Analysis of Gender Differences in HRV of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Mobile-Health Technology

Síndrome de fatiga crònica; Diferències de gènere; Variabilitat de la freqüència cardíacaSíndrome de fatiga crónica; Diferencias de género; Variabilidad del ritmo cardíacoChronic fatigue syndrome; Gender differences; Heart rate variabilityIn a previous study using mobile-health technology (mHealth), we reported a robust association between chronic fatigue symptoms and heart rate variability (HRV) in female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study explores HRV analysis as an objective, non-invasive and easy-to-apply marker of ME/CFS using mHealth technology, and evaluates differential gender effects on HRV and ME/CFS core symptoms. In our methodology, participants included 77 ME/CFS patients (32 men and 45 women) and 44 age-matched healthy controls (19 men and 25 women), all self-reporting subjective scores for fatigue, sleep quality, anxiety, and depression, and neurovegetative symptoms of autonomic dysfunction. The inter-beat cardiac intervals are continuously monitored/recorded over three 5-min periods, and HRV is analyzed using a custom-made application (iOS) on a mobile device connected via Bluetooth to a wearable cardiac chest band. Male ME/CFS patients show increased scores compared with control men in all symptoms and scores of fatigue, and autonomic dysfunction, as with women in the first study. No differences in any HRV parameter appear between male ME/CFS patients and controls, in contrast to our findings in women. However, we have found negative correlations of ME/CFS symptomatology with cardiac variability (SDNN, RMSSD, pNN50, LF) in men. We have also found a significant relationship between fatigue symptomatology and HRV parameters in ME/CFS patients, but not in healthy control men. Gender effects appear in HF, LF/HF, and HFnu HRV parameters. A MANOVA analysis shows differential gender effects depending on the experimental condition in autonomic dysfunction symptoms and HF and HFnu HRV parameters. A decreased HRV pattern in ME/CFS women compared to ME/CFS men may reflect a sex-related cardiac autonomic dysfunction in ME/CFS illness that could be used as a predictive marker of disease progression. In conclusion, we show that HRV analysis using mHealth technology is an objective, non-invasive tool that can be useful for clinical prediction of fatigue severity, especially in women with ME/CFS.This research was funded by “Ministerio de Ciencia e Innovación” of the Spanish Government, grant number PID2019-107473RB-C2

Hierarchical Cluster Analysis Based on Clinical and Neuropsychological Symptoms Reveals Distinct Subgroups in Fibromyalgia: A Population-Based Cohort Study

Cluster analysis; Fibromyalgia; Neuropsychological symptomsAnálisis de clústers; Fibromialgia; Síntomas neuropsicológicosAnàlisi de clústers; Fibromiàlgia; Símptomes neuropsicològicsFibromyalgia (FM) is a condition characterized by musculoskeletal pain and multiple comorbidities. Our study aimed to identify four clusters of FM patients according to their core clinical symptoms and neuropsychological comorbidities to identify possible therapeutic targets in the condition. We performed a population-based cohort study on 251 adult FM patients referred to primary care according to the 2010 ACR case criteria. Patients were aggregated in clusters by a K-medians hierarchical cluster analysis based on physical and emotional symptoms and neuropsychological variables. Four different clusters were identified in the FM population. Global cluster analysis reported a four-cluster profile (cluster 1: pain, fatigue, poorer sleep quality, stiffness, anxiety/depression and disability at work; cluster 2: injustice, catastrophizing, positive affect and negative affect; cluster 3: mindfulness and acceptance; and cluster 4: surrender). The second analysis on clinical symptoms revealed three distinct subgroups (cluster 1: fatigue, poorer sleep quality, stiffness and difficulties at work; cluster 2: pain; and cluster 3: anxiety and depression). The third analysis of neuropsychological variables provided two opposed subgroups (cluster 1: those with high scores in surrender, injustice, catastrophizing and negative affect, and cluster 2: those with high scores in acceptance, positive affect and mindfulness). These empirical results support models that assume an interaction between neurobiological, psychological and social factors beyond the classical biomedical model. A detailed assessment of such risk and protective factors is critical to differentiate FM subtypes, allowing for further identification of their specific needs and designing tailored personalized therapeutic interventions.This work was partially supported by the National Institute of Health “Carlos III” in Madrid, Spain through the grant (reference number: PI09/90301)

Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping

Myalgic encephalomyelitis; Blood analytics; DiagnosisEncefalomielitis miálgica; Análisis de sangre; DiagnósticoEncefalomielitis miàlgica; Anàlisi de sang; DiagnòsticBackground: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce. Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility. Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms. Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.This research was partially funded by the Association of Patients with ME/CFS and Fibromyalgia in Catalonia, Spain (ACAF; www.fibromyalgia.cat (accessed on 23 March 2019) to J.C.-M. and J.A.-M., and by a UCV 2020-270-001 grant to E.O

Pain and depression are associated with more anxiety in ME/CFS: A cross-sectional cohort study between Norway and Spain.

