Do people with ME/CFS and joint hypermobility represent a disease subgroup? An analysis using registry data.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multifaceted disease that affects millions globally. Despite its significant impact, the disease's etiology remains poorly understood, and symptom heterogeneity poses challenges for diagnosis and treatment. Joint hypermobility, commonly seen in hypermobile Ehlers-Danlos Syndrome (hEDS), has been observed in ME/CFS patients but its prevalence and clinical significance within this population are not well-characterized. Objective: To compare the characteristics of ME/CFS patients with and without joint hypermobility (JH+ and JH-) as assessed using the Beighton scoring system, and to explore whether JH+ ME/CFS patients exhibit distinct disease characteristics, comorbidities, and health-related quality of life (HRQOL). Methods: The study used cross-sectional, self-reported data from 815 participants of the You + ME Registry. Participants were categorized as JH+ or JH- based on self-assessed Beighton scores and compared across demographics, comorbidities, family history, and symptoms. HRQOL was assessed using the Short Form-36 RAND survey and Karnofsky Performance Status. Results: 15.5% (N = 126) of participants were classified as JH+. JH+ participants were more likely to be female, report Ehlers-Danlos Syndrome (EDS), Postural Orthostatic Tachycardia Syndrome (POTS), and a family history of EDS. They experienced worse HRQOL, particularly in physical functioning and pain, and a higher number of autonomic, neurocognitive, headache, gut, and musculoskeletal symptoms. Sensitivity analysis suggested that ME/CFS with concurrent JH+ and EDS was associated with more severe symptoms and greater functional impairment. Conclusion: ME/CFS patients with joint hypermobility, particularly those with EDS, demonstrate distinct clinical characteristics, including more severe symptomatology and reduced HRQOL. These findings highlight the need for comprehensive clinical assessments of ME/CFS patients with joint hypermobility. Understanding these relationships could aid in subgroup identification, improving diagnosis, and informing targeted therapeutic approaches. Further research is warranted to explore these associations and their implications for clinical practice.

Correction: The Facilitation of Clinical and Therapeutic Discoveries in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Related Diseases: Protocol for the You + ME Registry Research Platform.

[This corrects the article DOI: .].

Correction: Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0265765.].

The Facilitation of Clinical and Therapeutic Discoveries in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Related Diseases: Protocol for the You + ME Registry Research Platform.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex, heterogeneous disease that affects millions and lacks both diagnostics and treatments. Big data, or the collection of vast quantities of data that can be mined for information, have transformed the understanding of many complex illnesses, such as cancer and multiple sclerosis, by dissecting heterogeneity, identifying subtypes, and enabling the development of personalized treatments. It is possible that big data can reveal the same for ME/CFS. OBJECTIVE: This study aims to describe the protocol for the You + ME Registry, present preliminary results related to participant enrollment and satisfaction, and discuss the limitations of the registry as well as next steps. METHODS: We developed and launched the You + ME Registry to collect longitudinal health data from people with ME/CFS, people with long COVID (LC), and control volunteers using rigorous protocols designed to harmonize with other groups collecting data from similar groups of people. RESULTS: As of September 30, 2021, the You + ME Registry had over 4200 geographically diverse participants (3033/4339, 69.9%, people with ME/CFS; 833/4339, 19.2%, post-COVID-19 people; and 473/4339, 10.9%, control volunteers), with an average of 72 new people registered every week. It has qualified as "great" using a net promotor score, indicating registrants are likely to recommend the registry to a friend. Analyses of collected data are currently underway, and preliminary findings are expected in the near future. CONCLUSIONS: The You + ME Registry is an invaluable resource because it integrates with a symptom-tracking app, as well as a biorepository, to provide a robust and rich data set that is available to qualified researchers. Accordingly, it facilitates collaboration that may ultimately uncover causes and help accelerate the development of therapies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04806620; https://clinicaltrials.gov/ct2/show/NCT04806620. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36798.

Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study.

BACKGROUND: Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned. METHODS AND FINDINGS: A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible. CONCLUSIONS: UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.

A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

We propose a framework for the treatment, rehabilitation, and research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using a natural history of disease approach to outline the distinct disease stages, with an emphasis on cases following infection to provide insights into prevention. Moving away from the method of subtyping patients based on the various phenotypic presentations and instead reframing along the lines of disease progression could help with defining the distinct stages of disease, each of which would benefit from large prospective cohort studies to accurately describe the pathological mechanisms taking place therein. With a better understanding of these mechanisms, management and research can be tailored specifically for each disease stage. Pre-disease and early disease stages call for management strategies that may decrease the risk of long-term morbidity, by focusing on avoidance of further insults, adequate rest to enable recovery, and pacing of activities. Later disease stages require a more holistic and tailored management approach, with treatment-as this becomes available-targeting the alleviation of symptoms and multi-systemic dysfunction. More stringent and standardised use of case definitions in research is critical to improve generalisability of results and to create the strong evidence-based policies for management that are currently lacking in ME/CFS.

