Myalgic Encephalomyelitis/chronic Fatigue Syndrome Research Articles

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19.

To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment. A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention. Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02). Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN. This study provides Class III evidence. It is a retrospective cohort study.

SEVERITY OF NEUROLOGICAL LONG-COVID SYMPTOMS CORRELATES WITH INCREASED LEVEL OF AUTOANTIBODIES TARGETING VASOREGULATORY AND AUTONOMIC NERVOUS SYSTEM RECEPTORS

Objective: The Long-COVID syndrome is characterized by a variety of physical, cognitive and psychological symptoms. Worldwide, at least 65 million people are thought to be affected, nevertheless there is still insufficient knowledge about the pathogenesis of long-COVID. Studies on the Long-COVID related myalgicencephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest autoimmune-related changes, for example the formation of autoantibodies against G protein-coupled receptors. Design and method: This monocentric, cross-sectional study included patients who suffered a mild to moderate SARS-CoV-2 infection up to 12 months prior to enrollment with (n = 72) or without (n = 58) Long-COVID diagnosis according to the German S1 guideline or with no known history of SARS-CoV-2 infection (n = 70). Autoantibodies towards the vasoregulation associated Adrenergic Receptor (ADR) B1 and B2 and the CNS and vasoregulation associated muscarinic acetylcholine receptor (CHR) M3 and M4 were measured by ELISA. Neurological disorders and fatigue were quantified by internationally standardized questionnaires including Chalder Fatigue Scale, Short-Form-36 Questionnaire and the CERAD Neurophysiological Assessment Battery. Results: The prevalence and concentrations of evaluated autoantibodies were significantly higher in Long-COVID compared to the 2 other groups (p = 2.1∗10-9) with a significantly higher number of patients with simultaneous detection of more than one autoantibody in Long-COVID group (p = 0.0419). Importantly, the overall inflammatory state was low in all 3 groups. ARB1 and ARB2 correlated negatively CERAD Trail Marking A and B (R <= -0.26, p <= 0.043), while CHRM3 correlated positively with Chadler Fatigue Scale (R = 0.37, p = 0.0087). Conclusions: The present study shows that autoantibodies to GPCR are highly prevalent in patients with Long-COVID. These autoantibodies occur in healthy controls as well, but the prevalence is substantially lower. Concentrations of autoantibodies correlates to intensity of neurological disorders including psychomotor speed, visual search, attention, and fatigue.

Phenylephrine alters phase synchronization between cerebral blood velocity and blood pressure in ME/CFS with orthostatic intolerance.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CBV compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO2 and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CBV.NEW & NOTEWORTHY We evaluated cognitive function before and after CO2, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO2 nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO2 significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Exploring the Experience of Healthcare-Related Epistemic Injustice among People with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a chronic, disabling yet clinically “contested” condition, previously theorised through a lens of epistemic injustice. Phenomena conceptually close to epistemic injustice, including stigma, are known to have deleterious consequences on a person’s health and life-world. Yet, no known primary studies have explored how people with ME/CFS experience healthcare through a lens of epistemic injustice, whilst a dearth of research explicitly exploring healthcare-related injustice from a patient perspective has been noted. This qualitative study seeks to address this gap. Semi-structured interviews and interpretative phenomenological analysis (IPA) were used to explore the experiences of five people with ME/CFS in the UK, vis-à-vis healthcare-related epistemic injustice. One superordinate theme is presented, “Being de-centred in patient-centred care,” alongside two sub-themes: “Struggling for epistemic-existential validation” and “Negotiating socio-epistemic hierarchies, politics and ‘power’.” Findings suggest that healthcare-related epistemic injustice may differentially impact according to the patient’s social positionality (here, notably gender), and that a potential pathway of existential harm operates through threats to identity and personhood. Findings also indicate that cultural and political factors may further epistemic injustice in healthcare. Finally, epistemic injustice impacting as a chronic stressor cannot be ruled out and is worthy of further research. The experience of healthcare-related epistemic injustice can carry far-reaching yet varied consequences for patients. Future research should consider drawing upon more socio-demographically diverse samples and an intersectional approach is recommended. Further exploration of structural drivers of epistemic injustice may highlight a need for politically and socio-culturally cognisant clinical approaches.

