Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain 
Annemarie Dedek, Jian Xu, Louis-Étienne Lorenzo, Antoine G Godin, Chaya M Kandegedara, Geneviève Glavina, Jeffrey A Landrigan, Paul J Lombroso, Yves De Koninck, Eve C Tsai ... Show more
Brain, awab408, https://doi.org/10.1093/brain/awab408
Published:  23 March 2022
 Abstract
The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.
Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females.
This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

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Fatigue: Biomedicine, Health & Behavior    Volume 9, 2021 - Issue 2COVID-19 symptoms over time: comparing long-haulers to ME/CFSLeonard A. Jason, Mohammed F. Islam, Karl Conroy, Joseph Cotler, Chelsea Torres, Mady Johnson.     https://doi.org/10.1080/21641846.2021.1922140
ABSTRACT
IntroductionOur objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
ResultsOver time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
ConclusionsThese types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
 
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An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue SyndromeKlaus J Wirth 1, Carmen Scheibenbogen 2, Friedemann Paul 3
 J Transl Med. 2021 Nov 22;19(1):471.
 PMID: 34809664  PMCID: PMC8607226   DOI: 10.1186/s12967-021-03143-3
Erratum in·       Correction to: An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Wirth KJ, Scheibenbogen C, Paul F.J Transl Med. 2022 Jan 11;20(1):25. doi: 10.1186/s12967-021-03216-3.PMID: 35016692 
AbstractThere is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.
Keywords: Brain fog; Chronic Fatigue Syndrome; Cognitive impairment; Dysautonomia; Headache; Hypersensitivity; Myalgic Encephalomyelitis; Neurological symptoms; Post-Covid-19 syndrome; Sleep disturbance.
© 2021. The Author(s).

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Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis
 Felicia Ceban a,b , Susan Ling a,d , Leanna M.W. Lui a , Yena Lee a,c , Hartej Gill a , Kayla M. Teopiz a , Nelson B. Rodrigues a , Mehala Subramaniapillai a , Joshua D. Di Vincenzo a,d , Bing Cao e , Kangguang Lin f,g , Rodrigo B. Mansur a,h , Roger C. Ho i,j , Joshua D. Rosenblat a,d,h , Kamilla W. Miskowiak k,l , Maj Vinberg m,n , Vladimir Maletic o , Roger S. 
Brain Behavior and Immunity journal homepage: www.elsevier.com/locate/ybrbi
 
ABSTRACT Importance: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. Objective: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome. 
Data sources: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. Study selection: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. Data extraction & synthesis: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model. 
Main outcomes & measures: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome. 
Abbreviation: PCS, Post-COVID-19 syndrome. * Corresponding author at: University Health Network, 399 Bathurst S
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Does pre-infection stress increase the risk of long COVID? Longitudinal associations between adversity worries and experiences in the month prior to COVID-19 infection and the development of long COVID and specific long COVID symptoms
 View ORCID ProfileElise Paul,  View ORCID ProfileDaisy Fancourt
doi: https://doi.org/10.1101/2022.04.06.22273444 
 
Abstract
Summary
Background Long COVID is increasingly recognised as public health burden. Demographic and infection-related characteristics have been identified as risk factors, but less research has focused on psychosocial predictors such as stress immediately preceding the index infection. Research on whether stressors predict the development of specific long COVID symptoms is also lacking.
Methods Data from 1,966 UK adults who had previously been infected with COVID-19 and who took part in the UCL COVID-19 Social Study were analysed. The number of adversity experiences (e.g., job loss) and the number of worries about adversity experiences within the month prior to COVID-19 infection were used to predict the development of self-reported long COVID and the presence of three specific long COVID symptoms (difficulty with mobility, cognition, and self-care). The interaction between a three-level index of socio-economic position (SEP; with higher values indicating lower SEP) and the exposure variables in relation to long COVID status was also examined. Analyses controlled for a range of COVID-19 infection characteristics, socio-demographics, and health-related factors.
Findings Odds of self-reported long COVID increased by 1.25 (95% confidence interval [CI]: 1.04 to 1.51) for each additional worry about adversity in the month prior to COVID-19 infection. Although there was no evidence for an interaction between SEP and either exposure variable, individuals in the lowest SEP group were nearly twice as likely to have developed long COVID as those in the highest SEP group (OR: 1.95; 95% CI: 1.19 to 3.19) and worries about adversity experiences remained a predictor of long COVID (OR: 1.43; 95% CI: 1.04 to 1.98). The number of worries about adversity experiences also corresponded with increased odds of certain long COVID symptoms such as difficulty with cognition (e.g., difficulty remembering or concentrating) by 1.46 (95% CI: 1.02 to 2.09) but not with mobility (e.g., walking or climbing steps) or self-care (e.g., washing all over or dressing).
Interpretation Results suggest a key role of stress in the time preceding the acute COVID-19 infection for the development of long COVID and for difficulty with cognition specifically. These findings point to the importance of mitigating worries and experiences of adversities during pandemics both to reduce their psychological impact but also help reduce the societal burden of longer-term illness.
Funding The Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].
 
