive - may drive accelerated ageing of immune cells in ME patients. Her work seeks to establish whether HERV reactivation plays a causal role in immune dysfunction. She is also contributing to the RESTORE-ME clinical trial, a phase IIb placebo-controlled study investigating microbiota replacement therapy, and to the COMPASS ME Study, which analyses microbial communities - viruses, bacteria, and fungi - in the mucus of people with ME. Both fellowships sit at the heart of the strategy to develop the UK Centre of Excellence for ME at Norwich Research Park, supporting ongoing clinical trials and PhD studentships, and building the sustained research capacity that this seriously under-resourced condition demands. With revised estimates now placing the number of people with ME in the UK at over 400,000 - a figure that continues to grow in the wake of the Covid pandemic - the urgency of this work has never been clearer. Invest in ME Research Page 6 of 35

JOURNAL OF IIMER May 2026 Invest in ME Research has always maintained a clear focus: directing funding towards rigorous biomedical research with real potential, building a sustainable research base, and driving meaningful progress. The fellowships at Norwich Research Park are a direct expression of that commitment. Further information on Dr Seton: https://quadram.ac.uk/people/katherine-seton/ Further information on Dr Perera: https://tinyurl.com/Quadram-Krishani Light ME Up – Exploring Red Light Therapy for ME In April 2024, Dr Katharine Seton, PhD – the Ian Gibson Fellow funded by Invest in ME Research – began a pilot study looking at whether red light therapy could be helpful for people with ME. Red light therapy is already an approved treatment (by the FDA) for conditions such as chronic pain, wound healing, and hair regrowth. However, it has not previously been formally tested in people with ME/CFS. Early research in other conditions suggests it may help improve energy levels, reduce pain, and support blood circulation. These are all areas that can be challenging for people with ME, so it made sense to explore whether this therapy might offer some benefit. Red light is absorbed by the mitochondria – often described as the “batteries” inside our cells – where it may help increase energy production. Research also suggests that timing matters, as the therapy appears to work best in the morning, in line with the body’s internal (circadian) clock, particularly between 9am and 11am. Importantly, the device used in this study was a targeted single-wavelength red light specifically designed for research purposes. This is difference from many commercially available products, which usually emit a broad spectrum of light. We would strongly advise patients not to purchase or use red light devices based on this early-stage research. How the study worked Over a 12-month period, 26 people with ME from across the UK took part in this 9-week study. Importantly, the study was carried out entirely from home, so participants could take part in a way that suited their needs. This approach also made it possible for people who are more severely affected by ME to be involved in research. Before starting the therapy, participants completed a set of assessments to understand their symptoms and daily functioning. These included: • A questionnaire about their ability to carry out everyday activities (FUNCAP27) • Online cognitive (thinking and memory) tests • Wearing a wrist activity monitor for seven days • Keeping a sleep diary for seven days Once these were completed, participants were sent a red light lamp to use at home. Invest in ME Research Page 7 of 35 JOURNAL OF IIMER May 2026 They were asked to use the lamp for 2 minutes each morning, between 9am and 11am, for two weeks. After this two-week period, the same assessments were repeated to see whether there were any changes in symptoms. Participants were also asked to share feedback about their experience of taking part. What did participants tell us? Of the 26 people who started the study, 20 completed all aspects of it. The early findings show that most participants found the red light therapy easy to use: • 86% were able to set up and use the lamp on their own • All participants said they would be willing to use the lamp again • Around 14% said they would prefer a different time schedule More than half of participants found it difficult to use the lamp between 9am and 11am. Despite this, participants showed remarkable commitment, with everyone using the lamp for at least 12 out of the 14 recommended days. The therapy also appeared to be safe. Only one participant reported a mild reaction to the light. Feedback on study assessments Most people (86%) were able to wear the activity monitor for the full seven days. However, eight participants reported discomfort from the wrist strap, and some experienced worsening of eczema. As a result, the research team is now exploring more comfortable strap options for future studies. Participants were also asked to complete up to six cognitive tests in one sitting. Nearly everyone completed all the tests, but about one-third reported a temporary worsening of symptoms afterwards. This feedback is important and will help shape how assessments are designed in future research. What happens next? The research team is now carrying out the next stage of analysis. This includes working with a statistical expert to combine information from multiple sources, such as questionnaires, activity monitoring, sleep diaries, and cognitive tests, to explore whether red light therapy may provide any measurable benefits for people with ME. The team hope to have results ready by the autumn and they look forward to sharing further updates with you then. Sharing the research We are also pleased to share that Katharine presented the preliminary findings from this study at the Young EMERG Workshop in Vienna in November 2025. Her work was very well received, and she was awarded first place in the poster presentation competition – a fantastic achievement and recognition of the importance of this research. Invest in ME Research Page 8 of 35

JOURNAL OF IIMER May 2026 LUNANOVA FELLOWSHIP - RESEARCH IN FOCUS Ancient Viruses, Modern Disease - The Role of Human Endogenous Retroviruses in ME A review published in the International Journal of Molecular Sciences argues that human endogenous retroviruses - ancient viral sequences embedded in our genome - may be active drivers of the biological processes underlying ME. Written by Perera, Oltra and Carding of the Quadram Institute Bioscience and Norwich Research Park, it represents a significant step towards understanding ME as a mechanism-driven, biologically distinct condition. What Are Human Endogenous Retroviruses? Human endogenous retroviruses (HERVs) are the remnants of ancient viral infections that integrated into human DNA millions of years ago. They now make up approximately 8% of the human genome. Under normal conditions they are kept inactive. When that suppression breaks down - through infection, stress, or immune dysfunction - HERVs can reactivate and begin producing viral proteins and RNA. This can amplify immune responses, drive chronic inflammation, and disrupt normal gene regulation. Reactivated HERVs have already been implicated in autoimmune diseases including multiple sclerosis, lupus, and juvenile rheumatoid arthritis. The Link to ME The review proposes that reactivated HERVs are plausible contributors to the hallmark features of ME - persistent post-infectious immune dysfunction, chronic inflammation, and the neurological and cognitive symptoms that characterise the disease. Three principal mechanisms are identified. First, HERV proteins trigger sustained immune responses that may perpetuate the immune activation seen after acute viral infection. Second, HERV elements can act as alternative gene switches, upregulating inflammatory networks in ways consistent with the immune patterns observed in ME. Third, HERV reactivation disrupts the very mechanisms that would normally suppress it, creating a self-reinforcing cycle. The paper draws on evidence from multiple sclerosis research, where a specific endogenous retrovirus has been the most thoroughly studied. The authors argue that the immune and inflammatory changes associated with HERV reactivation closely mirror those documented in ME - including altered natural killer cell function, T-cell exhaustion, and elevated pro-inflammatory cytokines. Viral infections known to trigger ME onset - including SARS-CoV-2, Epstein-Barr virus, and enteroviruses - are also known to reactivate HERVs, providing a coherent molecular link between post-infectious onset and the chronic immune dysregulation that follows. Biomarkers and Treatment Implications ME currently has no validated biological diagnostic test. The review identifies HERV expression patterns as a promising approach for distinguishing ME from healthy controls and from overlapping conditions such as fibromyalgia, long COVID, and depression. If validated, HERV signatures could also provide a quantitative measure of disease severity and a means of monitoring treatment response. On the therapeutic side, the paper identifies several candidate strategies: HERV-targeted antibodies, antiviral agents that suppress HERV activity, immune modulators targeting downstream inflammation, and epigenetic interventions aimed at restoring HERV suppression at source. The authors are careful to present these as directions requiring clinical validation, not established treatments. They specifically call for clinical trials enrolling patients selected on the basis of defined HERV expression profiles as the necessary next step. Invest in ME Research Page 9 of 35 JOURNAL OF IIMER May 2026 The authors’ explicit goal is to transform ME from a symptom-based syndrome into a mechanism-driven, treatable condition. This review is a substantive step in that direction. Original Paper Perera KD, Oltra E, Carding SR. Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics. Int. J. Mol. Sci. 2026, 27(10), 4309. DOI: 10.3390/ijms27104309 - Published: 12 May 2026 - Open Access (CC BY) COMPASS-ME The COMPASS-ME Study - Investigating the Microbial Landscape of ME One of the questions that has persistently complicated ME research is deceptively simple: what role, if any, do microbes play in triggering or sustaining the disease? Many patients report a viral infection preceding the onset of their symptoms, and the overlap with long COVID has reinforced the view that post-infectious mechanisms are central to understanding ME. Yet despite decades of investigation, no single pathogen has been definitively linked to the condition, and the broader microbial picture - encompassing not only viruses but bacteria and fungi - has remained poorly characterised. The COMPASS-ME study, funded by Invest in ME Research and based at the Quadram Institute Bioscience on Norwich Research Park, is designed to address precisely this gap. Led by LunaNova fellow Dr Krishani Perera, working within Professor Simon Carding's research group, the study will analyse the mucosal microbial communities - including viruses, bacteria, and fungi - of individuals with and without ME, using mucosal swab samples taken from sites where microbial infections commonly begin. The approach is both scientifically rigorous and practically considered: given the significant mobility difficulties experienced by many people with ME, sampling methods have been chosen specifically to minimise the burden on participants and ensure the study is as inclusive as possible. Dr Perera brings to this work a background in molecular virology developed across Kansas State University and postdoctoral research in France, where she studied viruses that persist in immune-privileged sites in the body and contribute to long-term health consequences. That expertise in viral persistence and immune evasion is directly relevant to ME, where the mechanism by which an initial infection might give rise to chronic, systemic illness remains one of the field's central unanswered questions. The longer-term ambition of the COMPASS-ME study is to contribute to the development of reliable diagnostic tools for a disease that currently has none, and to identify the biological mechanisms that might, in time, be amenable to targeted treatment. It is work that is painstaking, methodologically careful, and - given the complexity of ME and the number of intersecting biological systems involved - necessarily cautious in its conclusions. That caution is a strength, not a limitation. The field has suffered from premature certainty in the past. What is needed now is precisely the kind of systematic, well-grounded investigation that this study represents. Further information: quadram.ac.uk Invest in ME Research Page 10 of 35

JOURNAL OF IIMER May 2026 SEE ME A clinical innovation fund which benefits patients through research by bringing together Quadram Institute (QI) scientists and doctors at the Norfolk and Norwich University Hospital (NNUH) has selected five new projects for funding. The Quadram Institute Clinical Seedcorn Fund was first established in 2021/2022 to help clinicians develop research ideas with scientists at the Quadram Institute. The fund supports secondments of NHS staff to Quadram Institute laboratories and associated research costs. Quadram Institute Bioscience (QIB) in partnership with the Norfolk & Norwich Hospitals Charity have provided £100,000 each to jointly fund £200,000 of new collaborative clinical research projects. Included in this is a project entitled SEE-ME - Retinal Biomarkers of Visual Disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – and this will be run by ‘Ian Gibson fellow’ Dr Katharine Seton (QI) and NNUH consultant ophthalmologist Mr Colin Jones (NNUH). This is a very novel research pathway and another spin-off from the ME research being carried out at the centre. Further information: quadram.ac.uk RESTORE-ME Clinical Trial The RESTORE-ME trial - a phase IIb, randomised, placebocontrolled study of microbiota replacement therapy at the Quadram Institute - remains the UK’s only clinical trial of its kind for ME, and one of the first to use objective outcome measures. Progress has taken longer than originally anticipated. Microbiota replacement therapy is regulated by the MHRA as an investigational medicinal product, and obtaining the necessary manufacturing licence and regulatory approvals has proved a complex and time-consuming process. The pandemic added further delay to building and infrastructure work required at the Quadram Institute. The research team continues to work on related studies that will optimise the trial protocols alongside the regulatory preparations. A further update will be shared as soon as there is more to report. Meanwhile the associated PPI group that has been formed for the trial continues to meet, with the next meeting scheduled for July. Further information: quadram.ac.uk Invest in ME Research Page 11 of 35 JOURNAL OF IIMER May 2026 The Centre of Excellence for ME - A Case for Investment The research infrastructure at Norwich Research Park was constructed over more than a decade through the sustained commitment of a volunteer-run charity and its supporters, and the dedication of a handful of researchers - without government funding, without research council backing, and without the institutional infrastructure that better-resourced disease areas take as given. Five PhD studentships. The first dedicated fellowships for ME research in the UK. The RESTORE-ME trial - a phase IIb, randomised, placebo-controlled study of microbiota replacement therapy, using objective outcome measures, funded entirely by Invest in ME Research. A programme of basic science, immunology, virology, and microbiome research embedded within one of Europe's leading gut biology institutes in one of Europe's most advanced research parks. The Quadram Institute at Norwich Research Park houses one of Europe's largest endoscopy units, a clinical research facility, and world-class expertise in mucosal immunology and gut biology. It sits within a park of over 3,000 scientists spanning genomics, immunology, food science, and clinical medicine - one of the largest single-site concentrations of health research in Europe. Alongside RESTORE-ME, the COMPASS-ME study is investigating the mucosal microbes of people with ME, and Dr Krishani Perera's Luna Nova fellowship is examining the role of human endogenous retroviruses in immune ageing. The platform for translational biomedical ME research - the kind that moves between laboratory and clinic, generating findings that directly inform patient care - already exists. It was not created by a government initiative. What sustained public investment in that platform could deliver is not difficult to imagine. Even a relatively small amount of funding - say, £4-5 million - could fund the expansion of the centre with multiple fellowships, PhD studentships, and early-career researcher positions needed to grow and sustain the programme over the long term. It could establish and expand the biobank and clinical database infrastructure that translational research requires. It could accelerate the work already underway on viral, fungal, and microbial contributions to ME. It could catalyse the European collaboration building on already established links and partnerships. It could, in short, transform a functioning research foundation - driven and funded over twenty years without government or research council support - into the properly resourced centre of excellence that patients need and the science is ready to deliver. The context for that case is sobering. Between 2015 and 2020, UK public research funding for ME totalled just £6 million - compared to £53 million for Parkinson's disease and £22 million for multiple sclerosis, despite ME affecting comparable or greater numbers of people. The economic cost of ME to the UK was estimated at £3.3 billion annually by the 2020health Counting the Cost report - a figure based on 2014-15 data and a conservative prevalence estimate of 0.2% of the population, which the report itself acknowledged could be as high as 0.7%. That estimate is now a decade old, and with prevalence substantially revised upward and post-COVID case numbers having increased the affected population considerably, the economic burden will have risen in proportion. The case for directing serious, sustained investment towards research infrastructure that already exists, is already producing results, and was built without the support it deserved is not complex. It is simply overdue. The Centre at Norwich Research Park is not a proposal awaiting validation. It is a functioning reality that requires only the investment the establishment has thus far chosen to direct elsewhere. Invest in ME Research Page 12 of 35

JOURNAL OF IIMER May 2026 Dutch Research Award Virus infection and reactivation and the gastrointestinal microbiome in myalgic encephalomyelitis Rik Haagmans, one of the PhDs funded by Invest in ME Research, recently completed his project and, with the Quadram Institute, applied to the Dutch ZonMW agency for a recent round of awards for research as part of the ongoing Dutch strategy in their 10 year plan for research into ME. We are glad to report that Rik was successful in this application and so continues with research into ME and has established now a collaboration with the Dutch programme. Here below Rik has written a brief description of the new project. Viral infections have long been associated with ME/CFS, and may trigger or contribute to maintaining ME/CFS. In addition, gut microbiome as well as immune system abnormalities have been found in ME/CFS patients and gastrointestinal disturbances are a frequent occurrence in ME/CFS. Gut microbiota play an important role in regulating the immune system and microbiome abnormalities may affect the immune reaction against viral infections, and chronic viral infections may contribute to immune system abnormalities themselves. How the gut microbiome and viral infections interact and contribute to ME/CFS is still unclear, however. Our project is funded by the Dutch funding organisation ZonMw through their ME/CFS research programme. We will be investigating the activity of several viruses commonly associated with ME/CFS, as well as the composition of the gut microbiome and virome and markers of gut barrier integrity. This will be done in the Dutch ME/CFS Biobank and Cohort (NMCB) and ME/CFS Lines cohort, as well as in a group of patients participating in the RESTORE-ME study which will take place at the Quadram Institute in the UK. Invest in ME Research Page 13 of 35 JOURNAL OF IIMER May 2026 This way we hope to get a better understanding of the mechanisms underlying ME/CFS, as well as gain more insight into potential biomarkers and treatments. More information about the project can be found at the QR code link on the right. This project investigates the relationship between viruses and the gut microbiome in ME/CFS patients. This may assist in developing new diagnostic biomarkers for ME/CFS and identifying patients who may benefit from antiviral or microbiome-targeted treatments, such as faecal microbiota transplantation (FMT). In a faecal microbiota transplantation, stool containing healthy bacteria from a healthy donor is transferred to the intestines of a patient to restore the balance of bacteria. Summer Student Bursaries for 2026 In 2026, Invest in ME Research again partners with the Quadram Institute to encourage knowledge and awareness of ME amongst undergraduate students via the Invest in ME Research Summer Student Bursaries. Quadram Institute will offer up to three awards. The successful applicants will begin in June. Invest in ME Research, in collaboration with the Quadram Institute at Norwich Research Park, is pleased to announce that we will again partner to establish new Summer Student Bursaries for 2026. These bursaries are designed to support undergraduate students in gaining practical experience in biomedical research, with a focus on Myalgic Encephalomyelitis. This initiative aligns with the charity’s objective of raising education and fostering the next generation of doctors and researchers. The discovery of new treatments relies heavily on research into the causes of the disease. The Summer Student Bursaries provide a unique opportunity for students to contribute to this vital research while developing their skills and knowledge in biomedical science - raising awareness of ME and influencing the next generation of researchers in the process. Three eight-week bursaries are being offered, with involvement in various research projects at the Quadram Institute. Summer students will join an active research group working on microbiological and immunological aspects of ME. Projects will be aligned with ongoing research activities and may involve a combination of laboratory-based and computational approaches. More details: https://quadram.ac.uk/vacancies/invest-in-me-research-summer-student-bursaries-2/ We are grateful to the Quadram Institute and Carding Lab for making this opportunity possible, further building on the excellent Centre of Excellence for ME foundations that already exist in Norwich Research Park. Thanks to our supporters for making this, and the other forthcoming projects which we have initiated and in which we are involved, possible. Invest in ME Research Page 14 of 35