Objectives: Lasting, unexplained and high levels of pain may cause anxiety in patients with chronic fatigue syndrome. The objectives of the current study were to test assumptions of the association between pain and anxiety in patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and to clarify the role of depression in this relationship. Methods: Data were collected from 664 participants (age 18-65 years) with 133 ME/CFS patients and 201 healthy controls from Norway and 330 CFS patients from Spain. Binary logistic regression model was applied to test relationships between the included variables in the samples. Results: Both pain and depression made significant direct contributions to the level of anxiety. The strongest risk for higher levels of anxiety was the combination of high levels of depression and high levels of pain in the overall sample (OR=49.70; P < 0.001), not so much in the Spanish cohort (OR=11.99; P < 0.0001) and most of all in the Norwegian cohort (OR=88.21; P < 0.001) sample. Conclusions: It was the combination of high pain levels and high levels of depression that to the greatest extent increased the risk of anxiety in patients with CFS/ME. Whatever diagnostic criterion that is applied, anxiety and depression should be mandatory to assess in the clinical assessments performed for diagnosing the ME/CFS. Approaches addressing anxiety-related pain and treatment of depression should be warranted.publishedVersio

Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Creatina quinasa; Encefalomielitis miàlgica/síndrome de fatiga crònica; Anàlisis de sang de rutinaCreatina quinasa; Encefalomielitis miálgica/síndrome de fatiga crónica; Análisis de sangre de rutinaCreatine kinase; Myalgic encephalomyelitis/chronic fatigue syndrome; Routine blood testsThere is a lack of research regarding blood tests within individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and between patients and healthy controls. We aimed to compare results of routine blood tests between patients and healthy controls. Data from 149 patients diagnosed with ME/CFS based on clinical and psychiatric evaluation as well as on the DePaul Symptom Questionnaire, and data from 264 healthy controls recruited from blood donors were compared. One-way ANCOVA was conducted to examine differences between ME/CFS patients and healthy controls, adjusting for age and gender. Patients had higher sedimentation rate (mean difference: 1.38, 95% CI: 0.045 to 2.714), leukocytes (mean difference: 0.59, 95% CI: 0.248 to 0.932), lymphocytes (mean difference: 0.27, 95% CI: 0.145 to 0.395), neutrophils (mean difference: 0.34, 95% CI: 0.0 89 to 0.591), monocytes (mean difference: 0.34, 95% CI: 0.309 to 0.371), ferritin (mean difference: 28.13, 95% CI: −1.41 to 57.672), vitamin B12 (mean difference: 83.43, 95% CI: 62.89 to 124.211), calcium (mean difference: 0.02, 95% CI: −0.02 to 0.06), alanine transaminase (mean difference: 3.30, 95% CI: −1.37 to -7.971), low-density lipoproteins (mean difference: 0.45, 95% CI: 0.104 to 0.796), and total proteins (mean difference: 1.53, 95% CI: −0.945 to 4.005) than control subjects. The patients had lower potassium levels (mean difference: 0.11, 95% CI: 0.056 to 0.164), creatinine (mean difference: 2.60, 95% CI: 0.126 to 5.074) and creatine kinase (CK) (mean difference: 37.57, 95% CI: −0.282 to 75.422) compared to the healthy controls. Lower CK and creatinine levels may suggest muscle damage and metabolic abnormalities in ME/CFS patients.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

Yeast Beta-Glucan Supplementation with Multivitamins Attenuates Cognitive Impairments in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

Beta-glucan; Myalgic encephalomyelitis; Vitamin B6Betaglucano; Encefalomielitis miálgica; Vitamina B6Betaglucà; Encefalomielitis miàlgica; Vitamina B6This research aimed to examine the potential alleviative effects of beta-glucan administration on fatigue, unrefreshing sleep, anxiety/depression symptoms and health-related quality of life in ME/CFS. A 36-week unicenter, randomized, double-blind, placebo-controlled trial was conducted in 65 ME/CFS patients, who were randomly allocated to one of two arms to receive four capsules each one of 250 mg beta-glucan, 3.75 µg vitamin D3, 1.05 mg vitamin B6, and 7.5 mg zinc (n = 35), or matching placebo including only microcrystalline cellulose as an excipient (n = 30) once daily. The findings showed that the beta-glucan supplementation significantly improved cognitive fatigue (assessed with FIS-40 scores) after the 36-week treatment compared to the baseline (p = 0.0338). Taken together, this study presents the novel finding that yeast-derived beta-glucan may alleviate cognitive fatigue symptoms in ME/CFS. Thus, it offers valuable scientific insights into the potential use of yeast beta-glucan as a nutritional supplement and/or functional food to prevent or reduce cognitive dysfunction in patients with ME/CFS. Further interventions are warranted to validate these findings and also to delve deeper into the possible immunometabolic pathomechanisms of beta-glucans in ME/CFS.J.C.-M. received financial support and honoraria from Vitae Health Innovation S.L. (Montmeló, Barcelona, Spain). This study was supported by Vitae Health Innovation S.L. (Montmeló, Spain) which supplied both treatments (funding number: 2020-0445)