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Front. Neurol., 11 April 2022 | https://doi.org/10.3389/fneur.2022.841310
Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature ReviewShin-ichi Hirano1*, Yusuke Ichikawa1,2, Bunpei Sato1,2, Yoshiyasu Takefuji3,4 and Fumitake Satoh1,2

• 1Department of Research and Development, MiZ Company Limited, Kamakura, Japan

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.

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Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunctionFriedberg, Fred PhD1; Adamowicz, Jenna L. MA2; Bruckenthal, Patricia PhD, APRN-BC, FAAN3; Milazzo, Maria PhD, RN3; Ramjan, Sameera MA4; Quintana, Daniel PhD5
Author Information
Psychosomatic Medicine: April 15, 2022 - Volume - Issue - 10.1097/PSY.0000000000001082
doi: 10.1097/PSY.0000000000001082
AbstractObjective To test a model of non-improvement in chronic fatigue syndrome (CFS) utilizing self-report activity patterns (e.g., “push-crash”), uplifts and hassles, and a biological measure of cardiac autonomic function. Activity pattern impacts on symptoms and objective measures of autonomic and physical activity were also examined.
Methods This prospective study in CFS collected all data remotely, including six months of weekly web diaries that recorded symptom ratings, activity patterns, and hassles and uplifts. In addition, six months of weekly heart monitoring and three months of daily waking actigraphy data were collected. Improvement or non-improvement status was assessed using semi-structured interviews at 6 months follow-up.
Results 148 individuals (87.2% female) were enrolled and 12.2% were lost to follow-up. Participants reporting non-improvement (n = 92), as compared to improvement (n = 38) showed greater autonomic dysfunction (lower heart rate variability [HRV], group difference = 5.93 (SE = 2.73) ms; p = .032) and lower mean intensity of behavioral uplifts (group difference = 0.14 (SE = 0.16); p = .043), but no significant differences in any activity pattern, including push-crash, limiting activity, and healthy pacing.
Conclusions This study provided evidence for linking patient-reported non-improvement to a biological variable indexing autonomic dysfunction and a behavioral measure indicating a deficit in psychological uplifts. These findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS.
Trial Registration: ClinicalTrials.gov ID: NCT02948556
Copyright © 2022 by the American Psychosomatic Society

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Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFSby 
Yoshiaki Soejima Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Ko Harada. Kenta Nakamoto, Naruhiko Sunada, Yasue Sakurada, Kou Hasegawa, Hideharu Hagiya,Keigo Ueda, and Fumio Otsuka
 *Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
Medicina 2022, 58(4), 536; https://doi.org/10.3390/medicina58040536
Received: 18 March 2022 / Revised: 7 April 2022 / Accepted: 11 April 2022 / Published: 13 April 2022
(This article belongs to the Special Issue Advances in ME/CFS Research and Clinical Care)
Abstract
After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient’s fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male’s Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient’s symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).
Keywords: general fatigue; free testosterone; late-onset hypogonadism; long COVID; post-COVID condition

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Frontiers in Neuroendocrinology Available online 11 April 2022, 100995The underlying sex differences in neuroendocrine adaptations relevant to Myalgic Encephalomyelitis Chronic Fatigue SyndromeAuthor links open overlay panel       NatalieThomasaCarolineGurvichbKatherineHuangaPaul RGooleyaChristopher WArmstronga
https://doi.org/10.1016/j.yfrne.2022.100995Get rights and content
Abstract
IntroductionMyalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem disease characterised by severe and disabling new-onset symptoms of post-exertional malaise (PEM), fatigue, brain fog, and sleep dysfunction that lasts for at least six months. Accumulating evidence suggests that sex and endocrine events have a significant influence on symptom onset and moderation of ME/CFS, with female sex being one of the most consistent and credible predictive risk factors associated with diagnosis. Such sex differences suggest sex chromosomes and sex steroids may play a part in the development of the condition or moderation of symptoms, although this has yet to be explored in detail.
Methods/AimsThis narrative review outlines sex differences in ME/CFS in terms of vulnerability factors and clinical phenotype and explores the known sex differences in neuroendocrine systems affected in ME/CFS and how this may relate to disease risk, onset, pathophysiology, and potential treatment avenues.
ConclusionsThere is clear evidence of a sex dimorphism with regards to prevalence (3:1 female preponderance), clinical phenotypes, and aetiological triggers prior to symptom onset of ME/CFS. Endocrinological events, particularly those throughout the female lifespan, are associated with ME/CFS and include reproductive menstrual cycle fluctuations, pregnancy, post-partum and perimenopause. Further, there is evidence for gonadal sex, adrenal stress and renal neuroendocrine systems as implicated in ME/CFS, including changes in estrogen, progesterone compounds, aldosterone, and cortisol levels, of which there are established sex differences. The broad effects of steroid hormones on the physiological systems may also speak to the diversity of ME/CFS symptomatology observed in patients. Further attention must be paid to sex, age, and steroid biology in ME/CFS.