JOURNAL OF IIMER May 2026 Last Year’s Bursary Students From over 50 applications, three students were selected for the 2025 bursaries: Mya Pearce (University of York, Biology), Paige Cameron (University of Southampton, Biomedical Sciences) and Tayyibah Sarwar (University of Westminster, Biomedical Sciences). Following their six-week placement at the Quadram Institute, they shared their reflections. Their motivations were personal as well as academic. Paige’s sister has ME, making the research feel urgent and meaningful. Mya was drawn to under-researched, idiopathic conditions. Tay discovered the bursary almost by chance through LinkedIn - and applied immediately. All three arrived expecting a step beyond the teaching lab. What they found exceeded that. Mya investigated antibody reactivity to fungal antigens, learning flow cytometry alongside DNA extraction and PCR. Paige and Tay both worked on the virome in mucosal cavities of ME patients, developing qPCR, cDNA synthesis, and bioinformatic analysis skills - much of it entirely new to them. The Quadram team made a strong impression. The students describe a welcoming, collaborative environment where questions were encouraged and expertise was freely shared. Tay noted that everyone - from scientists to canteen staff - was approachable. All three leave with deepened ambitions: Mya is heading towards a masters in immunology, Paige towards biomedical research in disease mechanisms, and Tay towards drug development - with ME treatments in her sights. As Tay put it: “It was incredibly rewarding to know that the work I was contributing to could one day help improve understanding and treatment of ME.” Further information: Invest in ME Research Young EMERG Workshop Series The idea behind the formation of the Young EMERG network was to build awareness and provide opportunities for emerging researchers in Europe and create a support network that could encourage interest in research into ME, thereby increasing capacity. Last year Young EMERG held their workshop in Vienna last November. Invest in ME Research Page 15 of 35 JOURNAL OF IIMER May 2026 Supporting Young Researchers at Young EMERG Vienna Workshop In addition to supporting Young EMERG committee members, Invest in ME Research offered a number of grants for young European researchers to attend the Young EMERG International ME Workshop in Vienna, enabling full engagement in the workshop at the Medical University of Vienna. The charity's ongoing efforts to promote and develop ME research capacity are part of almost two decades of commitment to collaborative research. Awardees shared their experiences for our supporters, highlighting the importance of advancing ME research. Feedback from Young EMERG Vienna Workshop 2025 "The Young EMERG workshop in Vienna was exceptionally well organised, with engaging and relevant content throughout. It was inspiring to see young researchers exploring diverse approaches to ME/CFS. The programme was enriched by activities and the chance to connect with fellow researchers. My expectations were high, yet the workshop exceeded them. I am deeply grateful to the UK charity Invest in ME Research for supporting my participation." Aline Zamoro Martinez MSc Nutrition and Health Wageningen University & Research "Participating in the Young EMERG Workshop in Vienna was an absolutely exceptional and deeply inspiring experience for me. From the very beginning, I felt that the workshops were prepared with great attention to every detail, both in terms of academic content and organization. Everything was executed at the highest level, which allowed me to fully focus on learning, exchanging experiences, and personal development. The atmosphere throughout the workshop was incredibly supportive, open, and motivating. I truly felt part of an engaged, ambitious, and kind community of young people who share a passion for learning and continuous self-improvement. The energy was very uplifting and gave me a great deal of motivation to move forward and keep developing. The lecturers made a particularly strong impression on me. Their expertise, experience, openness, and genuine commitment to working with participants were truly inspiring. The way they delivered the content was engaging, accessible, and thought-provoking. I often found myself reflecting deeply on the Invest in ME Research Page 16 of 35

JOURNAL OF IIMER May 2026 topics discussed, as they challenged my perspective and encouraged me to ask important questions about my future development, both professionally and personally. The Young EMERG Workshop Vienna was much more than just a series of workshops for me. It was a true impulse for growth, reflection, and further action. I am extremely grateful for the opportunity to participate in this event, and I can confidently say that it was one of the most valuable educational experiences I have ever had." Hanna Tabisz Nicolaus Copernicus University in Torun Collegium Medicum in Bydgoszcz Poland "I recently received a travel grant from Invest in ME Research to attend the Young EMERG workshop in Vienna, where I presented our upcoming project aimed at better characterising the mechanisms underlying post-exertional malaise (PEM). This project will use non-invasive metabolic imaging techniques to investigate muscle metabolic alterations during PEM. Attending the Young EMERG workshop provided an excellent opportunity to gain a comprehensive overview of current research directions and priorities within the ME/CFS field. As with fatigue symptoms in other chronic conditions, the aetiology of ME/CFS is complex and multifactorial, requiring multidisciplinary approaches to identify underlying mechanisms and inform the development and testing of treatment targets. The workshop showcased a broad range of ongoing research, with presentations spanning health economics, immunology, metabolism, and other relevant disciplines. I found it particularly valuable to learn about current initiatives aimed at strengthening collaboration within the field, including funding opportunities for visiting fellowships designed to support cross-institutional partnerships. Such collaborations will be essential for accelerating progress in ME/CFS research. As a result of this experience, we have identified potential external research collaborators and aim to continue developing and applying metabolic imaging approaches to better characterise the mechanisms contributing to fatigue in ME/CFS. Ultimately, we plan to integrate these novel techniques into future study protocols to enhance mechanistic understanding and to provide objective measures of organ function and metabolism when assessing responses to management strategies and pharmacological interventions." Jordan McGing Oxford Centre for Clinical Magnetic Resonance Research University of Oxford Invest in ME Research Page 17 of 35 JOURNAL OF IIMER May 2026 Mike’s European Marathons Spring 2026 update I’ve just returned from running my 39th marathon for Invest In ME Research in European country 35 in Sarajevo, Bosnia. Now entering my 12th year running for the charity, I’ve managed to raise £53K through my European marathon running project, interviewing people with ME in 30 countries that I’ve visited. Sarajevo Marathon is only in it’s 7th year and I lined up with only around 250 runners in warm temperatures (c20c) to run a single lap of the centre and out towards the West of the city with it’s villages and mountainous backdrop. There was a 5 hour cut-off which I needed to be aware of but I got around the course fairly steadily and well within the limit. There were plenty of parts to the race where I didn’t see anyone else on the course and had to ask the police for directions! Sarajevo itself was a wonderful mix of Ottoman and Orthodox architecture with beautiful mosques and churches, historic bridges and lush green hills all around. Full race report and trip pictures: https://www.mikeseumarathons.eu/sarajevo-bosnia.html Next up for me is Reykjavik Marathon on August 22nd where I’m hoping to meet and liaise with ME Felag, the country’s ME Association to help raise money and awareness. I’ve been to Iceland 10 years ago with my wife and enjoyed doing the ‘Gold Circle’ and exploring Reykjavik. I never thought I’d be back to run a marathon there! I’ve heard positive things about the race and the cool temperatures will be a welcome gift given all the hot races I’ve been through in Southern Europe. From what I understand, the course is relatively flat with often windy conditions and hopefully some stunning scenery to keep my brain occupied. Although Iceland has a small population, my understanding is that there are quite a few people struggling with ME and that the Icelandic ME Association has been doing some excellent work in supporting them. I think they have had runners in the marathon fundraising before and I’m aware that they have some representatives coming to the Invest In ME Conference which I look forward to attending for the first time in 8 years. I’m working on plans for next year, it’s proving tricky as there aren’t many countries left in Europe to go but I do still have Albania, Moldova, Turkey, Kosovo, Vatican, Faeroe Islands, Wales, Scotland and England(!) left to go. After that, I have a few more on my ‘bucket-list’ with a mix of big and small races -one of which includes a race that runs through Switzerland, Austria and Germany around Lake Constance which looks awesome. I may also run a few more local half-marathons to me and see if I can raise the profile of ME in local media which I’ve done before a few times. If you’d like to sponsor me and help fund biomedical research then please visit: https://www.justgiving.com/fundraising/mikeseumarathons Invest in ME Research Page 18 of 35

JOURNAL OF IIMER May 2026 Germany Takes Action: A Decade of Funding for Post-Infectious International collaboration has always been central to this charity's strategy - and European partnership in particular. The formation of EMEA, EMERG, EMECC, and Young EMERG reflects a long-held conviction that progress in ME research would be built across borders before it was built within them. Experience suggested that meaningful change in the UK would depend, in part, on what was demonstrated and achieved elsewhere first. That conviction shaped the programme for IIMEC18. Rather than look to UK ministers or research agencies to open the conference - an avenue pursued many times over the years without result - we looked to where genuine political will for post-infectious disease research had actually materialised. The announcement of a decade of dedicated federal funding for post-infectious disease research in Germany represented exactly the kind of sustained, strategic commitment that patients with ME have long needed to see. So we invited Federal Minister of Research, Technology and Space Dorothee Bär to open IIMEC18. Minister Bär was unable to attend in person, but she kindly contributed the following to our journal. Journal of IiMER Invest in ME Research Page 20 of 35

JOURNAL OF IIMER May 2026 Bundesministerium für Forschung, Technologie und Raumfahrt, Berlin Dorothee Bär MdB Federal Minister of Research, Technology and Space Berlin, arch 2026 Invitation to deliver the opening address at the 18th Invest in ME Research Conference Dear Invest in ME Research, Thank you for invitation to deliver the opening address at the 18th Invest in ME Research Conference on 29 May 2026 in Hinxton Hall, UK. I appreciate your kind words about the leading role of the German National Decade Against PostInfectious Diseases. I can assure you that research and development of effective therapies against post-infectious diseases are of great importance to me and the Federal Ministry of Research, Technology and Space (BMFTR). I know from many conversations with patients that everyday life is difficult or even impossible to manage independently for people suffering from ME. This disease is an enormous bürden for those affected, for their relatives as well as for our entire society. That is why organisations like yours and the commitment to funding biomedical ME research and enabling network events through Conferences and colloquia are important in countering this disease. As you mention, the BMFTR will intensify research in this area over the next ten years as part of the National Decade Against Post-Infectious Diseases. Funds totalling 500 million euros have been earmarked for this purpose and for the duration of the Decade. In accordance with the latest scientific findings, the focus within the National Decade will be on research into biomedical causes of these diseases and, building on this, improved diagnostic and therapeutic procedures. I want to assure all those affected by post-infectious diseases that we are taking the necessary steps into the right direction. We are committed to further creating the ideal research basis for realising treatment options that can provide a eure or significantly alleviate their suffering. With the Decade, we are making significant leaps towards achieving these goals together. Thank you once again for your kind Invitation and the honour of delivering the opening address at IIMEC18. Unfortunately, I am unable to take part due to other commitments. Yours sincerely, Dorothee Bär Invest in ME Research Page 21 of 35 JOURNAL OF IIMER May 2026 The BRMEC Colloquia - Fifteen Years of Building ME The Biomedical Research into ME Colloquium series began in 2011 with what the charity described at the time as a "Corridor Conference" - an informal gathering of clinicians and researchers during the IIMEC6 conference weekend, discussing ways to collaborate and progress knowledge. Fifteen years on, that idea has grown into one of the most distinctive annual events in international ME research. The colloquia are unique symposia designed specifically for biomedical researchers working on ME, or able to bring relevant expertise into the field. Unlike larger open conferences, they are focused, invitationbased gatherings - CPD-accredited, and attended by delegates from more than 20 countries. They bring together scientists, clinicians and early-career researchers in an environment that prioritises exchange and collaboration over presentation. That emphasis on collaboration has had tangible results. The colloquia have been directly instrumental in forming new ME research partnerships across continents, and have spawned lasting international structures including the European ME Research Group (EMERG) and its associated early-career researcher network, Young EMERG. Across fifteen colloquia the themes have shifted as the field has evolved - from early work on aetiology and autoimmunity, through metabolomics and systems biology, to the emergence of long COVID as both a parallel and a lens. BRMEC15 in 2026 addresses mechanisms and treatment strategies across nine sessions spanning systems biology, post-genomics, chronic infection, neuroinflammation, metabolism, immunology, biomarker discovery and therapeutics. The ethos has remained constant throughout: volunteer-run, invitation-based, and focused solely on advancing the science that patients with ME need. The colloquia have been chaired since 2019 by Professor Simon Carding of the Quadram Institute Bioscience, Norwich Research Park. Professor Carding brings exceptional breadth to the role. His research career has spanned postdoctoral work at New York University School of Medicine and Yale University, where he worked on the Invest in ME Research Page 22 of 35

JOURNAL OF IIMER May 2026 molecular genetics of gamma-delta T cells - a field of direct relevance to immune dysfunction in ME - and faculty positions at the University of Pennsylvania, the University of Leeds, and the University of East Anglia. At the Quadram Institute he leads the Gut Microbes and Health research programme, one of the foremost centres for gut biology and mucosal immunology in Europe. He is co-chair of EMERG, and has been a central figure in building the international research infrastructure around ME. https://www.investinme.org/brmec15-news-the-colloquia.shtml This year’s sessions are as follows - Session 1: A Systems Biology Approach to ME Moderated by Tamas Korcsmaros, Imperial College Londo, a systems biologist at Imperial College London whose work focuses on signalling networks, multi-omics data integration and the application of network medicine to complex disease. Systems biology offers ME research something it has long needed - a way of looking at the whole picture. Rather than examining individual genes, proteins or pathways in isolation, it integrates data from across biological systems, combining computational modelling with experimental findings to reveal how the parts interact. For a disease as complex and variable as ME, this kind of joined-up approach may prove essential. Dezső Modos, also of Imperial College London, applies network biology to understand how genetic variants - particularly those in non-coding regions of the genome - drive disease at the cellular level. His iSNP platform maps how these variants affect regulatory networks, building patient-specific models of disease pathogenesis that are directly relevant to the challenge of translating ME genomic data into meaningful biological insights. Marek Ostaszewski of the Luxembourg Centre for Systems Biomedicine brings a different but complementary perspective. As a lead contributor to the COVID-19 Disease Map and a core member of the Disease Maps Project, his work focuses on building structured, reusable computational repositories of molecular interaction data - the kind of infrastructure that allows findings from across the ME research community to be integrated and interrogated systematically. Veronika Kedlian, a postdoctoral fellow in the Saez-Rodriguez group at EMBL-EBI, will present work on a Human Thymus Ageing Cell Atlas that defines a spatially resolved model of thymic involution. The thymus plays a central role in adaptive immune development, and its decline with age has direct implications for immune function. Kedlian will also address current known links between thymic involution, immune ageing and ME - bringing single-cell and spatial transcriptomics approaches to bear on questions that matter directly to this audience. Together, the three presentations reflect a field beginning to harness the full power of computational and systems-level science in the pursuit of ME's mechanisms. Invest in ME Research Page 23 of 35 JOURNAL OF IIMER May 2026 Session 2: A Post-Genomics Approach to ME The sequencing of the human genome was a beginning, not an end. Post-genomics research takes what that sequencing revealed and asks the harder questions - how are genes expressed, how is expression regulated, and how do molecular processes go wrong in disease? For ME, a condition whose biological mechanisms remain incompletely understood, these tools are proving increasingly powerful. The session is moderated by Dr Elisa Oltra, professor of Cell and Molecular Biology at the Universidad Católica de Valencia and a member of the EMERG. Dr Oltra has investigated the molecular basis of ME, identifying irregularities in RNAseL expression and miRNA profile changes in patients - work that places her at the intersection of molecular biology and ME research. Andrew Grimson, Professor of Molecular Biology and Genetics at Cornell University and Associate Director of the Cornell NIH ME Research Center, will present on T cell dysregulation in ME. His laboratory has used single-cell RNA sequencing to examine circulating immune cells in ME patients, finding evidence of T cell exhaustion - a state in which immune cells become progressively less effective, associated with chronic immune stimulation or long-term pathogen exposure. Published in the Proceedings of the National Academy of Sciences, the findings also identified changes in platelet gene expression during post-exertional malaise. The same pattern of T cell exhaustion has been observed in long COVID. Dr Vilma Lammi of the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, coordinates the international Long COVID Host Genetics Initiative. Her work spans the genetics of both long COVID and ME, including a genome-wide association study of long COVID published in Nature Genetics in 2025. At BRMEC15 she will present findings on common genetic variants across long COVID and ME from large-scale international cohorts - evidence that the two conditions may share underlying biological architecture. Dr Elizabeth Worthey, Director of the Center for Computational Genomics and Data Science at the University of Alabama at Birmingham, brings a precision medicine perspective. A pioneer in clinical genomics, she was part of the team that in 2009 performed the first successful use of genomic sequencing to change a patient's treatment. At BRMEC15 she will present on actionable molecular stratification of ME using an N-of1 precision medicine approach - work with direct implications for how patients might one day be diagnosed and treated according to their individual molecular profiles. The three presentations reflect a field moving from description towards mechanism - and from mechanism towards the prospect of targeted intervention. Session 3: Chronic Infection Aetiology The role of chronic or persistent infection in ME has been debated for decades, but the tools to investigate it rigorously are now available. Viral persistence in tissue reservoirs, myeloid reprogramming, intracellular pathogens and the long-term consequences of immune activation following infection are all areas where ME research is now making meaningful progress. The parallels with long COVID - where spike Invest in ME Research Page 24 of 35