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data

Expresión génica; Encefalomielitis miálgica/síndrome de fatiga crónica; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVExpressió gènica; Encefalomielitis miàlgica/síndrome de fatiga crònica; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVGene expression; Myalgic encephalomyelitis/chronic fatigue syndrome; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVPeople with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Given that this reporting agrees with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed at answering whether the expression of the human angiotensin-converting enzyme 2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in these patients. In particular, a low expression of ACE2 could be indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients when compared to healthy controls. Accordingly, in newly collected data, there was evidence for a significant higher proportion of samples with an ACE2 expression below the limit of detection in patients than healthy controls. Altogether, patients with ME/CFS can be at a higher COVID-19 risk and, if so, they should be considered a priority group for vaccination by public health authorities. To further support this conclusion, similar research is recommended for other human cell entry receptors and cell types, namely, those cells targeted by the virus.João Malato and André Fonseca were fully funded by FCT – Fundação para a Ciência e Tecnologia, Portugal (ref.grant: SFRH/BD/149758/2019 and SFRH/BD/147629/2019, respectively). Nuno Sepúlveda and Clara Cordeiro were partially funded by FCT – Fundação para a Ciência e a Tecnologia, Portugal (ref. grant: UIDB/00006/2020). Luís Nacul and Eliana M Lacerda acknowledge the funding from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH -Award Number: R01AI103629), and from the ME Association (Award number: PF8947) for their studies on ME/CFS

Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Coenzima Q10; Mitocondrias; Encefalomielitis miálgicaCoenzyme Q10; Mitochondria; Myalgic encephalomyelitisCoenzim Q10; Mitocondris; Encefalomielitis miàlgicaMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating neuroimmune disease, probably of post-viral multifactorial etiology. Unfortunately, no accurate diagnostic or laboratory tests have been established, nor are any universally effective approved drugs currently available for its treatment. This study aimed to examine whether oral coenzyme Q10 and NADH (reduced form of nicotinamide adenine dinucleotide) co-supplementation could improve perceived fatigue, unrefreshing sleep, and health-related quality of life in ME/CFS patients. A 12-week prospective, randomized, double-blind, placebo-controlled trial was conducted in 207 patients with ME/CFS, who were randomly allocated to one of two groups to receive either 200 mg of CoQ10 and 20 mg of NADH (n = 104) or matching placebo (n = 103) once daily. Endpoints were simultaneously evaluated at baseline, and then reassessed at 4- and 8-week treatment visits and four weeks after treatment cessation, using validated patient-reported outcome measures. A significant reduction in cognitive fatigue perception and overall FIS-40 score (p < 0.001 and p = 0.022, respectively) and an improvement in HRQoL (health-related quality of life (SF-36)) (p < 0.05) from baseline were observed within the experimental group over time. Statistically significant differences were also shown for sleep duration at 4 weeks and habitual sleep efficiency at 8 weeks in follow-up visits from baseline within the experimental group (p = 0.018 and p = 0.038, respectively). Overall, these findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients. Future interventions are needed to corroborate these clinical benefits and also explore the underlying pathomechanisms of CoQ10 and NADH administration in ME/CFS.J.C.-M. received financial support and honoraria from Vitae Health Innovation Co., S.L. (Montmeló, Barcelona, Spain). This study was partially supported by the Vall d’Hebron Hospital Research Institute (Barcelona, Spain). Vitae Health Innovation Co. supplied both treatments (Coenzyme Q10 and NADH supplement tablets and placebo)

European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe

Encefalomielitis miàlgica/síndrome de fatiga crònica; Cura; DiagnòsticMyalgic encephalomyelitis/chronic fatigue syndrome; Care; DiagnosisEncefalomielitis miálgica/síndrome de fatiga crónica; Cuidado; DiagnósticoDesigned by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)—COST action 15111—from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.This research received no external funding. EUROMENE receives funding for networking activities from the COST programme (COST Action 15111), via the COST Association