Cluster analysis of long COVID symptoms for deciphering a syndrome and its long-term consequence

The long-term symptoms of COVID-19 are the subject of public and scientific discussions. Understanding how those long COVID symptoms co-occur in clusters of syndromes may indicate the pathogenic mechanisms of long COVID. Our study objective was to cluster the different long COVID symptoms. We included persons who had a COVID-19 and assessed long-term symptoms (at least 4 weeks after first symptoms). Hierarchical clustering was applied to the symptoms as well as to the participants based on the Euclidean distance h of the log-values of the answers on symptom severity. The distribution of clusters within our cohort is shown in a heat map.From September 2021 to November 2023, 2371 persons with persisting long COVID symptoms participated in the study. Self-assessed long COVID symptoms were assigned to three symptom clusters. Cluster A unites rheumatological and neurological symptoms, cluster B includes neuro-psychological symptoms together with cardiorespiratory symptoms, and a third cluster C shows an association of general infection signs, dermatological and otology symptoms. A high proportion of the participants (n = 1424) showed symptoms of all three clusters. Clustering of long COVID symptoms reveals similarities to the symptomatology of already described syndromes such as the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or rheumatological autoinflammatory diseases. Further research may identify serological parameters or clinical risk factors associated with the shown clusters and might improve our understanding of long COVID as a systemic disease. Furthermore, multimodal treatments can be developed and scaled for symptom clusters and associated impairments.

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.

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. 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. 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. The MyFatigue project opened to enrollment in November 2023. Initial results are expected to be published by the end of 2024. 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. PRR1-10.2196/50157.

The influence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) family history on patients with ME/CFS.

It is unclear if individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with family histories of ME/CFS differ from those with ME/CFS without this family history. To explore this issue, quantitative data from patients with ME/CFS and controls were collected, and we examined those with and without family histories of ME/CFS. The samples included 400 patients with ME/CFS, and a non-ME/CFS chronic illness control group of 241 patients with multiple sclerosis (MS) and 173 with post-polio syndrome (PPS). Confirming findings from prior studies, those with ME/CFS were more likely to have family members with ME/CFS than controls. We found family histories of ME/CFS were significantly higher (18%) among the ME/CFS group than the non-ME/CFS controls (3.9%). In addition, patients with ME/CFS who had family histories of ME/CFS were more likely to have gastrointestinal symptoms than those with ME/CFS without those family histories. Given the recent reports of gastrointestinal difficulties among those with ME/CFS, our findings might represent one predisposing factor for the emergence of ME/CFS.

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

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. 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 (10min 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. 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-1β (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. 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.

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.

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.

The presence of attentional and interpretation biases in patients with severe MS-related fatigue.

Severe fatigue is a prevalent and disabling symptom in multiple sclerosis (MS). This study tested if a fatigue- andphysical activity-related attentional bias (AB) and a somatic interpretation bias (IB) are present in severely fatigued patients with MS. Biases were compared to healthy controls and patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Severely fatigued patients with MS or ME/CFS and healthy controls completed a Visual Probe Task (VPT) assessing fatigue- and physical activity-related AB and an IB task that assesses the tendency to interpret ambiguous information in either a somatically threatening way or in a more neutral manner. The VPT was completed by 38 MS patients, 44 ME/CFS patients, and 46 healthy controls; the IB task was completed by 156, 40 and 46 participants respectively. ANOVA showed no statistically significant group differences in a fatigue-related AB or physical activity-related AB (omnibus test of interaction between topic × condition: F2,125 = 1.87; p = .159). Both patient groups showed a tendency to interpret ambiguous information in a somatically threatening way compared to healthy controls (F1,2 = 27.61, p < .001). This IB was significantly stronger in MS patients compared to ME/CFS patients. IB was significantly correlated with cognitive responses to symptoms in MS patients. MS patients tend to interpret ambiguous information in a somatically threatening way. This may feed into unhelpful ways of dealing with symptoms, possibly contributing to the perpetuation of severe fatigue in MS.

Exploring the content validity of the Chalder Fatigue Scale using cognitive interviewing in an ME/CFS population

ABSTRACT Background The Chalder Fatigue Scale, also known as the Chalder Fatigue Questionnaire (CFQ) is a Patient Reported Outcome Measure (PROM) comprising 11 items designed to measure physical and cognitive fatigue. It is widely used with people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). There is no published evaluation of the content validity of the CFQ. Objectives To elicit information regarding the cognitive processes undertaken by people living with ME/CFS, when completing the CFQ to allow examination of the CFQ’s content validity. Methods A qualitative study utilising semi-structured cognitive interviewing. All data were collated according to the CFQ item but some general criticisms of the content validity of the CFQ were also identified. Results The CFQ currently consists of one item clearly related to physical symptoms (1.6), four items clearly related to cognitive function (1.8, 1.9, 1.10, 1.11) and one item relating to fatigue (1.5) which could be interpreted as cognitive and/or physical fatigue. The other five items have been identified by participants as lacking clarity (1.1, 1.7), relating to behaviour not symptoms (1.2, 1.4), or relating to sleepiness not fatigue (1.3). Conclusion Participants provided a wealth of insight into the challenges related to relevance, comprehensiveness, and comprehensibility of the CFQ, indicating that revision is required. This strengthens the case for participation of people with lived experience at all stages of PROM development. There is a need for an assessment tool/PROM for clinical and research use ME/CFS which has undergone content validation involving people living with ME/CFS.

