Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling condition affecting millions of adults and children worldwide. Despite the development of multiple criteria sets for defining this disorder, agreement on the core symptoms and other implications of ME/CFS point to the importance of understanding their role in oral health care. Overall, care for the homebound and bedbound population with ME/CFS issues has been under-addressed in the literature to date and there has been little consideration of the oral health needs of this population. Evaluation, diagnosis and treatment of dental concerns may be hindered by many of the diverse symptoms of ME/CFS. The present paper utilizes the International Consensus Criteria (ICC) in discussing treatment considerations for the most severely affected patients with ME/CFS, both in oral evaluation and active care. While no specific dental pathology is linked to ME/CFS, proper care for the patient so affected must take into account the disorder’s symptoms and severity.

The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published in October 2021, makes significant changes in treatment recommendations. It acknowledges the complexity of this chronic medical condition, which always impacts quality of life and can be profoundly disabling, recognising the prejudice and stigma that people with ME/CFS often experience in the absence of any specific diagnostic test. The guideline outlines steps for accurate diagnosis, recognising post-exertional malaise as a core symptom; importantly, ME/CFS can now be diagnosed after just 3 months in a bid to improve long-term health outcomes. It recommends the need for individual, tailored management by a multi-disciplinary team, ensuring that the wellbeing of the individual is paramount. The guideline makes clear that any programme based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered as a treatment for ME/CFS and emphasises that cognitive behavioural therapy (CBT) should only be offered as a supportive intervention. Because of the rigorous methodology required by NICE Committee review and the inclusion of the testimony of people with lived experience as committee members, this guideline will influence the future diagnosis and management of ME/CFS in the UK and beyond.

Application of protocols without parameter standardization and rigorous controls has led manual therapy (MT) and other physiotherapy approaches to controversial outcomes. Thus, there is an urgency to carefully define standard protocols that elevate physiotherapy treatments to rigorous scientific demands. One way this can be achieved is by studying gene expression and additional physiological changes that associate to particular, parameter-controlled, treatments in animal models and translating this knowledge to properly design objective, quantitatively-monitored clinical trials. Here, we propose a Molecular Physiotherapy Approach (MPTA), requiring multidisciplinary teams, to uncover the scientific reasons behind the numerous reports of MT that historically attribute benefits to these treatments. The review focuses in the identification of MT-induced physiological and molecular responses that could be used for the treatment of fibromyalgia (FM) and CFS/ME. The systemic effect associated to mechanical-load responses is considered of particular relevance as it suggests that defined, low-pain areas could be selected for treatments with overall benefits, an aspect that might result essential to treat FM. Additionally, MT can provide muscle conditioning to sedentary patients without demanding strenuous physical effort, detrimental for CFS/ME patients, placing MT as a real option for integrative medicine programs to treat FM and CFS/ME.

We propose a framework for the understanding of the pathophysiology and management of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to an insult, or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune and autonomic manifestations, underlined by a hyper-metabolic state, that characterise early disease, may be followed by various processes leading to multi-systemic related symptoms. This abnormal metabolic state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiralling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. Disease management and research efforts should seek to identify and apply strategies targeted at the different pathophysiological dysfunctions that characterise different disease stages. As disease presentation varies over time, no single case description, set of diagnostic criteria, or molecular feature is currently diagnostic for all patients at all times. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may improve research design and health care interventions for people with ME/CFS.

Fibromyalgia (FM) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are diseases of unknown etiology presenting complex and often overlapping symptomatology. Despite promising advances on the study of miRNomes of these diseases, no validated molecular diagnostic biomarker yet exists. Since FM and ME/CFS patient treatments commonly include polypharmacy it is of concern that biomarker miRNAs are masked by drug interactions. Aiming at discriminating between drug-effects and true disease-associated differential miRNA expression, we evaluated the potential impact of commonly prescribed drugs on disease miRNomes, as reported by the literature. By using the web search tools SM2miR, Pharmaco-miR and repoDB, we found a list of commonly prescribed drugs that impact on FM and ME/CFS miRNomes and therefore could be interfering in the process of biomarker discovery. On another end, disease-associated miRNomes may incline patient´s response to treatment and toxicity. Here, we explored treatments for diseases in general that could be affected by FM and ME/CFS miRNomes finding a long list of them, including treatments for lymphoma, a type of cancer affecting ME/CFS patients at a higher rate than healthy population. We conclude that FM and ME/CFS miRNomes could help refine pharmacogenomic/pharmacoepigenomic analysis to elevate future personalized medicine and precision medicine programs in the clinic.