How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS.

We propose a framework for understanding and interpreting the pathophysiology 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 singular 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 manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal 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 spiraling 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. With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.

Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology.

This review aimed at determining the prevalence and incidence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe. We conducted a primary search in Scopus, PubMed and Web of Science for publications between 1994 and 15 June 2019 (PROSPERO: CRD42017078688). Additionally, we performed a backward-(reference lists) and forward-(citations) search of the works included in this review. Grey literature was addressed by contacting all members of the European Network on ME/CFS (EUROMENE). Independent reviewers searched, screened and selected studies, extracted data and evaluated the methodological and reporting quality. For prevalence, two studies in adults and one study in adolescents were included. Prevalence ranged from 0.1% to 2.2%. Two studies also included incidence estimates. In conclusion, studies on the prevalence and incidence of ME/CFS in Europe were scarce. Our findings point to the pressing need for well-designed and statistically powered epidemiological studies. To overcome the shortcomings of the current state-of-the-art, EUROMENE recommends that future research is better conducted in the community, reviewing the clinical history of potential cases, obtaining additional objective information (when needed) and using adequate ME/CFS case definitions; namely, the Centers for Disease Control & Prevention-1994, Canadian Consensus Criteria, or Institute of Medicine criteria.

Non-communicable diseases in sub-Saharan Africa: a scoping review of large cohort studies.

BACKGROUND: Non-communicable diseases (NCDs) cause a large and growing burden of morbidity and mortality in sub-Saharan Africa. Prospective cohort studies are key to study multiple risk factors and chronic diseases and are crucial to our understanding of the burden, aetiology and prognosis of NCDs in SSA. We aimed to identify the level of research output on NCDs and their risk factors collected by cohorts in SSA. METHODS: We conducted a scoping review to map the extent of current NCDs research in SSA by identifying studies published after the year 2000 using prospectively collected cohort data on any of the six NCDs (cardiovascular diseases, diabetes, obesity, chronic kidney disease, chronic respiratory diseases, and cancers), ≥1 major risk factor (other than age and sex), set only within SSA, enrolled ≥500 participants, and ≥12 months of follow-up with ≥2 data collection points (or with plans to). We performed a systematic search of databases, a manual search of references lists from included articles and the INDEPTH network website, and study investigators from SSA were contacted for further articles. RESULTS: We identified 30 cohort studies from the 101 included articles. Eighteen countries distributed in West, Central, East and Southern Africa, were represented. The majority (27%) set in South Africa. There were three studies including children, twenty with adults, and seven with both. 53% of cohorts were sampled in general populations, 47% in clinical populations, and 1 occupational cohort study. Hypertension (n = 23) was most commonly reported, followed by obesity (n = 16), diabetes (n = 15), CKD (n = 6), COPD (n = 2), cervical cancer (n = 3), and breast cancer (n = 1). The majority (n = 22) reported data on at least one demographic/environmental, lifestyle, or physiological risk factor but these data varied greatly. CONCLUSIONS: Most studies collected data on a combination of hypertension, diabetes, and obesity and few studies collected data on respiratory diseases and cancer. Although most collected data on different risk factors the methodologies varied greatly. Several methodological limitations were found including low recruitment rate, low retention rate, and lack of validated and standardized data collection. Our results could guide potential collaborations and maximize impact to improve our global understanding of NCDs (and their risk factors) in SSA and also to inform future research, as well as policies.

Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity. We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L). The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02-0.15) compared to controls, and OR = 0.16 (95% CI = 0.07-0.40), compared to mild cases). This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.

