Sex and disease severity-based analysis of steroid hormones in ME/CFS.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and decreased daily activity following physical and/or cognitive exertion. While ME/CFS affects both sexes, there is a higher prevalence in women. However, studies evaluating this sex-related bias are limited. METHODS: Circulating steroid hormones, including mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone), were measured in plasma samples using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Samples were obtained from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17). RESULTS: After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm, and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC). In addition, female ME/CFSmm showed a significant increase in progesterone levels compared to HC. In contrast, our study found that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively. CONCLUSION: Our findings suggest the potential value of including steroid hormones in future studies aimed at improving stratification in ME/CFS. Additionally, our results provide new perspectives to explore the clinical relevance of these differences within specific patient subgroups.

Videoconference-delivered group Cognitive Behavioral Stress Management for ME/CFS patients who present with severe PEM: A randomized controlled trial.

Background: In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), post-exertional malaise (PEM) is associated with greater distress and symptoms. Cognitive Behavioral Stress Management (CBSM) has demonstrated beneficial effects for ME/CFS and may mitigate stress-related triggers of PEM. We tested a virtual CBSM intervention to increase access, and we report on its effects on stress and symptoms in ME/CFS patients with severe PEM. Methods: Data were from a randomized controlled trial (NCT01650636) comparing 10-week videoconference-delivered group CBSM (V-CBSM, n=75) to a 10-week Health Information active control (V-HI, n=75) in Fukuda criteria ME/CFS patients (71 classified as highPEM, 79 lowPEM). Linear regression explored PEM-by-Treatment interactions on overall symptom frequency and intensity, perceived stress, and fatigue-specific interference and intensity, at 5-month follow-up. Logistic regression tested V-CBSM effects on 5-month PEM status. Analyses controlled for age, gender, race/ethnicity, mode of symptom onset, and time since diagnosis. Results: The sample was middle-aged (47.96±10.89 years), mostly women (87%) and non-Hispanic White (65%), with no group differences on these variables or baseline PEM. For highPEM patients, V-CBSM (versus V-HI) demonstrated medium to large effects on follow-up symptom frequency, symptom intensity, fatigue interference, and fatigue intensity (p's < .05) and trending to significant reductions in perceived stress (p =.07). Differences were not evident for lowPEM patients. Treatment predicted follow-up PEM status at a trend (p = .058), with patients receiving V-CBSM demonstrating half the risk of highPEM classification versus V-HI. Conclusions: V-CBSM demonstrates benefits for ME/CFS patients presenting with severe PEM and may reduce the expression of PEM over time.

Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function. The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome. In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.

Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus 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. This 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 the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.

Development of an expert system for the classification of myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition with an uncertain origin and a dismal prognosis. There is presently no precise diagnostic test for ME/CFS, and the diagnosis is determined primarily by the presence of certain symptoms. The current study presents an explainable artificial intelligence (XAI) integrated machine learning (ML) framework that identifies and classifies potential metabolic biomarkers of ME/CFS. Metabolomic data from blood samples from 19 controls and 32 ME/CFS patients, all female, who were between age and body mass index (BMI) frequency-matched groups, were used to develop the XAI-based model. The dataset contained 832 metabolites, and after feature selection, the model was developed using only 50 metabolites, meaning less medical knowledge is required, thus reducing diagnostic costs and improving prognostic time. The computational method was developed using six different ML algorithms before and after feature selection. The final classification model was explained using the XAI approach, SHAP. The best-performing classification model (XGBoost) achieved an area under the receiver operating characteristic curve (AUCROC) value of 98.85%. SHAP results showed that decreased levels of alpha-CEHC sulfate, hypoxanthine, and phenylacetylglutamine, as well as increased levels of N-delta-acetylornithine and oleoyl-linoloyl-glycerol (18:1/18:2)[2], increased the risk of ME/CFS. Besides the robustness of the methodology used, the results showed that the combination of ML and XAI could explain the biomarker prediction of ME/CFS and provided a first step toward establishing prognostic models for ME/CFS.

Machine learning algorithms for detection of visuomotor neural control differences in individuals with PASC and ME.