JOURNAL OF IIMER May 2026 protein persistence and sustained immune dysregulation have been documented - have added new impetus to this work and new frameworks through which to interpret it. The session is moderated by Dr Friðbjörn Sigurðsson, Akureyri Hospital, Iceland / EMERG and a leading figure in ME clinical services in Iceland. He was instrumental in founding the Akureyri Clinic - a nationally designated specialist service for ME and long COVID patients opened in 2024 - and has long championed awareness of the 1948-49 Akureyri Disease epidemic, one of the earliest and best-documented outbreaks of what would later be recognised as ME. Fernando Real of the Institut Pasteur de Lille will present on viral persistence in tissue reservoirs and myeloid reprogramming. His work examines how macrophages and other myeloid cells can act as long-term hosts for persistent intracellular pathogens, and what this means for understanding chronic infection in ME. Professor Greg Towers of Queen Mary University of London brings a molecular virology perspective. His research on host-virus interactions - including innate immune responses to HIV and SARS-CoV-2 - informs his BRMEC15 presentation on inflammatory responses to viral infection and how they might drive post-viral syndromes. Professor Maureen Hanson of Cornell University has been one of the most productive ME researchers of the past two decades, with work spanning the microbiome, immune cell gene expression and exercise challenge studies. At BRMEC15 she will present on the search for chronic infection in ME. Professor Nancy Klimas of Nova Southeastern University is one of the world's foremost clinician-researchers in ME and long COVID. Her landmark immunological work includes establishing natural killer cell dysfunction as a feature of ME. At BRMEC15 she will present on spike protein antigen persistence and long COVID from a monoclonal antibody perspective - work that speaks directly to the question of what sustains illness following acute infection. Professor Branislav Milovanović of the Institute for Cardiovascular Diseases Dedinje, Belgrade, and a member of EMERG, will present findings on intracellular infection with coxiella burnetii and bartonella in ME patients, and the relationship between these infections and dysautonomia - connecting the chronic infection hypothesis directly to one of ME's most consistent c linical features Invest in ME Research Page 25 of 35 JOURNAL OF IIMER May 2026 Session 4: Nervous System and Neuroinflammation Moderated by Dr Jon Brooks, University of Liverpool, UK Neurological symptoms are among the most disabling features of ME - cognitive impairment, unrefreshing sleep, sensory sensitivity and autonomic dysfunction are reported consistently across patient populations worldwide. Yet the biological mechanisms underlying these symptoms remain poorly understood. Neuroimaging, neuro-PET and postmortem brain research are now beginning to reveal structural and inflammatory changes in the central nervous system in ME and related post-viral conditions, offering the prospect of both biological explanation and, in time, therapeutic targets. The session is moderated by Dr Jon Brooks, Senior Lecturer at the University of Liverpool, whose research uses MRI-based neuroimaging techniques to study changes in the central nervous system in chronic pain and related conditions, including ME. Associate Professor Gwenaëlle Douaud of the Wellcome Centre for Integrative Neuroimaging at the University of Oxford brings one of the most powerful datasets in neuroscience to bear on post-viral illness. As a core member of the UK Biobank imaging team, she has contributed to the analysis of brain scans from 100,000 participants. She led the landmark 2022 Nature study demonstrating that SARS-CoV-2 infection is associated with measurable changes in brain structure - including greater reduction in grey matter thickness in the orbitofrontal cortex and parahippocampal gyrus - findings with direct relevance to understanding the neurological basis of ME and long COVID. Her BRMEC15 presentation title is to be confirmed. Dr Denise Visser of Amsterdam UMC will present Neuro-PET data from postCOVID patients. Her imaging work has demonstrated significant neuroinflammation throughout the brain in patients with long-term post-COVID symptoms - providing some of the first direct in vivo evidence of widespread brain inflammation in living patients following COVID-19 infection. The parallels with ME are clear and the implications significant. Felipe Correa da Silva of the Netherlands Institute for Neuroscience works in postmortem brain research and neuroimmunology. At BRMEC15 he will present on microglial profiling in ME - examining the brain's resident immune cells directly in postmortem tissue from ME patients. This work offers a level of resolution into neuroinflammation in ME that has rarely been achieved before, and may help explain the cognitive and neurological symptoms that define the disease for so many patients. Session 5: Immune System - Primary and Secondary Immune dysfunction is one of the most consistently reported biological features of ME. Abnormalities have been identified across both innate and adaptive immune compartments - from natural killer cell dysfunction and T cell exhaustion to ion channel dysregulation and aberrant cytokine signalling. Whether these represent primary drivers of the disease or secondary consequences of another underlying process remains a central question in the field. This session brings together researchers working at the forefront of ME and post-viral immunology to examine the evidence from multiple angles. Invest in ME Research Page 26 of 35

JOURNAL OF IIMER May 2026 The session is moderated by Associate Professor Eva Untersmayr-Elsenhuber, a specialist in immunology and head of the Gastrointestinal Immunology research group at the Medical University of Vienna. A member of EMERG, her extensive research background in food allergy, gastrointestinal immunology and pathophysiology brings a broad immunological perspective to the session. Professor Leo Joosten of Radboud University Medical Centre in Nijmegen focuses on host defence mechanisms and the chronic inflammation that can follow pathogen exposure. His work on innate immune receptors, the inflammasome and Lyme disease pathogenesis is directly relevant to the question of how an initial infection can set in motion a sustained immune response. At BRMEC15 he will present on innate immunity and post-infectious immune dysregulation, and the insights this offers for ME research. Professor Sonya Marshall-Gradisnik, Director of the National Centre for Neuroimmunology and Emerging Diseases (NCNED) at Griffith University, Australia, is one of the world's leading ME researchers. Her laboratory has pioneered work on natural killer cell dysfunction and calcium ion channel dysregulation in ME, and has demonstrated significant overlaps between ME and long COVID in immune cell dysfunction and symptom presentation. At BRMEC15 she will present on ion channels, calcium signalling and inner cell function - work that sits at the intersection of immunology and cell biology. Marcus Buggert, Associate Professor Marcus Buggert, Center for Infectious Medicine, Karolinska Institutet studies human adaptive immunity to viral infections across blood and tissue compartments. His research on antigen-specific T cells and tissue-based immunology has informed understanding of how immune responses persist and become dysfunctional following infection. At BRMEC15 he will present on tissue-specific immune dysregulation in long COVID - findings with clear implications for ME. Session 6: Metabolism Metabolic dysfunction is increasingly recognised as a central feature of ME. Studies have identified abnormalities in energy metabolism, mitochondrial function, fatty acid oxidation and cellular oxygen utilisation in ME patients. These findings point towards a disease in which the body's ability to generate and use energy at the cellular level is fundamentally compromised - a hypothesis that may explain the post-exertional malaise that is the hallmark symptom of ME, and which distinguishes it from other conditions characterised by fatigue. Moderated by Associate Professor Rikke Katrine Jentoft Olsen, Aarhus University, Denmark / EMERG Invest in ME Research Page 27 of 35 JOURNAL OF IIMER May 2026 Rikke Katrine Jentoft Olsen’group has a longstanding focus on inborn errors of mitochondrial metabolism and fatty acid oxidation disorders. In recent years she has extended this work to examine the role mitochondria may play in ME - bringing deep expertise in mitochondrial biology to a question that is now central to the field. Professor Edmund Kunji of the MRC Mitochondrial Biology Unit, University of Cambridge, studies mitochondrial carrier proteins and their role in transporting metabolites, cofactors and ions across the inner mitochondrial membrane. His work on how these carriers regulate the flow of energy substrates is directly relevant to whether impaired mitochondrial transport underlies the energy metabolism failures observed in ME. At BRMEC15 he will present on the role of transport in mitochondrial energy metabolism. Dr Robert Phair of Integrative Bioinformatics Inc, USA, is a systems biologist with over 35 years of experience in kinetic modelling of complex biological systems. He has developed the Itaconate Shunt Hypothesis for ME pathogenesis - proposing that a metabolic switch involving the itaconate shunt, normally part of the innate immune response, is inappropriately activated in ME, diverting energy metabolism away from normal mitochondrial function. At BRMEC15 he will present model predictions and experimental tests of this hypothesis. Anouk Slaghekke of Vrije Universiteit Amsterdam is a PhD candidate whose research focuses on skeletal muscle adaptations in ME - peripheral muscle oxygenation, muscle structure and function, and post-exertional malaise. Her work on microvascular dysfunction and basal membrane thickening in skeletal muscle connects the metabolic abnormalities of ME directly to structural changes in tissue, offering a mechanistic account of why physical exertion produces such severe and prolonged consequences for ME patients. At BRMEC15 she will present on failures in the peripheral oxygen transport cascade - microvascular and mitochondrial dysregulation in long COVID and ME. Session 7: Keynote Professor Sarah Teichmann of the University of Cambridge is one of the world's leading computational biologists and a pioneer of single-cell genomics. As a founder of the Human Cell Atlas - the landmark international project to map every cell type in the human body - her work has transformed the way biology understands cellular diversity, tissue organisation and immune function. At BRMEC15 she will present on mapping the human body one cell at a time, bringing to the colloquium a perspective that spans the full breadth of modern biological science. Her presence as keynote speaker reflects the ambition of BRMEC15 to situate ME research within the wider frontier of biomedical discovery. Invest in ME Research Page 28 of 35

JOURNAL OF IIMER May 2026 Session 8: Biomarker Discovery and Emerging Research Approaches One of the most pressing needs in ME research is the development of objective, validated biomarkers - measurable biological indicators that can confirm diagnosis, stratify patients and track response to treatment. Progress in this area is now accelerating. But this session goes beyond biomarkers in the conventional sense, encompassing emerging research directions and novel therapeutic hypotheses that may shape the field in the years ahead. The session is moderated by Professor Jonas Bergquist, Full Chair in Analytical Chemistry and Neurochemistry at Uppsala University in Sweden, with a background spanning clinical neuroscience, analytical chemistry and ME research across more than two decades. Dr Jesper Mehlsen, co-chair of EMERG and a specialist in autonomic nervous system dysfunction with over 35 years of clinical and research experience, will present on objective tools for diagnosing autonomic dysfunction in ME - the tilt-test, Valsalva Manoeuvre, Heart Rate Variability and the COMPASS-31 questionnaire. These approaches offer a means of characterising the autonomic abnormalities consistently reported in ME patients and may contribute to validated diagnostic criteria. Professor Ronald W. Davis, Director of the Stanford Genome Technology Center and a world-recognised figure in the development of genomic and biotechnological methodologies, has in recent years dedicated substantial effort to ME research. His team have developed novel nanotechnology-based diagnostic tools, including a nanoelectronics assay that has attracted considerable international attention as a potential objective test for the disease. His presentation addresses oxidative stress in ME/CFS and Long COVID - a domain of growing significance as researchers seek to characterise the metabolic and mitochondrial disturbances that may underlie the illness - and reflects the session's ambition to pursue biomarker discovery through the most advanced technological means available. Dr Alexandre Akoulitchev of Oxford BioDynamics and Professor Dmitry Pshezhetskiy of the University of East Anglia will present on a potentially transformative development: the application of EpiSwitch 3D genomic profiling to ME. Their collaborative work, published in the Journal of Translational Medicine in 2025, identified a unique and reproducible pattern of three-dimensional chromatin architecture in ME patients absent in healthy controls, achieving diagnostic accuracy of 96% in an initial cohort - offering the prospect of the first reliable blood-based diagnostic test for the disease. The Carding Group at the Quadram Institute will present on bacterial extracellular vesicle research and the pathways and mediators of the gut-microbiome-brain axis - exploring how signals from gut microbes transmitted via extracellular vesicles may influence brain function and immune responses in ME. Invest in ME Research Page 29 of 35 JOURNAL OF IIMER May 2026 Dr Wenzhong Xiao of Harvard Medical School will present on a mouse model for reversing post-exertional malaise. If translatable to humans, this work could open a direct path towards therapeutic intervention for one of ME's most debilitating and defining features. Dr Steve Gardner, CEO of PrecisionLife, will address the question of GLP-1 receptor agonists for ME and long COVID - drugs that have transformed treatment of obesity and type 2 diabetes - examining the evidence, the hope and the potential risks of applying them to post-viral conditions. IIMEC18 International ME Conference Day – Colloquium Day 3 The day opens with an address from Dr Hans Kluge, WHO Regional Director for Europe. As members of the European ME Alliance we have been working with our European partners on several campaigns relating to WHO Europe initiatives. This will be the second time that WHO has contributed a message to the events. BRMEC15 Session 9: Therapeutics The Therapeutics session marks a pivotal point in the three-day programme - moving from the science of mechanisms towards the science of intervention. After two days of presentations on the biological underpinnings of ME, this session addresses what can now be done: clinical trial infrastructure, cognitive rehabilitation, mitochondrial intervention, and the use of digital and wearable technology to capture the complexity of ME in research and trials. Moderated by Professor Andrew Wilson, University of East Anglia, UK The final day of BRMEC15 merges with the 18th International ME Conference (IIMEC18), bringing researchers, clinicians and patients together for the first time in the programme. Professor Wilson also presents in his own right, on the development of a platform for clinical trials in ME - infrastructure that is essential if the growing body of mechanistic findings in ME research is to be translated into tested and validated treatments. Dr Vicky Whittemore is a Programme Director in the Division of Neuroscience at the National Institutes of Health, where she has played a central role in coordinating and advancing the NIH's investment in ME research. With a background spanning epilepsy, neurological disorders and translational neuroscience, she has served on key advisory and working groups shaping the direction of ME research at a national and international level, including the NIH P2P CFS Committee and the National Academy of Medicine's ME/CFS case definition working group. Her contribution to this session reflects the importance of sustained institutional commitment to the Invest in ME Research Page 30 of 35

JOURNAL OF IIMER May 2026 field, and the role of collaborative international frameworks in moving ME research forward. Professor Gitendra Uswatte of the University of Alabama at Birmingham will present preliminary findings from cognitive rehabilitation trials in adults with postviral syndromes. Brain fog is one of the most common and disabling symptoms reported by ME patients, yet it has received comparatively little attention as a target for intervention. His work explores whether targeted rehabilitation approaches can produce measurable improvements in cognitive function in this population. Associate Professor Rikke Katrine Jentoft Olsen of Aarhus University, who also moderates the Metabolism session at BRMEC15, will present on a randomised controlled trial examining hypoxia-induced mitochondrial stress-signalling in ME. This represents one of the most direct attempts yet to test and potentially intervene in the metabolic dysfunction that may lie at the heart of ME pathogenesis. Dr Caroline Dalton of Sheffield Hallam University will present on harnessing wearable data in ME research and trials - addressing both the potential of digital tools to capture the complexity of ME in ways that conventional clinical assessments cannot, and their role in supporting more rigorous and sensitive outcome measurement in clinical trials. The remainder of the IIMEC18 conference day will have the following presentations - Eva Untersmayr-Elsenhuber - Associate Professor of Pathophysiology and Allergy Research at the Medical University of Vienna, and a member of EMERG, presents on emerging research for the discovery of ME mechanisms, with a focus on the DISCOVER-ME project. Her background spans immunology, gastrointestinal immunology, and allergy research, and she leads the Department of Pathophysiology and Allergy's gastrointestinal immunology group. As a lead and co-investigator in the DISCOVER-ME consortium, she brings expertise in immune mechanisms to the pan-European effort to identify biological markers and disease subtypes in ME. Douglas D. Fraser - Professor and Clinician Scientist in Paediatric Critical Care at Western University in London, Ontario, presents on a global platform trial of repurposed drugs for long COVID. Director of the Translational Research Centre - a human tissue biobank with over fifteen years of operation - Professor Fraser leads two international multicentred long COVID research programmes examining sub-phenotypes and outcomes, and has extensive experience in profiling post-COVID patients for immune and proteomic changes. Invest in ME Research Page 31 of 35 JOURNAL OF IIMER May 2026 Rowan Gardner, co-founder of PrecisionLife, a UK-based precision medicine company, brings over thirty years of experience applying computational methods to life science and patient data. Her work at PrecisionLife focuses on identifying novel disease mechanisms and therapeutic targets through advanced combinatorial analytics applied to complex disease datasets, including ME. In this session she examines new mechanistic insights into ME from large-scale genomic analysis, and considers what emerging findings may offer for future research directions. Ana Palacio - University of Miami, presents follow-up findings from the Covid-UPP trial, examining outcomes in post-COVID patients and contributing to the growing evidence base on cardiovascular and systemic effects of long COVID and related post-viral conditions. Leo Tamariz - University of Miami, presents a comparison of cardiovascular symptoms across ME, long COVID, and Gulf War Syndrome (GWS) cohorts. This cross-condition analysis contributes to understanding the shared and distinct physiological features of post-viral and post-toxic multi-symptom illnesses, with implications for diagnosis and clinical management. Mari Gamme Sollie and Trine Alm Holterbakken - Røysumtunet, Norway, present on specialised care for seriously and very seriously ill people with ME. Røysumtunet is a Norwegian facility with particular expertise in managing severely affected ME patients, and this presentation addresses one of the most underserved areas in ME clinical practice - the provision of appropriate, safe, and informed care for those who are housebound or bedbound. Friðbjörn Sigurðsson - Akureyri Hospital, Iceland, and EMERG member, presents on clinical approaches to treatment in ME. Drawing on clinical experience from Iceland's national hospital in Akureyri, this presentation addresses the practical management of ME patients and contributes to EMERG's work on developing harmonised European clinical protocols. Per Julin - Karolinska Universitetssjukhuset, Sweden, and EMERG member, presents on the Karolinska Policlinic for Post-infectious Diseases, covering both its clinical work and associated research programme. The Karolinska clinic represents one of Europe's dedicated post-infectious disease centres, and this presentation describes its approach to the assessment and management of ME and related conditions alongside the research it generates. Invest in ME Research Page 32 of 35