Understanding the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that herpesviruses' infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment – symptoms consistent with ME/CFS and Long COVID. The paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within ECs of ME/CFS patients. This review offers a conceptual advance by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research towards potentially unexplored avenues in understanding and treating this complex syndrome.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is an acquired disease with significant morbidity that affects both children and adults. Effective tools to assess functional capacity (FC) are severely lacking which has significant consequences for timely diagnosis, assessments for patient disability benefits and assessing the impact and effectiveness of interventions. In interventional research the inability to assess FC can result in an incomplete assessment of the potential effect of the intervention. Specifically of concern is that if an intervention is effective in reducing symptom load, patients may increase their activity level to reach a pre-intervention symptom load. Thus, if FC is not accurately assessed, beneficial treatment outcomes may be missed. To address this issue, using extensive, repeated patient feedback we have developed a new questionnaire, FUNCAP, to achieve optimal FC assessment in ME/CFS patients. The questionnaire covers eight domains and activity types: A. Personal hygiene / basic functions, B. Walking / movement, C. Being upright, D. Activities in the home, E. Communication, F. Activities outside the home, G. Reactions to light and sound, and H. Concentration. Through five rounds of anonymous web-based surveys and a further test - retest validation round, two versions of the questionnaire were developed; a longer version comprising 55 questions (FUNCAP55) to improve diagnostic and disability benefit/ insurance FC assessments and a shorter version (FUNCAP27) for interventional research and less extensive FC assessments. FUNCAP may also be useful in other conditions where fatigue and PEM is present, such as Long Covid.

Background and Objectives The socioeconomics working group of the European ME/CFS Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs’ knowledge and understanding of ME/CFS. Materials and Methods A MEDLINE search was carried out. The papers identified were reviewed following the Synthesis Without Meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature. Results 33 papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades. Conclusions Lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.

The European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) was established after a successful grant application to the European Cooperation is Science and Technology (COST). This network aimed to assess the existing knowledge and/or experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the European countries and worldwide, and to enhance coordinated research and health care provision in this field. The EUROMENE proposal, was based on the establishment of interrelated working groups (WGs), where the participants contributed with specific knowledge and viewpoints according to their specialties and/or areas of interest. In this paper we outline the work of a multidisciplinary team of researchers, including epidemiologists, clinicians, statisticians, biomedical scientist and heath economists, who set out their recommendations to guide data acquisition for ME/CFS research, aiming to standardise data collection and improve epidemiological research.

This study leverages the relationships between the Great Plains low-level jet (GP-LLJ) and the circumglobal teleconnection (CGT) to enhance the 30-day rainfall forecast skill in the Northern Great Plains (NGP). The assessment of 30-day simulated precipitation using the Climate Forecast System (CFS) is contrasted with the North American Regional Reanalysis, searching for sources of precipitation predictability associated with extended wet and drought events. We analyze the 30-day sources of precipitation predictability using (1) the characterization of dominant statistical modes of variability of 900-mb winds associated with the GP-LLJ, (2) the large-scale atmospheric patterns based on 200-mb geopotential height (HGT), and (3) the use of GP-LLJ and CGT conditional probability distributions using a continuous correlation threshold approach to identify when and where the forecast of NGP precipitation occurs. Two factors contributing to the predictability of precipitation in the NGP are documented. We found that multi-scale geospatial interactions occur at the daily and sub-seasonal time windows. The CFS reforecast suggests that the ability to forecast sub-seasonal precipitation increases in response to the enhanced simulation of the GP-LLJ and CGT. Finally, the multi-dimensional analysis of covariance reveals that high-precipitation forecasting skill is associated with a better prognostic of GP-LLJ and CGT.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood monocytic cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase TORC1. These differences were correlated with disease severity, as measured by the Richardson and Lidbury Weighted Standing Test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and Receiver Operating Characteristic (ROC) curve analysis. We found that results from three different tests, lymphocyte death rate, mitochondrial respiratory function and TORC1 activity could each individually serve as biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.