The COVID-19 pandemic has affected millions worldwide, giving rise to long-term symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) infection, colloquially referred to as long COVID. With an increasing number of people experiencing these symptoms, early intervention is crucial. In this study, we introduce a novel method to detect the likelihood of PASC or Myalgic Encephalomyelitis (ME) using a wearable four-channel headband that collects Electroencephalogram (EEG) data. The raw EEG signals are processed using Continuous Wavelet Transform (CWT) to form a spectrogram-like matrix, which serves as input for various machine learning and deep learning models. We employ models such as CONVLSTM (Convolutional Long Short-Term Memory), CNN-LSTM, and Bi-LSTM (Bidirectional Long short-term memory). Additionally, we test the dataset on traditional machine learning models for comparative analysis. Our results show that the best-performing model, CNN-LSTM, achieved an accuracy of 83%. In addition to the original spectrogram data, we generated synthetic spectrograms using Wasserstein Generative Adversarial Networks (WGANs) to augment our dataset. These synthetic spectrograms contributed to the training phase, addressing challenges such as limited data volume and patient privacy. Impressively, the model trained on synthetic data achieved an average accuracy of 93%, significantly outperforming the original model. These results demonstrate the feasibility and effectiveness of our proposed method in detecting the effects of PASC and ME, paving the way for early identification and management of the condition. The proposed approach holds significant potential for various practical applications, particularly in the clinical domain. It can be utilized for evaluating the current condition of individuals with PASC or ME, and monitoring the recovery process of those with PASC, or the efficacy of any interventions in the PASC and ME populations. By implementing this technique, healthcare professionals can facilitate more effective management of chronic PASC or ME effects, ensuring timely intervention and improving the quality of life for those experiencing these conditions.

Personalized Management of Fatigue in Individuals With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Using a Smart Digital mHealth Solution: Protocol for a Participatory Design Approach.

BACKGROUND: Fatigue is the most common symptom in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID, impacting patients' quality of life; however, there is currently a lack of evidence-based context-aware tools for fatigue self-management in these populations. OBJECTIVE: This study aimed to (1) address fatigue in ME/CFS and long COVID through the development of digital mobile health solutions for self-management, (2) predict perceived fatigue severity using real-time data, and (3) assess the feasibility and potential benefits of personalized digital mobile health solutions. METHODS: The MyFatigue project adopts a patient-centered approach within the participatory health informatics domain. Patient representatives will be actively involved in decision-making processes. This study combines inductive and deductive research approaches, using qualitative studies to generate new knowledge and quantitative methods to test hypotheses regarding the relationship between factors like physical activity, sleep behaviors, and perceived fatigue in ME/CFS and long COVID. Co-design methods will be used to develop a personalized digital solution for fatigue self-management based on the generated knowledge. Finally, a pilot study will evaluate the feasibility, acceptance, and potential benefits of the digital health solution. RESULTS: The MyFatigue project opened to enrollment in November 2023. Initial results are expected to be published by the end of 2024. CONCLUSIONS: This study protocol holds the potential to expand understanding, create personalized self-management approaches, engage stakeholders, and ultimately improve the well-being of individuals with ME/CFS and long COVID. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50157.

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.

BACKGROUND: Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. METHODS: This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10 min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. RESULTS: Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1ß (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. CONCLUSIONS: Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions.

Impaired Hand Grip Strength Correlates with Greater Disability and Symptom Severity in Post-COVID Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Background: Post-COVID syndrome (PCS) encompasses a diverse array of symptoms persisting beyond 3 months after acute SARS-CoV-2 infection, with mental as well as physical fatigue being the most frequent manifestations. Methods: In 144 female patients with PCS, hand grip strength (HGS) parameters were assessed as an objective measure of muscle fatigue, with 78 meeting the Canadian Consensus Criteria for postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The severity of disability and key symptoms was evaluated using self-reported questionnaires. Results: Patients with ME/CFS exhibited heightened overall symptom severity, including lower physical function (p < 0.001), a greater degree of disability (p < 0.001), more severe fatigue (p < 0.001), postexertional malaise (p < 0.001), and autonomic dysfunction (p = 0.004) compared to other patients with PCS. While HGS was impaired similarly in all patients with PCS and exhibited a significant correlation with physical function across the entire patient group, HGS of patients with ME/CFS uniquely demonstrated associations with key symptoms. Conclusions: Thus, impaired HGS serves as an objective marker of physical function in patients with PCS. Only in patients meeting ME/CFS criteria is impaired HGS also associated with the severity of hallmark symptoms. This suggests a common mechanism for muscle fatigue and other symptoms in the ME/CFS subtype, distinct from that in other types of PCS.

Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics.

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity. Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic. Results: We found few statistically significant and no clinically significant differences between clinics in their patients' standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures. Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case-control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms.

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders.

Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

The Head-Up Tilt Table Test as a Measure of Autonomic Functioning among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often experience autonomic symptoms. In the present study, we evaluated 193 adults seeking treatment for ME/CFS, who were recruited from an outpatient clinic. The participants completed a head-up tilt table test to assess two common types of orthostatic intolerance, namely, postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH). During the tilt test, 32.5% of the participants demonstrated POTS or OH. The participants with either of these two common types of orthostatic intolerance were found to have more problems with sleep and post-exertional malaise as assessed by the DePaul Symptom Questionnaire; these patients also reported more physical and health function limitations. The implications of the findings are discussed.

IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS).

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. METHODS: In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. DISCUSSION: Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. TRIAL REGISTRATION: Registration Number: NCT05710770 . Registered on 02 February 2023.

Clinical evidence of the link between gut microbiome and myalgic encephalomyelitis/chronic fatigue syndrome: a retrospective review.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous disorder with elusive causes, but most likely because of clinical and other biological factors. As a vital environmental factor, the gut microbiome is increasingly emphasized in various refractory diseases including ME/CFS. The present study is aimed to enhance our understanding of the relationship between the gut microbiome and ME/CFS through data analysis of various clinical studies. We conducted a literature search in four databases (PubMed, Cochrane Library, Web of Science, and Google Scholar) until May 31, 2023. Our analysis encompassed 11 clinical studies with 553 ME/CFS patients and 480 healthy controls. A comparative analysis of meta data revealed a significant decrease in α-diversity and a noticeable change in ß-diversity in the gut microbiome of ME/CFS patients compared to healthy controls. The notable ratio of Firmicutes and Bacteroides was 2.3 times decreased, and also, there was a significant reduction in the production of microbial metabolites such as acetate, butyrate, isobutyrate, and some amino acids (alanine, serine, and hypoxanthine) observed in ME/CFS patients. The lack of comparison under similar conditions with various standardized analytical methods has impeded the optimal calculation of results in ME/CFS patients and healthy controls. This review provides a comprehensive overview of the recent advancements in understanding the role of the gut microbiome in ME/CFS patients. Additionally, we have also discussed the potentials of using microbiome-related interventions and associated challenges to alleviate ME/CFS.

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.

Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome.

Background: Fatigue of unknown origin is a hallmark symptom in chronic fatigue syndrome (CFS) and is also found in 20% of hypothyroidism patients despite appropriate levothyroxine treatment. Here, we suggest that in these disorders, peripheral serotonin levels are low, and elevating them to normal range with L-carnitine is accompanied with reduced fatigue. Methods: We conducted a retrospective analysis of follow-up clinical data (CFS N=12; hypothyroidism with fatigue N=40) where serum serotonin and fatigue levels were compared before vs. after 7 weeks of oral L-carnitine supplementation. Results: After L-carnitine, serotonin increased (8-fold in CFS, Sig. = 0.002, 6-fold in hypothyroidism, Sig. < 0.001) whereas fatigue decreased (2-fold in both CFS and hypothyroidism, Sig. = 0.002 for CFS, Sig. < 0.001 for hypothyroidism). There was a negative correlation between serotonin level and fatigue (for CFS, rho = -0.49 before and -0.67 after L-carnitine; for hypothyroidism, rho = -0.24 before and -0.83 after L-carnitine). Conclusions: These findings suggest a new link between low peripheral serotonin, L-carnitine, and fatigue.

'The world was going through what we go through everyday': The experiences of women with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) living with their partners during the COVID-19 lockdown in the United Kingdom.