Journal of IiMER May 2025 Welcome to International ME Conference Week 2025 Welcome to International ME Conference Week 2025. Another opportunity to reflect on the progress made and the challenges that remain in our objective of improving the lives of people with Myalgic Encephalomyelitis (ME, sometimes referred to as ME/CFS). We approach the twentieth anniversary of Invest in ME Research and continue to emphasise the urgent need for real, lasting change for people with ME. Our work has spanned pragmatic advocacy, raising standards in education and clinical care, and facilitating and funding biomedical research. The vision of a Centre of Excellence for ME - an integrated hub for research, clinical trials, and patient care - has been a core element of our strategy. Over the past fifteen years, this vision has taken root at Norwich Research Park, where we have supported pioneering researchers, funded multiple PhD and postdoctoral positions, and enabled the UK’s only clinical trial for ME. This progress has only been possible through the dedication of our supporters and the collaborative spirit of the leading researchers. Norwich Research Park provides a unique environment, combining university, medical school, hospital, clinical trials unit, genomics institute on a single site, with a nearby ME clinic supporting research. This impressive setting has allowed us to lay the groundwork for sustainable progress. Our collaborations with researchers such as Dr Ian Gibson and Professor Simon Carding have resulted in a unique momentum and innovative projects that address the biomedical basis of ME, while support from The Hendrie Foundation, LunaNova and our wider community of supporters. Recognising that meaningful progress depends on collaboration, we established European networks to enhance research capabilities and promote greater cooperation among scientists across Europe, allowing harmonisation of methodologies and facilitating joint projects. This also included initiating a European network to strengthen the link between clinical experience and research priorities, ensuring that patient needs are central to our efforts. With the launch of Young EMERG (YEMERG), we are facilitating development of the next generation of ME researchers, providing mentorship and resources to ensure this momentum continues. Invest in ME Research Page 1 of 43 Journal of IiMER May 2025 Over nearly two decades, our charity has worked tirelessly to advance ME research and facilitate meaningful collaborations. Whilst being thankful for the foundations our supporters have enabled and established - evident in the growth of research networks at Norwich and across Europe - we must also acknowledge the persistent challenges that have tempered progress. Our recent experience with the DHSC working group, where our proposals to accelerate research and collaboration were regrettably ignored, serves as a reminder of the obstacles that arise when the same incumbent influences consistently dictate the pace of change, steering outcomes towards predetermined conclusions. As highlighted in our article Déjà vu?, published even before we were invited to be involved, such patterns risk perpetuating a status quo in which opportunities for genuine progress are repeatedly missed. Despite these setbacks, our resolve remains undiminished. The robust research infrastructure and partnerships built through the dedication of our supporters and the wider ME community now offer an invaluable platform for meaningful advancement. It is vital that this momentum is not lost - nor that existing efforts are overlooked, unnecessarily duplicated, and especially not reinvented at the expense of real progress. Instead, we should support the foundations already established, ensuring that the groundwork laid by our collective efforts can be fully realised for the benefit of people with ME. To new researchers joining our field: you are entering a community that values innovation, collaboration, and the resolve to challenge inertia. In these challenging times for researchers, your commitment is welcome. We invite you to build on these foundations and work with us to improve this critical situation for people with ME and their families. Our annual international conferences and colloquia have become important platforms for knowledge exchange, setting research priorities, and fostering new collaborations. This year’s BRMEC14 colloquium and IIMEC17 conference, focused on translating research into diagnostics and treatments, demonstrate our intent to bridge the gap between scientific discovery and meaningful patient outcomes. Systems biology, which integrates multiple layers of biological data, remains a key focus for discovery of the complex nature of ME. As we come together for this week of learning, discussion, and collaboration, we invite all delegates to engage fully, share ideas, and forge new partnerships. The collective expertise and dedication within this community are vital to our shared goal: a future where people with ME receive the care, understanding, and hope they deserve, and where a sustained strategy of biomedical research ultimately leads to effective treatments. Thank you for your continued support and commitment, Kathleen McCall Chair, Invest in ME Research UK charity Nr. 1153730 PO Box 561 Eastleigh SO50 0GQ Hampshire, UK Email: info@investinme.org Web: www.investinme.org 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 Page 2 of 43

Journal of IiMER May 2025 Sponsoring IIMEC17 Invest in ME Research gratefully acknowledges a generous donation from our European ME Alliance partners, the Irish ME Trust (IMET), to support the IIMEC17 International ME Conference. This vital contribution continues a longstanding partnership that has significantly advanced biomedical research into Myalgic Encephalomyelitis (ME) since the conference series began in 2006. The charity dedicates substantial resources to organising the conference week, which includes not only arranging the main events but also supporting the European ME Research Group (EMERG), the Young EMERG early-career researcher network, and an increasing number of researchers and clinicians. This support fosters collaboration, brings new expertise into the field, and helps overcome barriers to research progress at a time when funding is increasingly threatened by political and societal challenges. Thanks to supporters like IMET, Invest in ME Research has been able to sustain and augment these efforts each year. IMET’s commitment is especially notable for its longevity and selflessness; for over twenty years, they have supported Invest in ME Research without seeking promotion or special recognition. As a founding member of the European ME Alliance, IMET has played a key role in building a pan-European research community. Their past donations have helped fund important projects such as research at the UK/European Centre of Excellence for ME at Norwich Research Park. This year, IMET’s sponsorship frees Invest in ME Research resources to focus on building research capacity by subsidising attendance for early-career researchers at the IIMEC17 conference, the 14th Biomedical Research into ME Colloquium (BRMEC14), and the Young EMERG Workshop. These events nurture the next generation of ME researchers by reducing financial barriers, encouraging participation, and fostering connections with established experts. Supporting emerging researchers is crucial for sustaining momentum and encouraging innovative, cross-disciplinary approaches. IMET’s support also reflects a broader tradition of generosity from Irish organisations and individuals towards the charity’s efforts in facilitating research into ME, funding fellowships, clinical trials, and international CPD-accredited scientific meetings. These efforts have created opportunities for healthcare professionals, patients, and carers to engage with the latest developments in ME research. The conference week continues to attract and expand a family of international researchers from Europe, North America, and beyond, including representatives from the NIH and CDC, providing a unique platform for advancing biomedical research into ME through open, collaborative dialogue. Invest in ME Research extends its sincere thanks to the Irish ME Trust for their enduring generosity and partnership. With such partners, Invest in ME Research continues to strive to sustain a global community dedicated to collaboration, innovation, and the development of the next generation of scientific leaders in ME research. Invest in ME Research Page 3 of 43 Journal of IiMER May 2025 Young EMERG The European ME Research Group early career researcher network, formed in 2023, brings together the new wave of researchers to form a European support base that can facilitate collaboration with early career investigators in other continents. The group is linked to the European ME Research Group (EMERG) The Young EMERG 2025 Symposium for Promoting the Advancement of Research Knowledge in ME (SPARK ME) is another a unique gathering tailored for young and early career researchers, and medical students, passionate about advancing research in ME and post-viral illnesses. Organised by Young EMERG and Invest in ME Research, YE SPARK ME aims to facilitate collaboration, knowledge exchange, and networking among early career researchers in the field of ME. At SPARK ME, early career researchers have the opportunity to showcase their work through oral and poster presentations. The event offers a safe space for early career researchers to discuss challenges and gain valuable insights into pursuing ME research. Through engaging talks, participants will be equipped with knowledge of postdoctoral research funding opportunities, career development and ME/CFS study design and much more! For this year’s event the different nationalities and career stages of those attending the workshop consist of 25% of attendees being UK-based, 45% are based in other European countries, and around 20% are US-based. Then there are a few people from other countries, such as Australia and South Africa. Around half of them are PhD students, the rest are post-docs, other academic researchers, undergraduate students, and some other various job descriptions. The attendees represent a wide range of research fields, primarily within the biological sciences, including electrophysiology, immunology, neuroscience, genetics, metabolomics, and metagenomics. Additionally, participants from the medical sciences, such as medicine, cardiology, and public health, and from computational and data sciences, including biomarker mining, bioinformatics, and statistics, contributed to the vibrant interdisciplinary atmosphere. The event even attracts PIs – although not always with the approval of the younger researchers! “The most helpful aspect of the conference was] … giving perspectives from other fields and learning how they connect to my own” Young EMERG 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 Invest in ME Research Page 4 of 43

Journal of IiMER May 2025 Young EMERG Joins WHO Youth 4 Health In 2023, the European ME Alliance (EMEA) achieved Non-State Actor accreditation from WHO’s Regional Office for Europe, enabling active participation in WHO meetings and ensuring ME representation in WHO initiatives. In 2024, as part of the EMERG/EMECC/EMEA/YE strategy, we facilitated the connection of Young EMERG to the WHO Youth4Health network, strengthening ties between ME advocacy and European health initiatives. Johanna Rohrhofer from the Medical University of Vienna has been the representative for YE and passes that role to another in YE this year. At last year’s WHO Regional Committee for Europe, key groups including the European ME Research Group (EMERG), and Young EMERG (supported by WHO’s Youth4Health) convened in Copenhagen to highlight ME as a major health challenge and promote youth engagement in European health policy. Their shared priorities include:  Official recognition of ME/CFS as a somatic illness by WHO  Implementation of WHO ICD codes for ME/CFS in national health systems  Ensuring timely physical, financial, medical, and social support for sufferers  Incorporating the latest scientific evidence into medical curricula  Developing disease registries using current diagnostic criteria  Securing funding for biomedical research  Rapidly advancing Centres of Excellence for MES During the NSA event, Young EMERG represented youth perspectives in a private meeting with Dr Hans Kluge, WHO Regional Director for Europe. As our first Youth4Health focal point, Young EMERG connects early career researchers, fostering long-term commitment to ME research, care, and policy improvements. Through Youth4Health, WHO offers young people a platform to influence health policy, amplifying ME issues within WHO discussions and promoting understanding among youth and healthcare stakeholders. The partnership equips young researchers with resources to build collaborative, interdisciplinary networks and advocate for funding during critical career stages. Invest in ME Research Page 5 of 43 Journal of IiMER May 2025 Summer Bursaries: Inspiring a Future for ME Research Invest in ME Research, in collaboration with the Quadram Institute at Norwich Research Park, announced the Summer Student Bursaries for 2025. These bursaries are designed to support undergraduate students in gaining practical experience in biomedical research, with a focus on Myalgic Encephalomyelitis (ME). This initiative aligns with the charity's objective of raising education and fostering the next generation of doctors and researchers. The discovery of new treatments relies heavily on research into the causes of the disease. The Summer Student Bursaries provide a unique opportunity for students to contribute to this vital research while developing their skills and knowledge in biomedical science. Simultaneously, it raises awareness of ME and influences the next generation of the medical community, which in turn influences peers. This is not the first time Invest in ME Research has funded summer students, having done so in recent years. Three eight-week bursaries are being offered, with involvement in various research projects at the Quadram Institute. These projects include investigating the virome in mucosal cavities, exploring fungal and yeast diversity, identifying microbes driving inflammation, analysing the prevalence of fungal infections, and studying gastrointestinal viruses in ME patients. Each project offers hands-on experience with advanced molecular and microbiological techniques, providing a solid foundation for future careers in biomedical research. There have been over 50 applications for these Invest in ME Research Summer Student bursaries. Quadram Institute had interviewed candidates and offered three applicants these awards, and they have all been accepted. The successful applicants will begin in July. Thanks to our supporters for making this possible. Invest in ME Research Page 6 of 43 1PhDs and Students Funded by Invest in ME Research at our IIMEC10 conference

Journal of IiMER May 2025 Invest in ME Research Fellowships Invest in ME Research, in partnership with the Quadram Institute, has established two key fellowships based at Norwich Research Park: the Ian Gibson Fellowship and the LunaNova Fellowship. These fellowships are designed to advance biomedical research into myalgic encephalomyelitis (ME), focusing on understanding disease mechanisms and developing new treatments. Both fellowships address the critical need for dedicated ME research funding and expertise in the UK. They strengthen the research base at the centre, and support ongoing clinical trials and PhD studentships. Ian Gibson Fellowship Launched in 2022 and named in honour of Dr Ian Gibson, this is the first postdoctoral fellowship in the UK dedicated to ME research. The fellowship supports fundamental biomedical studies, particularly in gut health, microbiology, and immunology. It is part of the broader strategy to develop further a UK Centre of Excellence for ME at Norwich Research Park, ensuring continuity and growth of ME research in a collaborative, multidisciplinary environment. LunaNova Fellowship Introduced in 2023 and funded by the technology company LunaNova, this two-year fellowship further expands ME research capacity at the Quadram Institute. The LunaNova Fellowship focuses on the gut-immune-brain axis and the search for biomarkers, with strong links to international partners, including the European ME Research Group. This collaborative approach brings together expertise from across Europe and supports the development of a robust research ecosystem for ME. Our LunaNova fellowship – Krishani Perera Dr Krishani Perera, PhD, was awarded the Invest in ME Research Luna Nova Fellowship and joined Professor Simon Carding’s laboratory at the Quadram Institute of Bioscience (QIB) in Norwich in July 2024. As a recent entrant to the field of ME research, Krishani is highly motivated to contribute to ongoing investigations into the causes and treatment options for ME/CFS at QIB. Her two-year fellowship will focus on understanding the link between the reactivation of human endogenous retroviruses (HERVs)-genes embedded within our genome, usually kept inactive-and the accelerated ageing of immune cells in ME/CFS patients. This work is based on clues from previous studies which have shown either dysfunctional immune cells, signs of premature ageing, or the reactivation of different HERV families in people with ME/CFS. Krishani’s project aims to demonstrate a causal link between these findings, exploring whether the reactivation of HERVs plays a key role in cellular and immunosenescence, which could help explain the origins of Page 7 of 43 Invest in ME Research Journal of IiMER May 2025 ME/CFS. Her research will also contribute to the RESTORE-ME clinical trial, a phase IIb, placebocontrolled study investigating microbiota replacement therapy in ME/CFS patients at the Quadram Institute. Krishani brings a strong background in virology and molecular biology, having completed her PhD in Pathobiology and MSc in Veterinary Biomedicine at Kansas State University, USA. Her research there focused on discovering and characterising antiviral compounds against animal and human coronaviruses, including SARS-CoV-2, and studying how viruses develop resistance to these treatments. She also worked on animal caliciviruses and explored host susceptibility to SARS-CoV-2 during the COVID-19 pandemic. Following this, Krishani undertook postdoctoral research at Irset in Rennes, France, where she investigated immune responses and the persistence of viruses such as Zika, Chikungunya, and Mumps in immune-privileged sites in the human body. At the Quadram Institute, Krishani is examining ME/CFS through a microbial lens, focusing on the detection of microbes-especially viruses-that may be involved in the condition. She explains, “My research focuses on detecting microbes, particularly viruses, that may be involved in ME/CFS.” ME/CFS is a serious and often disabling condition, affecting an estimated 17 to 24 million people worldwide, including around 250,000 in the UK. Despite its prevalence, ME/CFS remains underrecognised and is frequently misunderstood and misdiagnosed. Those affected experience a wide range of symptoms, including extreme exhaustion following minimal mental or physical activity (postexertional malaise), immune dysfunction, and digestive issues. These symptoms can make daily life overwhelming, and many people with ME rely on carers for basic activities such as eating and personal hygiene. As Krishani notes, “Many individuals with ME/CFS face severe mobility issues. This means we must prioritise patient accessibility and comfort when collecting samples, ensuring our studies are as inclusive and accommodating as possible.” Currently, there is no cure for ME/CFS and the exact cause remains unknown. Krishani explains, “We believe it’s due to a combination of factors, including viral or bacterial infections, immune system dysfunction, and persistent immune activation.” In Professor Carding’s group, Krishani and her colleagues are striving to bring scientific clarity to ME/CFS and to help those affected by this debilitating condition. While no single virus has been definitively linked to ME/CFS, several are suspected to play a role, with many patients reporting viral infections such as SARS-CoV-2 prior to the onset of symptoms. Some viruses can persist in the body long after the initial infection and may contribute to ongoing immune dysfunction, but research to date has not provided a clear picture and conclusions remain elusive. Krishani is investigating the links between microbes present in mucus and blood and the development of ME/CFS. At the Quadram Institute, a study funded by Invest in ME Research-the COMPASS ME Study-will analyse the mucosal microbial communities, including viruses, bacteria, and fungi, in individuals with and without ME/CFS. She is also examining the communities of viruses in the bloodstream of people with ME/CFS to determine whether they play a role in immune dysregulation. Part of her research involves studying microbial Invest in ME Research Page 8 of 43

Journal of IiMER May 2025 extracellular vesicles-tiny membrane-bound packages that may carry microbial components and could serve as diagnostic or therapeutic marker targets for ME/CFS. Her path to researching the role of viruses in ME/CFS is grounded in her extensive experience in molecular virology. She says, “My expertise spans from identifying antiviral compounds to understanding how viruses develop resistance.” Her work has deepened her interest in how certain viruses evade immune responses and contribute to long-term health issues. Looking ahead, Krishani hopes to develop future diagnostics for ME/CFS. “Longer term, I want to understand ME/CFS pathology and disease progression. By identifying potential causes and underlying mechanisms, I hope to contribute to the development of better diagnostic tools for early and accurate detection. Ultimately, my goal is to explore effective and targeted treatments to improve patient outcomes and quality of life.” She stresses the complexity of ME/CFS: “Because there is no one known cause for ME/CFS and it’s a complex condition with interconnected biological mechanisms, we need to be cautious when interpreting data on potential links between symptoms, immune dysfunction and microbes. A simplistic approach could overlook crucial factors, so a comprehensive, interdisciplinary perspective is essential when studying ME/CFS.” Krishani concludes, “At the end of the day, it’s not just about scientific rigour but about raising awareness-not only to improve research and treatment options but also to foster empathy and respect for those living with this invisible illness. By understanding ME/CFS, we can help create a more supportive and inclusive world for those affected.” She expresses her gratitude: “I am very grateful to the Invest in ME Research charity and the LunaNova fellowship for their support with funding for the research I am conducting.” Further information: https://tinyurl.com/Quadram-Krishani Light ME Up: Red Light Therapy Study for ME at Quadram Institute The Quadram Institute, in partnership with the University of East Anglia (UEA) and with support from Invest in ME Research, is conducting a feasibility study called Light ME Up to explore the potential of red light therapy for ME. Launched in 2024, this study investigates whether photobiomodulation can help relieve symptoms of ME. By targeting mitochondrial dysfunction, thought to contribute to ME’s debilitating fatigue, the study aims to open new avenues for treatment. Light ME Up was set up initially to involve ten participants with ME, recruited through the charity’s network. This has now been expanded. The lamp is designed to stimulate mitochondrial function and Invest in ME Research Page 9 of 43 Journal of IiMER May 2025 potentially boost cellular energy. Participants’ symptoms are tracked for two weeks before and after the intervention using the FUNCAP27 questionnaire, online cognitive tests, activity monitors, and sleep diaries. The study, which received ethical approval from UEA, lasts seven weeks per participant, covering baseline, intervention, follow-up, and feedback. Led by Dr Katharine Seton, IiMER Ian Gibson Fellowship holder, the study hypothesises that PBM may improve physical and cognitive function by enhancing mitochondrial ATP production. The team is also piloting Mantal, an online research management platform, to facilitate participation for those who are house- or bed-bound-ensuring the study is accessible and patient-inclusive. The Light ME Up study is a modest yet significant step in ME research, reflecting IiMER and Quadram’s commitment to exploring novel interventions. By testing PBM’s feasibility and refining remote research methods, the study lays groundwork for scalable trials and enhanced patient engagement. From Broken Wings to Clearer Skies: Finding New Paths for Connection Invest in ME Research has been active on Twitter (now X) since the early days of the platform's existence. Twitter has long served as a valuable tool for raising awareness about the charity’s work, including the research being funded and facilitated at the Norwich Research Park centre. Yet it will not have escaped many people's notice that times have changed. The last thing people with ME, or their families and carers, need is added stress or an environment that many now consider toxic and unproductive. Despite this, a platform is still necessary for learning, sharing, and discussing ME-related issues and progress. Invest in ME Research has been active on Bluesky for some time, and we are gradually sharing more of our news on this platform. Our website will be updated in the next revision to include this new platform. If you are on Bluesky, you can find us at: https://bsky.app/profile/investinmeresearch.bsky.social Invest in ME Research 2026 International ME Conference Week Continuing our commitment to international collaboration, Invest in ME Research has already set dates for International ME Conference Week 2026 – 25–29 May 2026. This will also be the twentieth anniversary of the charity being formed - and twenty years since our very first conference. Invest in ME Research Page 10 of 43