Current pharmacological treatments of Fibromyalgia (FM) are merely symptom palliative, as clinical trials have so far failed to provide overall benefits without associated harms. Polypharmacy often leads to patient´s health deterioration and chronic drug use to an eventual lack of patient´s response. Emerging evidence support that physiotherapy treatments based on mechanical triggers improve FM symptoms and therefore could be used for therapeutic purposes by themselves, or in combination with current pharmacological treatments, as part of integrative medicine programs. However, a paucity of studies rigorously and systematically evaluating this possibility exists. This study uses scores from validated standardized questionnaires, algometer pressure point threshold (PPT) readings and responses from a custom self-developed questionnaire to determine the impact of a pressure-controlled manual protocol on FM hyperalgesia/allodynia, fatigue and patient´s quality of life. The results show that patient´s baseline sensitivity to pain inversely correlates with treatment response in FM. Moreover, patients presenting comorbid ME/CFS do not seem to respond to the applied therapy as those presenting FM only. Thus, pre-treatment PPTs and ME/CFS comorbidity may serve as indicators to predict patient´s response to physiotherapy programs based on mechanical triggers, as the one evaluated here. These unexpected findings grant further explorations including the study of gene expression profiles associating to patient´s treatment response in the blood collection of samples generated by this study.

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Gulf War Ill-ness (GWI) and control subjects had fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction Methods: Activated midbrain nuclei were inferred by re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI had greater activation during cognition than ME/CFS in left pedunculotegmental nucleus. Postexercise ME/CFS had greater activation than GWI for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI indicating reciprocal patterns of activation. Controls had no changes. Conclusions: Exercise caused opposite effects with increased activation in ME/CFS but decreased activation in GWI indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

Background and objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS is a common complex multi-system disease with a significant impact on the quality of life of patients and their families, yet the majority of ME/CFS patients go unrecognised or undiagnosed. For two decades the medical education establishment in the UK has been challenged to remedy these failings, but little has changed. This study was designed to ascertain the current UK medical school education on ME/CFS and to identify challenges and opportunities to inform the future of medical education. Materials and methods: A questionnaire, developed under the guidance of the Medical Schools Council, was sent to all 34 UK Medical Schools to collect data for the academic year 2018-2019. Results: Responses were provided by 22 out of a total of 34 medical schools (65%). 59% of respondents taught ME/CFS, led by specialists drawn from 6 medical disciplines. Teaching delivery was usually by lecture; however, discussion case studies and e-learning were used. 7 schools included questions on ME/CFS in their examinations and 3 schools reported likely clinical exposure to ME/CFS patients. 64% of respondents were interested in receiving further teaching aids in ME/CFS. None of the schools shared details of their teaching syllabus so it was not possible to ascertain what students were being taught. Conclusions: UK medical school teaching in ME/CFS is shown to be inadequate. Several medical disciplines, with known differences about the disease, need to set these aside to give greater clarity in teaching undergraduates so they can more easily recognise and diagnose ME/CFS. Improvements are proposed in ME/CFS medical education consistent with the international paradigm shift in biomedical understanding of this disease. Many medical schools (64% of respondents) acknowledge this need by expressing a strong appetite for the development of further teaching aids and materials. The GMC and MSC are called upon to use their considerable influence to bring about the appropriate changes to medical school curricula so future doctors can recognise, diagnose and treat ME/CFS. The GMC should also consider creating a registered speciality encompassing ME/CFS, post viral fatigue and Long Covid.

The development of nucleic acid sequencing technology and the unprecedented availability of metadata has evidenced that 45% of human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically needed. Aberrant regulation of TEs, and of human retroviral endogenous sequences (HERVs) in particular, associates with several neurologic and autoimmune diseases, including the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) frequently comorbid with fibromyalgia (FM). However, no study has yet addressed whether abnormal expression of these sequences correlates with FM. The work presented here shows, for the first time, that in fact HERVs of the H, K and W types are overexpressed in the cells of the immune system of FM patients with or without comorbid ME/CFS. The patients with increased HERV expression (N=14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. In support of our proposal that TE activation is a contributor to FM, we find that the tRNA pools are decreased in comparison to matched healthy participants (N=14). The findings reported here could explain the flu-like symptoms FM patients present with in the absence of concomitant infections. Future work towards identifying specific genomic loci differentially affected in FM and ME/CFS is granted.