Imbalanced Brain Neurochemicals in Long COVID and ME/CFS: A Preliminary Study Using MRI

PurposeLong COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures. MethodsMagnetic resonance spectroscopy data were acquired with a 3T Prisma magnetic resonance imaging scanner (Siemens Healthcare, Erlangen, Germany). We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n = 17), ME/CFS (n = 17), and healthy controls (n = 10) using Osprey software. The statistical analyses were performed using SPSS version 29 (IBM, Armonk, NY). Age and sex were included as nuisance covariates. ResultsGlutamate levels were significantly higher in patients with long COVID (P = .02) and ME/CFS (P = .017) than in healthy controls. No significant difference was found between the 2 patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (P = .012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS. ConclusionOur study identified significantly elevated glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the 2 patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.

The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives.

Like other infections, a SARS-CoV-2 infection can also trigger Post-Acute Infection Syndromes (PAIS), which often progress into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS, characterized by post-exercise malaise (PEM), is a severe multisystemic disease for which specific diagnostic markers or therapeutic concepts have not been established. Despite numerous indications of post-infectious neurological, immunological, endocrinal, and metabolic deviations, the exact causes and pathophysiology remain unclear. To date, there is a paucity of data, that changes in the composition and function of the gastrointestinal microbiota have emerged as a potential influencing variable associated with immunological and inflammatory pathways, shifts in ME/CFS. It is postulated that this dysbiosis may lead to intestinal barrier dysfunction, translocation of microbial components with increased oxidative stress, and the development or progression of ME/CFS. In this review, we detailed discuss the findings regarding alterations in the gastrointestinal microbiota and its microbial mediators in ME/CFS. When viewed critically, there is currently no evidence indicating causality between changes in the microbiota and the development of ME/CFS. Most studies describe associations within poorly defined patient populations, often combining various clinical presentations, such as irritable bowel syndrome and fatigue associated with ME/CFS. Nevertheless, drawing on analogies with other gastrointestinal diseases, there is potential to develop strategies aimed at modulating the gut microbiota and/or its metabolites as potential treatments for ME/CFS and other PAIS. These strategies should be further investigated in clinical trials.

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.

Myalgic encephalomyelitis/chronic fatigue syndrome from current evidence to new diagnostic perspectives through skeletal muscle and metabolic disturbances.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a demanding medical condition for patients and society. It has raised much more public awareness after the COVID-19 pandemic since ME/CFS and long-COVID patients share many clinical symptoms such as debilitating chronic fatigue. However, unlike long COVID, the etiopathology of ME/CFS remains a mystery despite several decades' research. This review moves from pathophysiology of ME/CFS through the compelling evidence and most interesting hypotheses. It focuses on the pathophysiology of skeletal muscle by proposing the hypothesis that skeletal muscle tissue offers novel opportunities for diagnosis and treatment of this syndrome and that new evidence can help resolve the long-standing debate on terminology.

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.

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

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. 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). 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. 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. 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.

A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts

AbstractLipid droplets (LDs) are dynamic cellular organelles that play an essential role in lipid metabolism and storage. LD dysregulation has been implicated in various diseases. However, investigations into the cellular LD dynamics under disease conditions have been rarely reported, possibly due to the absence of high performing LD imaging agents. Here a novel fluorogenic probe, AM‐QTPA, is reported for specific LD imaging. AM‐QTPA demonstrates viscosity sensitivity and aggregation‐induced emission enhancement characteristics. It is live cell permeable and can specifically light up LDs in cells, with low background noise and superior signals that can be quantified. After validation in cell model with LD accumulation induced by oleic acid treatment, AM‐QTPA is applied in a small proof‐of‐concept number of human fibroblast samples derived from people diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex and debilitating disease with unknown cause. The results indicate the presence of larger but fewer LDs in ME/CFS fibroblasts compared to the healthy counterparts, accompanying with frequent LD‐mitochondria contacts, suggesting potential upregulation of lipolysis in ME/CFS connective tissue like fibroblasts. Overall, AM‐QTPA provides new understanding of the anomalous LD dynamics in disease status, which, potentially, will facilitate in‐depth investigation of the pathogenesis of ME/CFS.

'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.

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. The study adopted a qualitative design comprising semi-structured interviews with participants. Interviews were analysed using thematic analysis (TA). 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. 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. 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.