Journal of IiMER May 2025 BRMEC14 – Integrating Systems Biology in ME Research The 14th Biomedical Research into ME Colloquium, themed “Investigating the Mechanisms of Myalgic Encephalomyelitis: From Pathogenesis and Aetiology to Treatment Innovation,” places systems biology at the heart of efforts to address the complexities of ME and related conditions such as Long Covid. ME, classified as a neurological disorder (ICD-11: 8.E49), presents with diverse symptoms affecting immune, neurological, endocrine, and metabolic systems. Despite decades of research, its mechanisms remain unclear, with hypotheses including viral triggers, immune dysregulation, and mitochondrial dysfunction. The disease’s complexity and patient heterogeneity have hindered progress in identifying causal pathways and targeted treatments. Systems biology offers a holistic framework by integrating genomics, proteomics, metabolomics, and environmental data to model complex biological networks. This approach reveals emergent properties and dynamic processes often missed by traditional methods, making it well suited to ME’s multisystem nature. Key features include multi-omics integration, computational modelling, and network analysis, which together help identify crucial biological interactions and therapeutic targets. A core strength of systems biology is its ability to bridge laboratory discoveries with clinical observations. By integrating patient data with experimental findings, researchers can stratify patients into meaningful subgroups, aiding biomarker discovery and personalised medicine, as well as informing clinical trial design. BRMEC14 brings together experts such as Tamas Korcsmaros, Dezso Modos, Marton Olbei (Imperial College London), Anna Niarakis (Toulouse University), and Aurelien Dugourd (EMBL-EBI), who are at the forefront of systems biology and computational medicine. Their collective expertise accelerates the translation of complex data into actionable insights: Disease Mapping: Dr Anna Niarakis’s work on disease maps for rheumatoid arthritis and COVID-19 demonstrates how these tools can be adapted for ME, integrating multi-omics data to visualise mechanisms and identify targets. Multi-Omics Integration: The Saez-Rodriguez group, presented by Aurelien Dugourd, illustrates how combining diverse datasets can illuminate chronic disease mechanisms, enabling drug repurposing and novel treatments. Network Medicine: Tamas Korcsmaros’s expertise in network analysis helps elucidate interconnected pathways in ME, providing a foundation for targeted interventions. Invest in ME Research Page 11 of 43 Journal of IiMER May 2025 Cell-Cell Communication: Marton Olbei’s research maps changes in cell communication during inflammation and infection, offering deeper insights into disease mechanisms. Computational Modelling: Dezso Modos applies advanced models to decipher complex biological networks and signalling pathways, enhancing understanding of disease dynamics and supporting novel therapeutic target identification. Recent studies show that ME/CFS, Gulf War Syndrome, and Fibromyalgia share metabolic disruptions, especially in lipid metabolism and energy production, alongside increased oxidative stress driving cellular damage and inflammation. Identifying reliable biomarkers is essential for earlier diagnosis and targeted therapies, with comprehensive metabolomic and proteomic analyses playing a vital role. Invest in ME Research’s focus on systems biology at BRMEC14 aims to help solve this continuing and devastating medical puzzle. By integrating computational, experimental, and clinical perspectives, systems biology stands to transform understanding of ME-from pathogenesis to treatment innovation. This holistic approach is crucial for addressing the variability and elusive nature of the disease. Long Covid and ME/CFS: Overlapping symptoms, shared research, and implications for diagnosis and treatment Long Covid and ME/CFS share striking similarities, necessitating research into their overlapping symptoms, shared biological mechanisms, and implications for diagnosis and treatment-hence their inclusion in the BRMEC14 colloquium. Both conditions, often triggered by viral infections, present with post-exertional malaise (PEM), profound fatigue, cognitive dysfunction, and autonomic issues, complicating differential diagnosis. Recent studies suggest common pathophysiological pathways, including immune dysregulation, mitochondrial dysfunction, and neuroinflammation, driving collaborative research. A 2023 study in Nature Reviews Microbiology noted that up to 50% of Long Covid patients meet ME/CFS diagnostic criteria, with PEM as a hallmark. Shared biomarkers-such as elevated cytokines, reduced natural killer cell function, and altered metabolomic profiles-point to common immune and metabolic deficits. For example, a 2024 NIH study identified T-cell exhaustion in both conditions, while metabolomic analyses reveal hypometabolism, suggesting potential diagnostic markers. These findings underscore the need for precise diagnostic tools to distinguish or co-diagnose the conditions, as misdiagnosis risks inappropriate treatment. Research synergies are accelerating progress. Long Covid’s global attention has boosted funding for ME/CFS. Trials targeting mitochondrial function, such as photobiomodulation (Quadram Institute, 2024), and immunomodulators like rapamycin (Mayo Clinic, 2025) show promise for both. BRMEC14 brings together researchers, clinicians, and patient advocates to discuss these advances. The focus on immunology, metabolomics, and patient-involved research provides a platform for sharing data, refining hypotheses, and planning multicentre studies, strengthening the ME/CFS research ecosystem. The implications are significant. Improved diagnostics could emerge from validated biomarkers, while shared treatment strategies may alleviate symptoms like PEM and fatigue. However, challenges remain, including heterogeneous patient cohorts and limited funding. BRMEC14 aims to foster collaboration and support efforts to translate research into better care for those with ME/CFS and Long Covid. Invest in ME Research Page 12 of 43

International ME Conference Week Speakers A hallmark of the BRMEC colloquia, since their inception in 2011, has increasingly been to take an approach of bringing together experts from various fields and countries, and introducing fresh perspectives to ME research. This aids in stimulating new ideas to accelerate progress and new knowledge and awareness to be raised amongst researchers. By consistently introducing varied expertise to the field, these events have become a catalyst for innovative thinking in ME research, with the ultimate goal of improving understanding and treatment of this debilitating condition. Colloquium and Conference Chair Simon Carding (Quadram Institute, UK) Research Leader, Quadram Institute Bioscience, Norwich Research Park, UK Simon Carding is Professor of Mucosal Immunology at Norwich Medical School, University of East Anglia, and Research Leader at the Quadram Institute Bioscience, Norwich Research Park. He is internationally recognised for his expertise in mucosal immunology and the gut microbiome, focusing on how gut microbes-including bacteria and viruses-interact with the immune system to influene health and disease. He leads projects investigating the role of the intestinal microbiome and virome in ME, aiming to identify microbial and viral signatures linked to disease onset or progression. His team is conducting comprehensive analyses of the gut virome in ME, including patients in phase 2 clinical trials, to clarify the impact of microbial dysbiosis on the condition and the gut–microbiome–brain axis, with relevance to mental health and neurodegenerative diseases. Professor Carding has been a consistent contributor to Invest in ME Research conferences since 2011, delivering expert talks on gut biology, immunology, and ME. He is a member of the Biomarkers and Immune Working Groups of the ME/CFS Common Data Element Project, reflecting his active role in shaping ME biomedical research. His leadership at the Quadram Institute and collaborations with other institutions highlight his commitment to multidisciplinary research bridging immunology, microbiology, and clinical science to improve understanding and treatment of ME. Invest in ME Research Page 13 of 43 Journal of IiMER May 2025 BRMEC14 Session: Systems Biology Approaches to Study Infections in Complex Diseases Session Chair: Tamas Korcsmaros (Imperial College London) Tamas Korcsmaros is a distinguished researcher and lecturer at Imperial College London, specialising in systems biology and network medicine. His work focuses on understanding the complex interactions within biological systems to uncover the mechanisms underlying diseases. With a strong background in bioinformatics and computational biology, he has made significant contributions to the field, particularly in network analysis and multi-omics data integration. Dr Korcsmaros is known for his innovative approaches to deciphering the intricate web of molecular interactions that influence health and disease. His research aims to bridge the gap between basic science and clinical applications, seeking to identify new therapeutic targets and strategies for treating complex conditions. At BRMEC14, Dr Korcsmaros will moderate the session on systems biology, bringing his expertise and insights to facilitate discussions on the latest advancements and future directions in the field. This session underscores the importance of integrative and collaborative research efforts in advancing our understanding of ME. Aurelien Dugourd (Saez-Rodriguez Group, EMBL-EBI, UK) BRMEC14: Application of Systems Biology to Understand Complex Chronic Diseases Aurelien Dugourd is a Staff Scientist in the Saez-Rodriguez Group at the European Bioinformatics Institute (EMBL-EBI), UK, specialising in computational biology and multiomics data integration. His work focuses on developing methods to extract mechanistic insights from genomics, proteomics, and metabolomics data, with the goal of understanding disease processes and supporting therapeutic innovation. Dr Dugourd’s research is particularly relevant to complex chronic diseases such as ME/CFS, where intricate molecular interactions contribute to disease heterogeneity. The Saez-Rodriguez Group, led by Julio Saez-Rodriguez, is renowned for its expertise in computational biology and systems medicine. The group's research integrates computational modelling with experimental data to unravel the molecular mechanisms underlying complex diseases. Their work aims to translate intricate biological data into actionable insights, driving the development of new therapeutic strategies. At BRMEC14, Aurelien will share his insights and the group's latest advancements in systems biology. His presentation will highlight how integrating multi-omics data can provide a comprehensive understanding of disease pathogenesis, particularly in ME. His participation underscores the importance of interdisciplinary research and collaborative efforts in advancing our knowledge of this complex condition. Invest in ME Research Page 14 of 43

Journal of IiMER May 2025 Anna Niarakis (Université de Toulouse III-Paul Sabatier - CNRS, France) BRMEC14: Disease Map Concept and its Application for Complex Conditions Dr. Anna Niarakis is a Full Professor of Computational Systems Biology at the University of Toulouse III-Paul Sabatier, affiliated with the Centre de Biologie Intégrative (CBI) and the Laboratory of Molecular and Cellular Dynamics. A prominent researcher with a multidisciplinary background in biochemistry, biology, pharmaceutical technology, and computational systems biology, Dr. Niarakis brings valuable expertise in systems biology and bioinformatics to the BRMEC14 colloquium. Internationally recognized for her leadership in disease mapping, Dr. Niarakis integrates diverse biological and multi-omics data to create detailed maps of molecular pathways and cell communication, advancing our understanding of complex diseases such as rheumatoid arthritis and COVID-19. Her experience in developing and applying disease maps demonstrates her ability to adapt these approaches to a range of conditions. At BRMEC14, Dr. Niarakis will showcase how these comprehensive disease maps can significantly advance ME research by providing an integrated representation of its complex mechanisms. Her work supports the identification of key pathways, the discovery of potential therapeutic targets, and the improvement of biomarker discovery, disease subtype characterization, and predictive modeling. Her contributions to collaborative projects like the COVID-19 Disease Map may highlight the potential for similar international efforts in ME research. Dr. Niarakis’ expertise in integrating complex biological data provides valuable insights into disease progression and heterogeneity, supporting a deeper understanding of ME. Her participation in the colloquium underscores the importance of integrative, data-driven approaches in understanding the complexities of ME, paving the way for improved diagnostics and targeted therapies. Marton Olbei (Imperial College London, UK) BRMEC!4: Mapping Cell-Cell Communication and its Changes Upon Inflammation and Infection Dr Marton Olbei, a research associate in the Tamas Korcsmaros Lab at Imperial College London, is a specialist in computational systems biology and network medicine. His work focuses on developing computational tools to map how cellular communication networks are altered by infection or inflammation – an approach directly relevant to understanding immune dysregulation in ME/CFS. At BRMEC14, Dr Olbei will present on "Mapping Cell-Cell Communication and Its Changes Upon Inflammation and Infection", demonstrating how advanced network analysis and multi-omics data integration can reveal how disease states disrupt cellular interactions. This systems biology approach helps identify key molecular pathways, potential biomarkers, and therapeutic targets by deciphering the complex immune and cellular networks involved in ME/CFS. Dr Olbei’s expertise, combined with the Korcsmaros Lab’s pioneering work in predictive computational modelling, supports the development of personalised medicine and deeper mechanistic insight into ME/CFS pathophysiology. His participation at BRMEC14 highlights the importance of collaborative, integrative research for tackling the complexities of ME. Invest in ME Research Page 15 of 43 Journal of IiMER May 2025 BRMEC14 Session: Genomics Simon Carding (Session Chair) Professor Carding will guide the genomics session, focusing on the role of genetic research in uncovering risk factors and mechanisms in ME/CFS. Chris Ponting (University of Edinburgh, UK) Blood and Genetic Biomarkers of ME/CFS Professor Chris Ponting is Chair of Medical Bioinformatics at the University of Edinburgh and Section Head at the MRC Human Genetics Unit. A Fellow of the Academy of Medical Sciences, he is internationally recognised for his work in genomics, protein science, and evolutionary biology. Professor Ponting leads the DecodeME genetic study of ME/CFS and has made significant contributions to understanding how genetic variation influences disease. He is actively involved in ME/CFS research initiatives, including the DecodeME study, which aims to identify genetic factors associated with ME/CFS. His work also extends to analysing blood biomarker data to understand differences between people with ME and healthy controls. Professor Ponting's presentation is expected to provide valuable insights into the genetic aspects of ME/CFS, potentially shedding light on the disease's pathogenesis and opening avenues for future treatment strategies. Marte Viken (University of Oslo, Norway) An Association Study of NK Cell Receptor Genes in ME Dr Marte Kathrine Viken is a senior researcher and project group leader at Oslo University Hospital and the University of Oslo. Her research focuses on immunogenetics, particularly the genetic factors influencing immune-mediated diseases, including ME/CFS and narcolepsy. Dr Viken leads studies investigating how genetic variation in immune cell receptors, such as natural killer (NK) cell receptors and HLA genes, may contribute to disease susceptibility and immune dysfunction. Dr Viken will present research examining associations between genetic variants in natural killer (NK) cell receptor genes and ME/CFS. Her work explores how differences in these immune cell receptors may influence susceptibility to ME/CFS and contribute to immune dysregulation observed in patients. The presentation will summarise findings from immunogenetic studies in Norwegian ME/CFS cohorts, discuss the relevance of NK cell function and HLA associations in disease mechanisms, and highlight the implications for understanding the role of immune genetics in ME/CFS pathogenesis. Invest in ME Research Page 16 of 43