The UK ME/CFS Biobank: A Disease-Specific Biobank for Advancing Clinical Research Into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized by unexplained incapacitating fatigue, accompanied by variable multi-systemic symptoms. ME/CFS causes a significant personal and public health burden, and urgently requires the coordination of research efforts to investigate its etiology and pathophysiology and to develop and validate sensitive and specific biomarkers to confirm diagnosis. This narrative paper describes how people with ME/CFS, together with a multidisciplinary team of researchers, have established the UK ME/CFS Biobank (UKMEB), a unique research infrastructure specifically designed to expedite biomedical research into ME/CFS. We describe the journey that led to its conceptualization and operation, and how the resource has served as a model disease-specific biobank, aggregating human biospecimens alongside comprehensive health information on participants. The UKMEB currently has data and samples from 600 donors including people with ME/CFS and a comparison group with multiple sclerosis and healthy controls. A longitudinal sub-cohort has been established of participants having follow-up assessments at multiple time-points. As an open resource for quality and ethical research into ME/CFS, biological samples and data have not only been analyzed within our research team but have also been shared with researchers across Europe, America and the Middle East. We continue to encourage researchers from academic and commercial sectors to access the UKMEB. Major steps have been taken and challenges remain; these include sustainability and expansion, and harmonization of processes to facilitate integration with other bioresources and databanks internationally.

Hand Grip Strength as a Clinical Biomarker for ME/CFS and Disease Severity.

Background: The diagnosis of myalgic encephalomyelitis (ME/CFS) in research and clinical practice has largely relied on clinical history, which can be subjective in nature. Clinical signs are often subtle, overlap with other conditions, and are not formally included as part of diagnostic workup. The characterization of clinical signs and biomarkers is needed for better diagnosis and classification of patients and to monitor treatment response. Hand grip strength (HGS) has been used as an objective measure of muscle strength and fatigue, which is a primary symptom of ME/CFS. We assessed the potential usefulness of HGS as a diagnostic marker in ME/CFS. Methods: We compared HGS measurements from participants in the UK ME/CFS Biobank, with groups consisting of people with ME/CFS of differing severity (n = 272), healthy (n = 136), multiple sclerosis (n = 76) controls, and others with chronic fatigue not meeting the diagnosis of ME/CFS (n = 37). We correlated the maximum and minimum of, and differences between, 3 repeated HGS measurements with parameters of disease severity, including fatigue and pain analog scales, and physical and mental component summaries from the SF-36v2TM questionnaire across recruitment groups. Results: HGS indicators were associated with having ME/CFS, with magnitudes of association stronger in severely affected than in mild/moderately affected patients. Compared with healthy controls, being severely affected was associated with a reduction in minimum HGS of 15.3 kg (95%CI 19.3-11.3; p < 0.001), while being mild/moderately affected was associated with a 10.5 kg (95%CI 13.2-7.8; p < 0.001) reduction. The association persisted after adjusting for age, sex and body mass index. ME/CFS cases also showed lower values of maximum HGS and significant drops in values from the first to second and third trials, compared to other study groups. There were significant correlations between HGS indicators and clinical parameters of disease severity, including fatigue analog scale (Spearman's Rho = -0.40, p < 0.001), pain analog scale (Rho = -0.38, p < 0.001), and physical component summary (Rho = 0.42, p < 0.001). Discussion: HGS is markedly reduced in ME/CFS, particularly in patients with more severe disease, and may indicate muscle and fatigue related symptoms. HGS is a potential diagnostic tool in ME/CFS, and could also be used to enhance patient phenotyping and as an outcome measure following interventions.

How does the association of general and central adiposity with glycaemia and blood pressure differ by gender and area of residence in a Malawian population: a cross-sectional study.

BACKGROUND: In high-income settings, body mass index (BMI) and measures of central adiposity, such as waist-to-hip ratio (WHR) are associated with cardiometabolic risk, but evidence from low-income settings, particularly sub-Saharan Africa (SSA), is limited. We assessed whether there are differences between central and general adiposity in their associations with fasting glucose, diabetes, systolic and diastolic blood pressures and hypertension, and whether these associations differ with gender or rural/urban setting in Malawi. METHODS: We used data from a population-based study of 27 880 Malawian adults aged ≥18 years, from both rural and urban areas. We used age-standardized z-scores of the means of BMI and WHR to directly compare their associations with glycaemic and blood pressure outcomes. RESULTS: Mean fasting glucose and blood pressure values and odds of hypertension increased linearly across fifths of BMI and WHR, with stronger associations with BMI. For both BMI and WHR, the associations with outcomes were stronger in urban versus rural residents. The association with diabetes was stronger in women than men, whereas for blood-pressure related outcomes a stronger association was seen in men. CONCLUSIONS: BMI is more strongly associated with cardiometabolic risk in SSA, and might be a more useful measure than WHR, in this population. The greater positive association of adiposity with cardiometabolic outcomes in urban residents (where rates of overweight/obesity are already high) highlights the particular importance of addressing obesity within urban SSA populations.