OBJECTIVES: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating illness characterised by profound and persistent fatigue (JAMA: The Journal of the American Medical Association, 313, 2015, 1101). The current study aims to explore the experiences of women with ME/CFS living with their partners during the COVID-19 pandemic in the United Kingdom. DESIGN: The study adopted a qualitative design comprising semi-structured interviews with participants. Interviews were analysed using thematic analysis (TA). METHODS: Participants were women with ME/CFS (n = 21) recruited through ME/CFS support groups in the United Kingdom. All participants were in romantic relationships and lived with their partners. RESULTS: Data were organised into three themes: (1) lockdown disrupting routine, (2) reducing difference and (3) fear of getting COVID-19. People with ME/CFS found that lockdown disrupted their well-established routines. Although routines were disrupted by partners and increased working-from-home practices, participants found having partners at home helpful. People with ME/CFS believed that the changes induced by the pandemic reduced the differences between themselves and the outside world which, prior to lockdown, had felt prominent. They were fearful of getting COVID-19 as they believed this would make their ME/CFS worse. This meant that for people with ME/CFS, the lifting of the lockdown restrictions was an anxiety-provoking time, hence impacting symptoms. People with ME/CFS continued to adhere to government guidelines after national restrictions were eased. CONCLUSIONS: This study outlines the experiences of women with ME/CFS during COVID-19, alongside the long-term impact this has had due to the changes that the pandemic imposed. These findings may have implications for those with long COVID.

Burnout, Compassion Fatigue, and the Long Haul of Caring for Long COVID.

The current landscape of clinician burnout is prompting the need for our health care system to revise its approach toward complex conditions such as long coronavirus disease (COVID), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other postinfectious fatiguing illnesses (PIFIs). We discuss our efforts here at Family Health Center of San Diego (FHCSD) to help share insight and glean perspective from clinicians who have participated in our Centers for Disease Control and Prevention (CDC)-funded 3-year continuing professional development initiative. The Long COVID and Fatiguing Illness Recovery Program uses multidisciplinary team-based case consultation and peer-to-peer sharing of emerging best and promising practices (ie, teleECHO [Extension for Community Healthcare Outcomes]) to support the management of complex cases associated with long COVID, ME/CFS, and other PIFIs. We believe that this perspective captures a key moment in the trajectory of postpandemic clinician burnout and prompts further reflection and action from the health care system to improve clinician- and patient-level outcomes related to the care of patients with postinfectious fatiguing illnesses.

Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease of significant public health and clinical importance. It affects multiple systems in the body and has neuro-immunological characteristics. The disease is characterized by a prominent symptom called post-exertional malaise (PEM), as well as abnormalities in the immune-inflammatory pathways, mitochondrial dysfunctions and disturbances in neuroendocrine pathways. The purpose of this study was to evaluate the impact of ME/CFS on the mental health and secondary psychosocial manifestations of patients, as well as their coping mechanisms. Method: In 2021, a descriptive cross-sectional study was conducted in Switzerland. A self-administered paper questionnaire survey was used to gather data from 169 individuals diagnosed with ME/CFS. Results: The majority of the patients (90.5%) reported a lack of understanding of their disease, resulting in patients avoiding talking about the disease due to disbelief, trivialization and avoidance of negative reactions. They felt most supported by close family members (67.1%). Two thirds of the patients (68.5%) experienced stigmatization. ME/CFS had a negative impact on mental health in most patients (88.2%), leading to sadness (71%), hopelessness for relief (66.9%), suicidal thoughts (39.3%) and secondary depression (14.8%). Half of the male patients experienced at least one suicidal thought since clinical onset. Factors significantly associated with depression were the lack of cure, disabilities associated with ME/CFS, social isolation and the fact that life was not worth anymore with ME/CFS. The three main factors contributing to suicidal thoughts were (i) being told the disease was only psychosomatic (89.5%), (ii) being at the end of one's strength (80.7%) and (iii) not feeling being understood by others (80.7%). Conclusion: This study provided first time significant insights into the mental and psychological well-being of ME/CFS patients in Switzerland. The findings highlight the substantial experiences of stigmatization, secondary depression and suicidal thoughts compared to other chronic diseases, calling for an urgent need in Switzerland to improve ME/CFS patient's medical, psychological and social support, in order to alleviate the severe mental health burden associated with this overlooked somatic disease.