Journal of IiMER May 2025 BRMEC14 Session: Molecular Biology Elisa Oltra (Universidad Catolica de Valencia San Vicente Mártir, Spain) Dr Oltra will introduce talks on molecular mechanisms, biomarkers, and therapeutic strategies for ME/CFS. Alain Moreau (Université de Montréal / CHU Sainte-Justine, Canada) BRMEC14: From Discovery to Hope: Novel Insights into Biomarkers and Treatments for Myalgic Encephalomyelitis Professor Alain Moreau is a Full Professor at the Université de Montréal, with appointments in the Faculty of Dentistry and the Department of Biochemistry and Molecular Medicine. He leads the Molecular Genetics Laboratory of Musculoskeletal Diseases at CHU Sainte-Justine and directs the Interdisciplinary Canadian Collaborative Myalgic Encephalomyelitis (ICanCME) Research Network. His research encompasses the molecular genetics of musculoskeletal conditions such as paediatric scoliosis and osteoarthritis, as well as complex adult diseases, including myalgic encephalomyelitis (ME/CFS). Professor Moreau’s work in ME/CFS centres on molecular profiling of patient samples to identify biomarkers and unravel disease mechanisms, with the ultimate aim of developing targeted treatments. At BRMEC14, he will present recent discoveries relating to novel biomarkers, including circulating microRNAs, and discuss how these findings are being translated into potential therapeutic approaches for ME/CFS. Professor Moreau will highlight how molecular profiling-particularly the analysis of circulating microRNAs-is advancing our understanding of ME/CFS pathophysiology and enabling the identification of distinct patient subgroups. These advances pave the way for precision medicine strategies, allowing treatments to be tailored to individual biological profiles. Anne Bertolotti (MRC Laboratory of Molecular Biology, Cambridge, UK) BRMEC14: Boosting Cellular Defence Mechanisms as a Treatment for Neurodegenerative Diseases Dr Anne Bertolotti specialises in cellular responses to misfolded proteins and chronic stress-processes increasingly recognised as relevant to ME/CFS. Her research focuses on the selective inhibition of phosphatases that regulate protein folding stress responses, which could provide insights into whether these protective pathways are disrupted in ME patients. At BRMEC14, Dr Bertolotti will discuss strategies to enhance cellular defences and improve protein homeostasis, with potential implications Invest in ME Research Page 17 of 43 Journal of IiMER May 2025 for ME/CFS and other chronic conditions. There is growing evidence that ME involves chronic cellular and oxidative stress, protein misfolding, and possible impairment of the unfolded protein response (UPR)-a key pathway ensuring proper protein folding and cellular resilience. Dr Bertolotti’s work directly targets these mechanisms, making her research highly relevant to understanding the molecular basis of ME. Her expertise bridges molecular biology, neuroimmune disease, and inflammation, offering valuable perspectives on how defects in protein clearance and stress responses may contribute to persistent symptoms in ME. As a leading expert in proteostasis regulation, Dr Bertolotti brings fresh ideas to ME research, addressing important but underexplored mechanisms in disease pathology and potential therapeutic targets. Session: Chronic Infection Aetiology Session Chair: David Price (Cardiff University, UK) Professor David Price is Chair of Infection and Immunity at Cardiff University School of Medicine and a leading member of the European ME Research Group (EMERG). He graduated with double first class honours in medical sciences and pathology from the University of Cambridge and completed his clinical training at King’s College Hospital, London. Professor Price specialised in internal medicine, infectious and tropical diseases, and subsequently earned a doctorate in molecular immunology at the University of Oxford. He has held academic clinical appointments and conducted research with fellowship support at the NIH Vaccine Research Center. Appointed to his current role at Cardiff in 2007, Professor Price’s research focuses on the development and application of advanced biotechnologies to characterise immune responses to globally significant pathogens, including HIV-1 and SARS-CoV-2. His work investigates how overactive or dysfunctional immune responses may contribute to long-term illness, and he is actively involved in research on immune mechanisms and persistent infection in conditions such as ME/CFS and Long Covid. Professor Price has also led initiatives to develop new diagnostic tests and treatments for post-infectious diseases. At the conference, Professor Price will chair the session on chronic infection as a potential driver of ME/CFS, drawing on his expertise in infection, immunity, and translational research. Douglas D. Fraser (Western University in London, Canada) Douglas Fraser is a Professor and Clinician Scientist in Paediatric Critical Care/Trauma Medicine at Western University in London, Ontario, Canada. He is a Fellow of the R oyal College of Physicians and Surgeons of Canada. Professor Fraser leads the Translational Research Centre at Western University, which includes a human tissue biobank that has supported research for over 15 years. His research focuses on immunology, infectious diseases, and the identification and validation of diagnostic and prognostic biomarkers for a range of conditions. Utilising advanced multiplex technologies, Invest in ME Research Page 18 of 43

Journal of IiMER May 2025 such as Proximity Extension Assay and Luminex Assay, his work aims to detect biomarker profiles that support early disease detection, monitoring, and therapeutic intervention. His team has identified novel proteins that may improve diagnostic precision and provide insights into disease mechanisms. BRMEC14: Large International Study LC-OPTIMIZE At BRMEC14, Professor Fraser will discuss how multiplex technologies can be applied to diagnostic processes and precision medicine. He will present findings from an international study investigating the long-term impact of COVID-19 and its potential overlap with ME/CFS, focusing on the identification of diagnostic and prognostic biomarkers. IIMEC17: Innovative Technologies and Clinical Applications Professor Fraser’s expertise in immunology and infectious diseases is relevant to ME/CFS research, particularly given the role of immune system dysfunction and potential infectious triggers in the condition. His research on systemic inflammation, long COVID, and biomarker discovery will be discussed during the chronic infection and biomarkers Professor Fraser’s clinical background ensures that his research findings have practical clinical relevance. His collaborative approach supports multidisciplinary discussions at BRMEC14, contributing to developments in biomarker research. Nancy Klimas (Nova Southeastern University, USA) BRMEC14: Comparative Analysis of Pre-Pandemic ME/CFS and Long COVID Cohorts: Phenotyping Insights and the Sipavibart Monoclonal Antibody Trial Professor Nancy Klimas is a clinical immunologist whose research focuses on the complex interactions between neuroinflammation, immune dysfunction, and energy metabolism in ME/CFS and related conditions. Her work employs advanced computational modelling to dissect disease mechanisms and identify targeted therapeutic strategies. A key area of her research involves a two-stage treatment approach aimed at reducing neuroinflammation and resetting the hypothalamic-pituitary-adrenal (HPA) axis, which is currently being tested in clinical trials. Her team investigates immune cell function abnormalities, including natural killer cell dysfunction, and explores how these contribute to chronic symptoms and disease progression. She applies multi-omics and phenotyping techniques to characterise patient subgroups, aiming to personalise treatment approaches. At BRMEC14, Professor Klimas will present comparative analyses of clinical and biological data from pre-pandemic ME/CFS and Long COVID cohorts to highlight shared and distinct features. She will also report on the ongoing sipavibart monoclonal antibody trial, evaluating its potential to modulate immune responses and improve outcomes in Long COVID, with implications for ME/CFS treatment strategies. Her research advances understanding of the neuro-immune mechanisms underlying these complex illnesses and supports the development of precision medicine approaches tailored to individual patient profiles. Invest in ME Research Page 19 of 43 Journal of IiMER May 2025 BRMEC14 Session: Nervous System and Neuroinflammation Session Chair: Jonas Bergquist (University of Uppsala, Sweden / EMERG) Professor Bergquist will moderate talks on neuroinflammation and nervous system dysfunction in ME/CFS. Stuart Bevan (Kings College London, UK) BRMEC14: Sensory Symptoms in Post-Covid Syndrome (PCS) Patients with Pain and Fatigue Professor Stuart Bevan is Professor of Pharmacology at King’s College London and an internationally recognised expert in sensory neuroscience and pain research. With a scientific career spanning several decades, he has made significant contributions to understanding how sensory signals are detected and transmitted by peripheral sensory neurons. His research has focused on the molecular and cellular mechanisms underlying pain, including the roles of ion channels such as TRPV1, TRPM8, and TRPA1 in mediating responses to heat, cold, and chemical stimuli. Before joining King’s College London, Professor Bevan spent 20 years as Head of Pain Research at Novartis, where he led efforts to identify new analgesic targets and advance pain therapeutics. He has collaborated extensively with clinical researchers to investigate pain mechanisms in conditions such as osteoarthritis, fibromyalgia, and neuropathic pain. Professor Bevan has published widely in leading scientific journals and is known for his work on the pharmacology of sensory neurons and the development of novel approaches to pain management. At BRMEC14, he will present research on sensory symptoms in Post-Covid Syndrome patients with pain and fatigue, exploring the overlap with ME/CFS and discussing potential shared mechanisms and therapeutic strategies. His expertise provides valuable insight into the biological basis of sensory dysfunction in chronic illness. Denise Visser (University Medical Center Utrecht, Netherlands) Dr Denise Visser is a postdoctoral researcher at University Medical Center Utrecht, specialising in neuroimaging and neuroinflammation. Her research uses advanced PET imaging to investigate brain inflammation and molecular changes in neurological conditions, including studies on tau pathology and cerebral blood flow in neurodegenerative diseases, with a focus on glial cell activity. BRMEC14: Neuro-PET Data of Post-COVID Patients At BRMEC14, Dr Visser will present neuro-PET data from post-COVID patients, highlighting evidence of neuroinflammation. Her findings provide insight into the neurological effects of post-COVID syndrome and may reveal mechanisms shared with ME/CFS, supporting a deeper understanding of these conditions. Invest in ME Research Page 20 of 43

Journal of IiMER May 2025 Felipe Correa-da-Silva (Netherlands Institute for Neuroscience, Netherlands) BRMEC14: Delineating Clinical Phenotypes and HPA-Axis Dysfunction in ME Dr Felipe Correa-da-Silva is a postdoctoral researcher at the Netherlands Institute for Neuroscience. His work centres on molecular biology and neuroendocrinology, particularly the role of neuron-glia interactions and hypothalamic function in disease. He has a strong interest in the hypothalamic-pituitary-adrenal (HPA) axis and its dysfunction in ME/CFS, exploring how this contributes to clinical phenotypes and symptom variability. His research aims to delineate subgroups within ME/CFS by combining clinical phenotyping with biological measures, supporting the development of more targeted and personalised treatment approaches. Dr Correa-da-Silva is also involved in the Netherlands Brain Bank’s ME/CFS donor programme, advancing research into the neurological aspects of ME/CFS. At BRMEC14, he will discuss how clinical phenotyping and HPA axis evaluation can help define distinct ME/CFS subgroups, facilitating more precise research and treatment strategies. Maxim N. Artyomov and Tomas Paulenda (Washington University in St. Louis, USA) BRMEC14: Itaconate modulates immune responses via inhibition of Peroxiredoxin 5 Professor Maxim N. Artyomov and Dr Tomas Paulenda are leading researchers in immunometabolism and systems immunology. Their recent work demonstrates that itaconate-a metabolite produced during inflammation-inhibits peroxiredoxin 5 (PRDX5), an antioxidant enzyme critical for managing mitochondrial oxidative stress in immune cells. This non-covalent inhibition alters mitochondrial peroxide levels and the redox environment in activated macrophages, significantly affecting immune signalling pathways and fine-tuning inflammatory responses. This discovery builds on Artyomov’s earlier work exploring itaconate’s role in modulating macrophage behaviour and inflammation. In light of their recent important research, the charity is delighted to announce the addition of Maxim N. Artyomov and Tomas Paulenda to the BRMEC14 programme. These findings are highly relevant to ME, a condition marked by immune dysregulation, mitochondrial dysfunction, and persistent oxidative stress. The study links itaconate’s regulation of mitochondrial redox balance to mechanisms often impaired in ME, suggesting that by inhibiting PRDX5, itaconate may influence the handling of reactive oxygen species in immune cells. This could contribute to the mitochondrial dysfunction and abnormal oxidative stress observed in ME patients. Invest in ME Research Page 21 of 43 Journal of IiMER May 2025 The research supports the view that immune-metabolic crosstalk is central to ME pathology, aligning with the metabolic trap hypothesis and highlighting how disruptions in immune cell metabolism may perpetuate ME symptoms. Demonstrating itaconate’s anti-inflammatory effects and its modulation of immune signalling, the study points to new therapeutic possibilities for managing chronic immune activation and inflammation in ME. At BRMEC14, Drs Artyomov and Paulenda will present their systems biology approach, which integrates computational modelling, multi-omics data, and redox signalling. Their work exemplifies the synergy between systems biology, immunology, and redox signalling, and supports the colloquium’s aim of translating molecular discoveries into clinical solutions. Their participation will enrich discussions on how metabolic rewiring and redox imbalances drive immune dysfunction in ME, advancing collaborative research in this complex field. BRMEC14 Session: Immune System Primary and Secondary Session Chair: Eva Untersmayr-Elsenhuber, Medical University of Vienna, Austria Professor Untersmayr-Elsenhuber, a leader in immunology and ME/CFS research, will guide the session, highlighting recent advances in understanding immune dysfunction and its role in ME/CFS pathogenesis. Muzlifah Haniffa, Wellcome Sanger Institute, UK BRMEC14: Impact of Viral (SARS-CoV-2) Infections on Immune Cells and Insights for ME Prof Haniffa is currently serving as the Interim Head of Cellular Genetics and Senior Group Leader at the Wellcome Sanger Institute and is a renowned immunologist and dermatologist. Her talk promises to offer valuable perspectives on the immunological aspects of ME. Prof Haniffa's research focuses on applying cutting-edge genomic technologies to unravel complex biological processes. As a key contributor to the Human Cell Atlas initiative, her work in mapping human cell types and states across tissues may offer new perspectives on the multi-system nature of ME. Her collaborative approach and interdisciplinary expertise make her a valuable addition to the ongoing efforts to understand and address this complex condition. Prof Haniffa is a pioneer in applying single-cell genomics technologies to understand tissue homeostasis, immunity, and disease pathogenesis. Her expertise in decoding the development and functional maturation of the human immune system is particularly relevant to ME research, as immune dysfunction is a key area of investigation in the field. This could provide valuable insights into the immunological aspects of ME, potentially shedding light on the disease's underlying mechanisms. The presentation will be part of the Immunology session, moderated by EMERG member Associate Professor Eva Untersmayr-Elsenhuber of the Medical University of Vienna, Austria. Professor Haniffa's research on the impact of SARS-CoV-2 on immune cells could provide crucial insights into ME, Page 22 of 43 Invest in ME Research

Journal of IiMER May 2025 potentially illuminating the similarities between post-viral fatigue syndromes and ME. Her innovative use of stem cell culture systems and skin organoids as experimental models may offer new avenues for understanding the complex pathophysiology of ME. As ME research continues to face challenges due to limited funding, the participation of esteemed researchers like Prof Haniffa in BRMEC14 is vital for advancing our understanding of this debilitating condition. Her presentation could potentially open new doors for collaborative research and innovative treatment strategies and showcases the international nature of the colloquium. Christian Puta Friedrich Schiller University Jena, Germany BRMEC14: Immunometabolic Aspects of PEM Dr Christian Puta, Professor of Sports Medicine and Health Promotion at Friedrich Schiller University Jena, will present on the immunometabolic aspects of post-exertional malaise (PEM) in ME/CFS. Dr Puta brings significant expertise in exercise physiology, sensory signal transduction, and health promotion to the field of ME research. His work focuses on the mechanisms underlying PEM, a core symptom of ME/CFS, and addresses the challenges of studying PEM without causing prolonged recovery in patients. Dr Puta’s research has identified key physiological changes during PEM, including reduced peak oxygen uptake, decreased systemic oxygen extraction, and alterations in red blood cell morphology. These findings shed light on the complex biological responses triggered by exertion in ME/CFS. As leader of the Pain, Perception, Prevention Workgroup, Dr Puta also investigates sensori-motor control in chronic pain and the interplay between the autonomic nervous system and inflammatory responses to pain and exercise. His multidisciplinary approach integrates immune profiling and metabolic assessments to better understand how immune and metabolic changes contribute to PEM and its impact on patient health. Dr Puta’s expertise and research will provide valuable insights into the biological basis of PEM, informing efforts to develop targeted therapeutic strategies and improve the management of ME/CFS. Maureen Hanson Cornell University, USA BRMEC14: Inflammatory signaling pathways revealed by cell-free RNA analysis Professor Hanson will share findings from her group’s studies on immune cell abnormalities in ME/CFS, including altered T and B cell function, cytokine profiles, and immune gene expression. Her research aims to identify biomarkers and clarify the role of immune dysregulation in disease persistence. Maureen Hanson is Liberty Hyde Bailey Professor of Molecular Biology and Genetics and Director of the Center for Enervating Neuroimmune Disease at Cornell University. Her research is internationally recognised for advancing the understanding of immune dysfunction in ME/CFS. Invest in ME Research Page 23 of 43 Journal of IiMER May 2025 Professor Hanson’s team investigates how the immune system is altered in people with ME/CFS, focusing on both immune cell metabolism and gene expression. Her group examines how immune cells, such as monocytes and T cells, adjust their metabolic processes in response to activation, and whether these responses are abnormal in ME/CFS. Using advanced techniques like the Seahorse flux analyser and flow cytometry, they study differences in fatty acid metabolism and energy production between ME/CFS patients and healthy controls. Her research also explores changes in gene expression and the content of extracellular vesicles-tiny packages released by cells that carry proteins, RNA, and other molecules-before and after exercise. These studies aim to identify molecular signatures that distinguish ME/CFS and reveal how immune signalling is disrupted, particularly in response to physical stress. In addition, Professor Hanson’s team analyses the gut and blood microbiome to understand their role in immune activation and persistent symptoms. By integrating findings from immune cell metabolism, gene expression, and microbiome studies, her work seeks to clarify the biological mechanisms underlying ME/CFS and to identify potential biomarkers for diagnosis and targets for therapy. Through major NIH-funded projects and collaborations, Professor Hanson’s research is helping to build a clearer picture of the immune abnormalities in ME/CFS, supporting the development of effective treatments and improved clinical care for people with this disabling condition. Session: Orthostatic Intolerance and Autonomic Physiology Session Chair: Jos Bosch, University of Amsterdam, Netherlands / EMERG Dr Bosch, an expert in psychophysiology and ME/CFS cohort research, will chair this session focused on autonomic dysfunction and orthostatic intolerance, which are common in ME/CFS. Linda van Campen, Stichting Cardio Zorg, Netherlands BRMEC14: Cardiac Aspects of Orthostatic Intolerance Dr Linda van Campen is clinician and researcher at Stichting Cardio Zorg in the Netherlands, with extensive experience in the assessment and management of cardiovascular dysfunction in ME/CFS. She has played a leading role in advancing the understanding of orthostatic intolerance-a common and debilitating symptom in ME/CFS patients, characterised by abnormal heart rate and blood pressure responses upon standing. Dr van Campen’s research has contributed to the identification of various forms of orthostatic intolerance in ME/CFS, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension. Her work has highlighted the importance of careful cardiovascular assessment in ME/CFS, as these abnormalities can often go unrecognised yet have a major impact on daily functioning and quality of life. At BRMEC14, Dr van Campen will present clinical and research findings on cardiac function in ME/CFS patients experiencing orthostatic intolerance. She will discuss patterns of heart rate and blood pressure abnormalities, their diagnostic value, and implications for patient management. Her talk will also address practical strategies for recognising and treating orthostatic intolerance in ME/CFS, aiming to improve outcomes and provide guidance for clinicians. Invest in ME Research Page 24 of 43

Journal of IiMER May 2025 Artur Fedorowski Karolinska Institutet, Stockholm, Sweden BRMEC14: Mechanisms Underlying Cardiovascular Autonomic Dysfunction, POTS and IST in Long COVID and ME Artur Fedorowski from the Karolinska Institutet in Stockholm, Sweden, will share his extensive knowledge on autonomic physiology and its dysregulation in ME. Dr. Federowski's work has significantly contributed to our understanding of the autonomic nervous system's role in chronic illnesses. His presentation at #BRMEC14 will explore the intricate mechanisms underlying autonomic dysfunction in ME patients, offering potential avenues for diagnostic and therapeutic interventions. Dr. Federowski's participation underscores the colloquium's commitment to fostering international collaboration and advancing ME research. Professor Fedorowski will present research on the mechanisms of postural orthostatic tachycardia syndrome (POTS) and inappropriate sinus tachycardia (IST), syndromes frequently seen in both ME/CFS and Long COVID. His work explores autonomic nervous system regulation and its disruption in these conditions. Peter Novak Brigham and Women's Hospital, Harvard Medical School, USA BRMEC14: Orthostatic Intolerance and its Management-Strategies for Clinicians and Researchers Dr Peter Novak is a neurologist and autonomic specialist at Brigham and Women’s Hospital and Harvard Medical School, with extensive expertise in orthostatic intolerance and autonomic disorders. His research has significantly advanced understanding of conditions such as postural orthostatic tachycardia syndrome (POTS) and hypocapnic cerebral hypoperfusion (HYCH), both of which frequently overlap with ME/CFS. Dr Novak’s work employs comprehensive autonomic testing, including tilt-table tests, cerebral blood flow velocity monitoring, and cardiopulmonary exercise testing, to characterise the physiological mechanisms underlying orthostatic intolerance. He has identified biomarkers such as hypocapnia and cerebral hypoperfusion that help distinguish subtypes of orthostatic intolerance and guide diagnosis and treatment. At BRMEC14, Dr Novak will present practical strategies for clinicians and researchers on diagnosing and managing orthostatic intolerance in ME/CFS, drawing on his extensive clinical experience and research into autonomic dysfunction. His insights aim to improve patient care and inform targeted therapeutic approaches for this complex and often debilitating aspect of ME/CFS.intolerance in ME/CFS, based on his extensive experience in autonomic testing and patient care. Invest in ME Research Page 25 of 43 Journal of IiMER May 2025 Mette Olufsen North Carolina State University, USA BRMEC14: Models Extracting the Sympathetic/Parasympathetic Tone Mette Olufsen is a distinguished professor from North Carolina State University, USA, who brings a unique perspective to the session with her expertise in mathematical modelling and physiology. Her work focuses on developing quantitative models to understand complex biological systems, including the autonomic nervous system. Professor Olufsen's presentation will highlight how mathematical modelling can be applied to unravel the intricacies of orthostatic intolerance in ME, providing a novel approach to research and treatment. Her participation in the colloquium exemplifies the interdisciplinary nature of #BRMEC14, fostering innovative solutions to complex medical challenges. Professor Olufsen will discuss mathematical and computational models that assess the balance between sympathetic and parasympathetic nervous system activity. These models can help objectively evaluate autonomic dysfunction in ME/CFS. Branislav Milovanović Institute for Cardiovascular Diseases-Dedinje, Serbia BRMEC14: Assessment of Autonomic Nervous System Function in Patients with ME and PostCOVID-19 Syndrome Presenting with Recurrent Syncope: Neurocardiological Approach Professor Branislav Milovanović is a full professor of Internal Medicine – Cardiology at the Faculty of Medicine in Belgrade and Chief of the Neurocardiologist Laboratory at the Institute for Cardiovascular Diseases-Dedinje in Serbia. He is also a professor at the Medical Faculty in Saransk, Russia, and an active member of the European Academy of Sciences and Arts. Professor Milovanović is a pioneer of neurocardiology in Serbia, having introduced clinical assessment protocols for autonomic nervous system function and organized key international symposia in the field. His expertise includes noninvasive electrocardiology, cardiovascular risk assessment, autonomic nervous system dysfunction, chronic fatigue syndrome (ME/CFS), syncope, and post-COVID-19 syndrome. At BRMEC14, Professor Milovanović will present a neurocardiological approach to assessing autonomic nervous system function in patients with ME/CFS and post-COVID-19 syndrome who experience recurrent syncope (fainting). His presentation will focus on how autonomic dysfunction contributes to these symptoms, using cardiovascular autonomic reflex tests and heart rate variability analysis to improve diagnosis and treatment strategies. This work highlights the importance of cardiovascular autonomic neuropathy in understanding and managing both ME/CFS and post-COVID conditions, offering a comprehensive clinical perspective on recurrent fainting in these patient groups. Invest in ME Research Page 26 of 43

Journal of IiMER May 2025 BRMEC14 Session: Metabolism Body and Cell Session Chair: Rikke Olsen Aarhus Universitet, Denmark Dr Rikke Katrine Jentoft Olsen is Associate Professor at the Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University. She holds a master’s degree in molecular biology and a PhD in medicine. Her research focuses on the molecular genetics and cellular pathology of inborn errors of metabolism, with particular emphasis on fatty acid oxidation disorders and mitochondrial dysfunction. She integrates genetic diagnostics with studies of cellular mechanisms and the development of novel treatments, including mitochondrial vitamins and cofactors. In recent years, Dr Olsen has initiated research programmes investigating the role of mitochondrial and metabolic dysfunction in post-inflammatory fatigue, specifically in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). She is actively involved in clinical and research networks, serving on the boards of the International Network for Fatty Acid Oxidation Research and Management (INFORM) and the European ME Research Group (EMERG). Dr Olsen also contributes to the Danish Neonatal Screening Programme for inborn errors of metabolism. At the conference, Dr Olsen will chair the session on metabolic pathways in ME/CFS, drawing on her extensive background in mitochondrial medicine and metabolic research to guide discussions on recent advances and their implications for diagnosis and treatment. Chris Armstrong University of Melbourne, Australia BRMEC14: Mitochondrial Dysfunction in ME: Insights from Metabolomics and Precision Medicine Dr Armstrong will present metabolomic data revealing mitochondrial dysfunction and altered energy metabolism in ME/CFS. His research aims to identify metabolic biomarkers and inform precision medicine approaches for diagnosis and therapy. Dr Christopher Armstrong, from the Department of Biochemistry and Molecular Biology at the University of Melbourne, Victoria, Australia, will be presenting in the Metabolism Body and Cell session at BRMEC14. His research focuses on applying metabolomics techniques to understand the biochemical alterations in ME patients. As a leading researcher in ME metabolism, Dr Armstrong has made significant contributions to the field since publishing the first metabolomics paper on ME in 2015. His work explores various aspects of metabolism in ME, including energy metabolism, amino acid metabolism, and oxidative stress. Dr Armstrong's presentation is expected to provide insights into the metabolic underpinnings of ME, potentially shedding light on the disease's pathogenesis and opening avenues for future diagnostic and treatment strategies. Invest in ME Research Page 27 of 43 Journal of IiMER May 2025 James Baraniuk Georgetown University Medical Centre, USA BRMEC14: Exertional Exhaustion (PEM) Evaluated by Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in ME Professor Baraniuk will discuss how exercise affects cerebrospinal fluid metabolites and lipids in ME/CFS patients, focusing on changes in the serine pathway. This work provides insights into the biochemical basis of post-exertional malaise. Dr Baraniuk's research focuses on ME, Gulf War Illness (GWI) and other pain conditions. His work employs advanced techniques including functional Magnetic Resonance Imaging (fMRI), biomarker discovery through proteomic, metabolomic, and transcriptomic assays in blood and cerebrospinal fluid, autonomic testing, and heart rate variability (HRV) analysis. Recent findings from Dr Baraniuk's team have revealed distinct molecular signatures in ME and GWI, suggesting they are separate conditions with unique brain chemistry profiles. His research has shown that these disorders produce different abnormal patterns of brain activity after moderate exercise, which could lead to improved diagnoses and treatments. Dr Baraniuk's work on exercise- induced changes in cerebrospinal fluid microRNAs has provided new insights into the biological basis of these conditions. Helena Cochemé, MRC Laboratory of Medical Sciences, UK BRMEC14: Redox Signalling in Aging and Its Implications for ME/CFS and Long-COVID Research Professor Helena Cochemé, Head of the Redox Metabolism Research Group at the MRC London Institute of Medical Sciences, is a leading biochemist specialising in redox signalling and mitochondrial dysfunction in metabolic health and ageing. Her research uses in vivo models, particularly Drosophila, to investigate how reactive oxygen species (ROS) and redox changes regulate cell signalling, stress responses, autophagy, and lifespan. Recent findings from her group have shown that redox regulation can modulate autophagy, extend lifespan, and that systemic extracellular acidification is a hallmark of ageing. Professor Cochemé also explores the interplay between mitochondrial function, redox state, and metabolic pathways in determining cellular health and disease susceptibility. Her team employs highthroughput screening and translational studies to identify redox-sensitive pathways as potential therapeutic targets. Her expertise is highly relevant to ME/CFS and Long COVID, as redox imbalance, oxidative stress, and mitochondrial dysfunction are increasingly recognised as contributors to fatigue, post-exertional malaise, and multi-system symptoms. Professor Cochemé’s work provides mechanistic insights into how disruptions in redox signalling may drive persistent symptoms in these conditions, suggesting new avenues for biomarker discovery and treatment strategies. Invest in ME Research Page 28 of 43

Journal of IiMER May 2025 At BRMEC14, Professor Cochemé will discuss how redox signalling and oxidative stress contribute to ageing and chronic disease, drawing important connections to ME/CFS and Long COVID. Her participation will enrich discussions, bridge basic science and clinical research, and inspire new collaborative efforts to better understand and treat these complex conditions. David Systrom Assistant Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA Dr David Systrom is Assistant Professor of Medicine at Harvard Medical School and a pulmonary and critical care physician at Brigham and Women’s Hospital, where he directs the Dyspnoea Clinic and the Advanced Cardiopulmonary Exercise Testing Program. With over 35 years on the Harvard faculty, he is internationally recognised for his research into exercise intolerance in ME/CFS and related conditions. Dr Systrom’s work focuses on invasive cardiopulmonary exercise testing (iCPET), which measures cardiovascular, respiratory, and metabolic responses during maximal exercise. He has shown that many people with ME/CFS experience impaired cardiac preload, reduced peak cardiac output, and poor systemic oxygen extraction during exercise. These abnormalities reflect neurovascular dysregulation and autonomic dysfunction rather than deconditioning, and his studies indicate that small fibre neuropathy may contribute to these circulatory and metabolic problems. His research helps explain the profound fatigue, post-exertional malaise, and orthostatic intolerance in ME/CFS. He is currently leading a major study using muscle biopsies to investigate skeletal muscle mitochondrial dysfunction in ME/CFS and has completed the first randomised controlled trial of pyridostigmine in ME/CFS, which improved exercise capacity by increasing cardiac output and right ventricular filling pressures. By comparing ME/CFS with long COVID, his work highlights shared mechanisms and supports the development of common treatment approaches. BRMEC14: Metabolic Insights from Invasive Cardiopulmonary Exercise Testing in ME Dr Systrom will present findings from invasive cardiopulmonary exercise testing in ME/CFS, highlighting abnormalities in oxygen delivery and utilisation, and their relationship to exercise intolerance and fatigue. IIMEC17: Neurovascular Dysregulation During Exercise in ME At the Invest in ME Research Conference, Dr Systrom will present on “Neurovascular Dysregulation During Exercise in ME”, sharing insights from his research into how abnormalities in vascular and autonomic function contribute to the hallmark symptoms of ME/CFS. His work supports efforts to better characterise disease mechanisms and identify potential therapeutic targets, in alignment with the aims of Invest in ME Research. Invest in ME Research Page 29 of 43 Journal of IiMER May 2025 Anouk Slaghekke Vrije Universiteit Amsterdam, Netherlands BRMEC14: Microvascular Abnormalities in Skeletal Muscle Anouk Slaghekke is a researcher specialising in physiology and movement sciences, with a focus on the interplay between muscle oxygenation, skeletal muscle structure and function, and immunology. Her research investigates how microvascular abnormalities in skeletal muscle contribute to the symptoms of ME/CFS, particularly exercise intolerance and post-exertional malaise. Recent studies involving Slaghekke have examined muscle biopsies from people with ME/CFS, both before and after exercise challenges. These studies aim to identify structural and functional changes in muscle tissue, such as impaired blood flow, reduced oxygen delivery, and the presence of microclots. By comparing findings in ME/CFS to those in long COVID and healthy controls, her work seeks to clarify whether microvascular dysfunction is a common underlying factor in these conditions. Understanding microvascular abnormalities is important because they may explain why patients experience rapid muscle fatigue and prolonged recovery after exertion. This research could lead to the identification of new biomarkers for ME/CFS and inform the development of targeted therapies to improve muscle function and quality of life for affected individuals. She will discuss evidence for microvascular dysfunction in the skeletal muscle of ME/CFS patients, which may contribute to impaired oxygen delivery and reduced exercise capacity. Session: In Vitro Models and Biomarker Discovery Session Chair: Simon Carding Quadram Institute, UK / EMERG Professor Carding will introduce this session on advanced laboratory models and biomarker discovery for ME/CFS. Elisa Oltra Universidad Catolica de Valencia San Vicente Mártir, Spain iPSC Dr Elisa Oltra is Professor of Cell and Molecular Biology at the Universidad Católica de Valencia San Vicente Mártir in Spain and a leading researcher in the application of induced pluripotent stem cells (iPSC) to biomedical research. Her group has pioneered the use of iPSC-based systems as sensitive bioassays to investigate metabolic and environmental factors present in the plasma of people with ME/CFS. Dr Oltra will discuss the use of induced pluripotent stem cells (iPSC) to model ME/CFS in vitro, enabling the study of disease mechanisms at the cellular level and supporting drug screening efforts. Invest in ME Research Page 30 of 43

Journal of IiMER May 2025 iPSCs are stem cells that can be generated from adult cells and have the ability to become any cell type in the body. Dr Oltra’s research explores how iPSCs can be used as “sensors” to detect disease-specific metabolic imbalances and responses to environmental cues. By exposing healthy iPSCs to plasma or serum from ME/CFS patients, her team studies changes in cell morphology, differentiation, growth, and metabolic activity. These changes can reveal the presence of disease-related factors in patient body fluids and provide evidence of altered cellular metabolism in ME/CFS. This approach offers several advantages over traditional cell lines or primary cell cultures. iPSC-based assays can be standardised, are highly sensitive to metabolic and environmental changes, and allow for high-throughput screening. Dr Oltra’s work also investigates how iPSC systems might predict individual responses to stem cell therapies and support the development of precision medicine strategies for ME/CFS. Her research is important for advancing in vitro disease modelling, identifying potential biomarkers, and developing new diagnostic and drug-screening platforms. In the context of BRMEC14, Dr Oltra’s expertise in iPSC technology provides valuable tools for understanding ME/CFS pathophysiology and for translating laboratory findings into clinical applications. Emily Jones Carding Group, Quadram Institute, UK BRMEC14: Organs-on-Chips Dr Emily Jones is a researcher at the Quadram Institute with expertise in developing organ-on-chip and microphysiological systems to model human tissues and disease processes. She has played a central role in collaborative projects that design and implement organ-on-chip technologies, such as the recently developed gut-brain axis microphysiological system. This platform connects a gut barrier model to a neuronal cell compartment, allowing researchers to study how substances-including neurotoxins-cross the gut lining and affect brain cells. Dr Jones’s work focuses on building simplified, cost-effective, and user-friendly organ-on-chip devices that can be used by a wide range of researchers, including those working in high-containment laboratories. Her research aims to provide more physiologically relevant models than traditional cell culture or animal testing, enabling the study of cell behaviour, inter-organ communication, and disease mechanisms in a controlled environment. By using human-derived cells and creating interconnected models, Dr Jones’s organ-on-chip systems help reveal how diseases develop and progress at the cellular level. This approach is particularly valuable for studying complex, multisystem conditions such as ME/CFS, where traditional models may not capture the intricacies of tissue interactions or immune responses. Her work also supports the identification of new therapeutic targets and the reduction of animal use in research, making organon-chip technology a powerful tool for translational biomedical science. Invest in ME Research Page 31 of 43 Journal of IiMER May 2025 The Carding Group will present their development of organ-on-chip platforms, which replicate human tissue environments to study ME/CFS pathology and test therapeutic interventions in a controlled setting. Tamas Korcsmaros Imperial College London, UK BRMEC14: Organoids Dr Korcsmaros will explain how organoid models-miniaturised, threedimensional tissue cultures-can be used to investigate ME/CFS mechanisms and host-microbe interactions. Organoids are three-dimensional, stem cell-derived structures that closely mimic the architecture and function of human tissues. Under Dr Korcsmaros’s leadership, the Organoid Facility at Imperial serves as a multidisciplinary hub, supporting the generation, culture, and biobanking of organoids from both induced pluripotent stem cells (iPSC) and adult biopsies. The facility provides expertise and training for researchers, facilitates the design and execution of organoid-based experiments, and develops complex disease models with integrated multi-omics readouts. Dr Korcsmaros’s research focuses on using organoids to model human disease more accurately than traditional cell cultures or animal models. By collaborating with engineering and clinical teams, his group is advancing the use of organoids and organ-on-chip systems to study cell-cell and cellmicrobiome interactions in a physiologically relevant context. This is particularly important for diseases like ME/CFS, where tissue-specific pathology and complex intercellular communication are central to disease mechanisms. Organoid models are revolutionising biomedical research by enabling patient-specific disease modelling, drug screening, and precision medicine approaches. The work of Dr Korcsmaros and his facility lowers the barrier for researchers to access these cutting-edge methods, supports the development of more accurate disease models, and helps translate laboratory findings into clinical applications. In the context of BRMEC14, his expertise is crucial for advancing in vitro modelling of ME/CFS and related conditions, supporting the discovery of novel therapeutic targets and personalised interventions. Dezso Modos, Imperial College London, UK BRMEC14: In Silico Models Dr Dezso Modos is a systems biologist and Imperial College Research Fellow with a background in medicine and computational biology. His research focuses on developing and applying in silico (computer-based) models to integrate and analyse complex biological data, particularly in the context of human disease. He has worked extensively on multi-omics data integration, network biology, and the use of computational tools to unravel disease mechanisms. Dr Modos has contributed to projects involving the reconstruction of signalling networks and the analysis of patient-specific pathways, including studies on inflammatory and immune-mediated Page 32 of 43 Invest in ME Research

Journal of IiMER May 2025 diseases. His expertise includes designing computational workflows that combine genomics, transcriptomics, proteomics, and metabolomics data to identify disease drivers and potential therapeutic targets. In the context of ME/CFS, in silico models are essential for handling the vast and heterogeneous datasets generated by modern research. Dr Modos’s work enables researchers to visualise and interpret complex biological interactions, predict disease-associated pathways, and prioritise hypotheses for experimental validation. This approach supports precision medicine by identifying patient subgroups and informing personalised treatment strategies. At BRMEC14, Dr Modos will present on the application of in silico models in ME/CFS research, demonstrating how computational analysis can accelerate biomarker discovery, improve disease stratification, and guide the development of targeted therapies. His contribution is particularly valuable for translating big data into actionable biological insights in ME/CFS and related complex diseases. Dr Modos will present computational (in silico) models that simulate biological processes in ME/CFS, aiding in hypothesis generation and the design of experimental studies. Dr Vicky Whittemore, Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States IIMEC17: Hinxton Criteria Dr Vicky Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster at the National Institute of Neurological Disorders and Stroke (NINDS), part of the US National Institutes of Health (NIH). She oversees a portfolio of research grants focused on neurological conditions, including ME/CFS, and plays a key role in coordinating NIH efforts to advance biomedical research into this complex disease. Dr Whittemore holds a PhD in anatomy from the University of Minnesota, followed by postdoctoral training at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm. She was previously on the faculty at the University of Miami School of Medicine, working with The Miami Project to Cure Paralysis, and has held leadership roles in several non-profit organisations including the Tuberous Sclerosis Alliance and Citizens United for Research in Epilepsy (CURE). She also served a four-year term on the National Advisory Neurological Disorders and Stroke Council. Recently, Dr Whittemore led the NIH Roadmap for ME/CFS project, overseeing programme development and management. She supports collaborative research initiatives and promotes multidisciplinary approaches to improve understanding of ME/CFS. A regular speaker at Invest in ME Research’s international conferences, she facilitates scientific exchange between US and European researchers. Invest in ME Research Page 33 of 43 Journal of IiMER May 2025 At IIMEC17, Dr Whittemore will discuss the Hinxton Criteria, which emerged from the 2024 Biomedical Research into ME Colloquium (BRMEC13) held at Hinxton Hall. This collaboration between NIH researchers, Invest in ME Research, and the European ME Research Group (EMERG) aims to establish refined diagnostic criteria and research standards for ME that reflect current scientific knowledge and encourage international cooperation. The Hinxton Criteria are distinct from the earlier International Consensus Criteria (ICC) and represent a complementary approach to diagnosis. Dr Jesper Mehlsen, Copenhagen University Hospital, Denmark IIMEC14:European Protocol for Pathobiology, Diagnosis, and Treatment of ME 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 over 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). Dr Mehlsen ran a clinic for ME patients in Copenhagen, Denmark, until recently where he provided clinical care and applies his research insights to patient management. He has been actively involved in developing a European consensus on treatment protocols for ME/CFS, aiming to establish standardised approaches that can be adopted across clinical settings. His research interests include methods for studying autonomic cardiovascular control, mathematical modelling of cardiovascular responses, and the neuroinflammatory reflex. Dr Mehlsen is also involved in discussions on clinical trials and standards within the ME research community, including chairing sessions at the Biomedical Research into ME Colloquium (BRMEC13). His work integrates clinical observation with advanced physiological and mathematical analyses to explore the underlying mechanisms of ME and related disorders. Invest in ME Research Page 34 of 43

Journal of IiMER May 2025 Rowan Gardner, Precision Life, UK IIMEC17: Precision diagnostic tests and personalised treatments for ME and Long COVID Rowan Gardner is Co-founder and Chief Business & Investment Officer at PrecisionLife, a UK-based precision medicine company focused on complex chronic diseases such as ME/CFS and Long COVID. With over 30 years of experience applying computational methods to life science and patient data, she specialises in identifying mechanistically defined patient subgroups to enable more targeted diagnostics and personalised treatments. Rowan holds a Master’s degree in biochemistry from the University of Oxford and has played key roles in pioneering life science ventures, including Oxford Molecular Group and collaborations with CERN on cloud computing in healthcare. She is also an independent board member at Digital Health and Care Wales, contributing to the digital transformation of NHS services. At the Invest in ME Conference, Rowan will present an update on PrecisionLife’s collaborative MetX study with the Metrodora Institute, which has achieved the first replicated genetic associations in both ME and Long COVID, confirming key genetic risk factors across diverse populations. She will discuss how these findings are being used to provide participants with detailed reports on disease mechanisms, support the development of novel diagnostic tools and targeted therapies, and design more effective clinical trials. Rowan will highlight how PrecisionLife’s advanced data analytics are accelerating the development of precision medicine approaches for ME/CFS and Long COVID, aiming to improve patient stratification, diagnosis, and treatment outcomes. Jonas Bergquist, Uppsala University, Sweden IIMEC17: Multi-Omic Biomarker Discovery for Diagnosis and Disease Mechanisms in ME/CFS Professor Jonas Bergquist, MD, PhD, is a Full Chair Professor in Analytical Chemistry and Neurochemistry at Uppsala University, Sweden, where he directs the Proteomics and Metabolomics platforms. He also holds adjunct and visiting professorships at the University of Utah, Binzhou Medical University in China, and the Swedish University of Agricultural Sciences. His research group focuses on developing advanced analytical tools for molecular diagnostics and biomarker discovery, particularly in cerebrospinal fluid and other complex biological samples. Professor Bergquist’s work aims to better understand neuroimmunological involvement in diseases such as ME/CFS by applying proteomics and metabolomics techniques. Since 2019, he has led a clinical collaborative research centre in Uppsala dedicated to ME, working in partnership with institutions including Harvard Medical School, Stanford University, Montreal University, and Melbourne University. His multidisciplinary approach integrates molecular data with clinical insights to identify biomarkers and explore disease mechanisms, including neuroinflammation Invest in ME Research Page 35 of 43 Journal of IiMER May 2025 and immune dysregulation. Professor Bergquist is also a member of the European ME Research Group (EMERG), which was established to develop coordinated biomedical research across Europe. In addition to his research activities, Professor Bergquist contributes to several collaborative initiatives, including the ME/CFS Common Data Element Project. His work supports efforts to develop objective diagnostic tools and improve understanding of ME/CFS pathophysiology, with the goal of facilitating better patient stratification and targeted treatment approaches. Professor Bergquist will discuss the latest advances in proteomic and metabolomic biomarker discovery for ME/CFS, aiming to improve diagnosis, disease monitoring, and understanding of disease mechanisms. Wenzhong Xiao, Harvard Medical School, USA IIMEC17: Patient-Reported Treatment Outcomes in ME/CFS and Long COVID Wenzhong Xiao, PhD, is Director of the Immuno-Metabolic Computational Center at Massachusetts General Hospital and Assistant Professor of Surgery (Bioinformatics) at Harvard Medical School. He also leads a Computational Genomics Group at Stanford Genome Technology Center, with a research career spanning computational genomics, bioinformatics, and the integrative analysis of complex molecular and clinical datasets relevant to immune and metabolic diseases, including ME/CFS and Long COVID. Dr Xiao holds a PhD in chemistry and structural biology from the University of California, Berkeley, and a master’s degree in statistics. His academic background is complemented by postdoctoral training in computational genomics at Stanford University School of Medicine5. He has played a pivotal role in developing data-driven approaches to interpret large-scale patient data, aiming to uncover disease mechanisms, identify diagnostic and predictive biomarkers, and inform the development of targeted therapies. A significant aspect of Dr Xiao’s work involves the application of advanced computational tools to analyse diverse data types, such as electronic health records, genomic sequencing, proteomics, and patient-reported outcomes. He has contributed to landmark studies, including the Severely Ill Patient Study, and has been instrumental in collaborative efforts that bridge research centres and patient communities, reflecting a spirit of partnership that aligns with Invest in ME Research’s ethos. At the Invest in ME Research Conference, Dr Xiao will present on “Patient-Reported Treatment Outcomes in ME/CFS and Long COVID”. His talk will explore findings from a large-scale survey involving thousands of patients, examining symptom profiles, comorbidities, and the effectiveness of over 150 treatments. The research highlights the value of patient-reported data in understanding real-world treatment responses, identifying patient subgroups, and guiding the design of future clinical trials. Dr Xiao’s expertise in computational analysis ensures that these complex datasets are translated into actionable insights, supporting the pursuit of improved diagnostics and personalised care for people with ME/CFS and Long COVID. Invest in ME Research Page 36 of 43

Journal of IiMER May 2025 Ola D. Saugstad, University of Oslo, Norway IIMEC17: A Review of Experiences of Treatment Protocols for Severely Affected People with ME Ola D. Saugstad is Professor Emeritus of Pediatrics at the University of Oslo and Research Professor at Oslo University Hospital. He is internationally recognised for his extensive research in neonatology, particularly in the fields of hypoxia, oxygen metabolism, and newborn resuscitation. Over his career, he has published more than 300 scientific articles and book chapters, and has received numerous awards for his contributions to paediatric medicine. In recent years, Professor Saugstad has contributed to research on ME, with a focus on the most severely affected patients. He has co-authored studies investigating genetic associations in ME/CFS, such as the 2022 publication examining the T cell receptor alpha (TRA) locus, which found no replication of previously reported genetic associations in ME/CFS. He has also published commentary on the need for improved recognition and care for young people with ME. At the Severely Affected Clinic in Oslo, Professor Saugstad has been involved in the development and review of treatment protocols for patients with severe ME. His work at this clinic informs his presentation at the Invest in ME Research Conference, where he will review experiences and outcomes related to treatment approaches for this patient group. His recent research and clinical activities reflect a commitment to advancing understanding and care for people with ME, in line with the objectives of Invest in ME Research. Olli Polo, Integrativ Clinic, Sweden IIMEC17: Dysautonomia in ME/CFS - The Role of Sleep Disturbance Olli Polo, MD, PhD, is a Finnish pulmonologist and sleep specialist with lo ngstanding expertise in ME/CFS, currently practising at the Integrativ Clinic in Stockholm, Sweden. He previously served as a professor of pulmonology at Tampere University and has been involved in clinical and research work focused on sleep disorders, autonomic dysfunction, and ME/CFS for over fifteen years. Dr Polo’s research and clinical interests centre on the interplay between the sympathetic nervous system, circadian rhythm disturbances, and tissue hypoxia in ME/CFS. He has published extensively on sleep disorders, including restless leg syndrome and sleep apnoea, and has contributed to the understanding of how sleep disturbance can exacerbate dysautonomia in ME/CFS. Dr Polo also explores the role of connective tissue abnormalities, such as Ehlers-Danlos syndrome, as potential contributors to the disease. His clinical approach includes both established and experimental therapies, such as low-dose naltrexone, supplemental oxygen, saline, vitamin B12, and dopamine agonists, while advising caution Invest in ME Research Page 37 of 43 Journal of IiMER May 2025 with psychiatric medications and certain sleep aids. Dr Polo is known for his patient-centred care and for advocating for improved recognition and treatment of ME/CFS in both clinical and public spheres. At IIMEC17 Dr Polo will draw on his clinical and research experience to discuss how sleep disruption may contribute to autonomic dysfunction in people with ME/CFS. Andrew Wilson, UEA, UK IIMEC17: Clinicians Panel Discussion - Translating Research into Diagnostics and Treatments This panel session will bring together clinicians and clinician-researchers to discuss current issues in the clinical management of ME. The discussion will focus on the challenges of diagnosis, the development and implementation of diagnostic tools, and the translation of research findings into practical treatment approaches. Panel members will share their experiences from clinical practice and research, consider barriers to effective diagnosis and care, and explore how new scientific developments can be integrated into routine clinical work. The session will be moderated by Andrew Wilson of the University of East Anglia, a clinical researcher with expertise in designing and conducting clinical trials and investigations into new treatments and biomarkers in respiratory and related diseases. The panel discussion includes clinicians involved in the colloquium and conference presentations. Eva Untersmayr-Elsenhuber, Medical University of Vienna, Austria IIMEC17 - Austria: Concerted research efforts for ME/CFS Eva Untersmayr-Elsenhuber is Professor at the Centre for Pathophysiology, Infectiology and Immunology at the Medical University of Vienna, where she leads several major research initiatives focused on ME/CFS. Her work is central to Austria’s growing national response to ME/CFS, bringing together multidisciplinary teams and patient organisations to address critical gaps in diagnosis, care, and research. Part of the EMERG group, Professor Untersmayr-Elsenhuber coordinates the “Care for ME/CFS” project, which has produced Austria’s first practical guideline for ME/CFS, based on scientific evidence and patient experience. This guideline aims to improve long-term care by accounting for disease-specific limitations and is freely accessible to clinicians and the public. Her team’s approach actively involves patients in the research process, ensuring that lived experience informs both clinical recommendations and future research priorities. Her recent studies have identified immune system alterations and possible biomarkers in ME/CFS, including differences in immune competence and intestinal barrier function among patient subgroups. These findings suggest that tailored diagnostic and therapeutic strategies may be needed for different groups of ME/CFS patients. Professor Untersmayr-Elsenhuber’s research also addresses the needs of severely and very severely affected individuals, using qualitative methods to understand their care requirements and inform the development of high-level home care and telemonitoring solutions. Invest in ME Research Page 38 of 43

Journal of IiMER May 2025 She is leading the establishment of Austria’s first ME/CFS Biobank, designed to support future research and facilitate international collaboration. Her ongoing projects include investigations into the impact of mast cell activation, the differentiation between ME/CFS and depression, and the assessment of healthcare pathways for post-acute infection syndromes. Austria is becoming one of the most active research hubs for ME and we are delighted that Professor Untersmayr-Elsenhuber will present at IIMEC17 with details of the research landscape emerging in Austria and the practical steps being taken to improve care and scientific understanding of ME/CFS. Jos Bosch, University of Amsterdam, Netherlands IIMEC17 - Netherlands: A Foundational Strategy of Research for ME/CFS Jos Bosch is Associate Professor at the University of Amsterdam and a leading figure in the Netherlands’ national biomedical research strategy for ME/CFS. He coordinates the Dutch ME/CFS Cohort- and Biobank (NMCB) Consortium, a major initiative funded by a ZonMw grant of over seven million euros, which brings together all Dutch university medical centres, patient organisations, and the Ministry of Health to address fundamental questions about ME/CFS: its underlying mechanisms, improved diagnosis, and potential treatments. Under his leadership, the consortium is implementing harmonised research protocols that align with international standards, enabling direct comparison with large cohorts in the UK, Germany, and Canada. This approach is designed to accelerate progress and enhance the quality and impact of Dutch research. The consortium’s work is structured around three themes: outreach, relevance, and clinic, each with dedicated advisory input from patients. At IIMEC17, he will outlining the collaborative, patient-centred approach that is shaping the Dutch research landscape aimed at advancing understanding and care for people with ME/CFS. Etianne Martini Sasso, National Centre for Neuroimmunology and Emerging Diseases (NCNED), Australia IIMEC17 - Neurological and Immunological mechanisms underlying ME: an innovative and multidisciplinary investigation Etianne Martini Sasso will represent Professor Sonya MarshallGradisnik’s group at the National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffith University, Australia, and will speak on the neurological and immunological mechanisms underlying ME. The NCNED research team is recognised for its studies into ion channel dysfunction-particularly the TRPM3 ion channel-in ME and Long COVID. Etianne’s current research focuses on characterising TRPM3 ion channel function in natural killer (NK) cells using advanced patch-clamp Invest in ME Research Page 39 of 43 Journal of IiMER May 2025 electrophysiology. This work has demonstrated impaired TRPM3 activity in NK cells from both ME and post-COVID-19 patients, suggesting shared pathomechanisms between the conditions. Additionally, the team investigates immune cell alterations and neuroimaging findings that reveal impaired brain connectivity and structural changes in ME and Long COVID. These findings are informing new approaches to diagnostic testing and pharmacotherapeutic interventions, with the aim of translating research discoveries into improved clinical care for people with ME and related disorders. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA IIMEC17 - Diagnostic Breakthroughs and Therapeutic Horizons for ME Ron Davis, PhD, is Professor of Biochemistry and Genetics at Stanford School of Medicine and Director of the Stanford Genome Technology Center. He is internationally recognised for his leadership in developing innovative technologies and for his longstanding commitment to advancing research into ME/CFS. Professor Davis’s recent work has focused on identifying reliable diagnostic biomarkers and exploring new therapeutic avenues for ME/CFS. His team developed the “nanoneedle” diagnostic platform, which distinguishes ME/CFS patients from healthy controls by measuring changes in the electrical properties of blood cells exposed to stress. This technology has shown high accuracy in early studies and is now being tested in larger cohorts to confirm its utility as a clinical diagnostic tool. The platform is also being used to screen potential drug treatments by observing whether candidate compounds can normalise the abnormal cellular responses seen in ME/CFS samples. In addition to the nanoneedle, Professor Davis’s group has pioneered a neutrophil assessment platform, revealing that neutrophils from ME/CFS patients move more slowly than those from healthy individuals. This work is ongoing and may yield further diagnostic markers. His research has also highlighted the role of factors in blood plasma that may drive the illness, with ongoing investigations into possible infectious or metabolic contributors. Professor Davis collaborates widely with international research teams and is involved in developing animal models to study disease mechanisms and test therapeutic candidates. At IIMEC17, he will summarise progress in biomarker discovery, the development of new diagnostic tools, and early results from therapeutic screening. His work is closely aligned with the goals of Invest in ME Research, aiming to accelerate the path toward effective diagnosis and treatment for ME/CFS. He is a world leader in biotechnology, especially in recombinant DNA and genomic methods applied to biological systems. As Director of the Stanford Genome Technology Center, he focuses on integrating nano-fabricated solid-state devices with biology. His team develops innovative genetic and molecular technologies for a range of organisms, including humans, setting standards in clinical genomics. Invest in ME Research Page 40 of 43

Journal of IiMER May 2025 Journal of IiMER May 2025

Journal of IiMER May 2025

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