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Health-related quality of life in Young People with Chronic fatigue syndrome/ Myalgic encephalomyelitis
Similä, Wenche Ann  Doctoral thesis  URI  https://hdl.handle.net/11250/2991015 Date 2022
Institutt for klinisk og molekylær medisin [2565]
Abstract
Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a disease that affects people of all ages. CFS/ME significantly limits the activity level of those affected, including in relation to physical activity, schooling, occupational life and social life. High levels of school absence among young people with CFS/ME result in loss of important learning and social development among peers. As such, there is increasing uncertainty about their future, and personal and socio-economic consequences could put them at risk of becoming disabled at a young age. Measurements of health-related quality of life (HRQoL), including being able to function in school, have shown that young people with CFS/ME score lower than their counterparts without CFS/ME.
Aims
The overall aim of this project was to explore HRQoL among young people with CFS/ME, including the factors associated with HRQoL in relation to school and everyday life. More specifically, the aim was to firstly (Study1) examine HRQoL, including factors that are positively or negatively associated with HRQoL, in a cohort of young people with CFS/ME. Study 1, along with the previous literature, provided the basis for an in-depth study (Study 2) to investigate the positive and negative factors that young people with CFS/ME experience in school and everyday life. Based on the findings from Study 1 and Study 2, a third study (Study 3) was planned to explore teachers’, counsellors’ and school nurses’ experiences with educational and social adaptation at school for young people with CFS/ME.
Method
To explore HRQoL and the factors associated with HRQoL among young people with CFS/ME (Studies 1 & 2), a cross-sectional survey- and interview-based study was conducted. The participants of the cross-sectional study were recruited to participate in the interview study. To explore the experiences of teachers, counsellors and school nurses with education and social adaptions at school for young people with CFS/ME (Study 3), an interview study was conducted with participants recruited among school personnel and school nurses in secondary school (educating students aged 13-16), high school (educating students aged 16-19) and educational psychological services (EPS).
Results
A total of 63 participants were included in the cross-sectional study, 18 of whom participated in the interview study. A total of 12 participants were included in the interview study with the teachers, counsellors and school nurses. In the cross-sectional study (Study 1), young people with CFS/ME scored lower on HRQoL than their counterparts who were healthy or had other chronic diseases. Contact with school and teachers was associated with a higher HRQoL among young people with CFS/ME. This association could be due to that more contact resulted from adaptations of education and social life at school, or that fewer health problems due to CFS/ME had abled the young people to maintain the contact with school and teachers. In Study 2, it was found that an adapted plan for education and social life at school for young people with CFS/ME could increase the possibility of continuing schooling with peers. The lack of an adapted plan for education and social life at school could lead to increased school absence as well as loss of education, social contact and development among peers. Subsequently, this could lead to depressive thoughts and worry about the future. The school personnel and school nurses in Study 3 experienced that young people with CFS/ME lost confidence in school. The challenges experienced by school personnel included (1) understanding students’ needs before they received a diagnosis and before school personnel received information from healthcare providers and (2) maintaining the teacher–student relationship and (3) the continuity of teaching. In terms of measures for better management, early problematization of school absence, interdisciplinary collaboration on early measures, ensuring the maintenance of the teacher–student relationship and increasing CFS/ME-related competence in schools were proposed. These measures could contribute to prevent loss of function and school absence among young people with CFS/ME.
Conclusion
HRQoL among young people with CFS/ME was associated with contact with school and teachers, but a causal relationship could not be proven. Interviews with young people with CFS/ME and school personnel suggested that interdisciplinary strategies for early adaptations to education and social life at school for young people with CFS/ME may benefit education and social development among peers for young people with CFS/ME. Lack of educational and social adaptations at school might lead to loss of education, social life and development among peers.
 
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Cognitive sequelae of long COVID may not be permanent: A prospective studyOscar H. Del Brutto,Denisse A. Rumbea,Bettsy Y. Recalde,Robertino M. Mera
First published: 16 December 2021  https://doi.org/10.1111/ene.15215
AbstractBackground and purposeCognitive decline is a recognized manifestation of long COVID, even among patients who experience mild disease. However, there is no evidence regarding the length of cognitive decline in these patients. This study aimed to assess whether COVID-19-related cognitive decline is a permanent deficit or if it improves over time.
MethodsCognitive performance was evaluated by means of the Montreal Cognitive Assessment (MoCA) in COVID-19 survivors and noninfected individuals. All study participants had four cognitive evaluations, two of them before the pandemic and the other two, 6 and 18 months after the initial SARS-CoV-2 outbreak infection in the village. Linear mixed effects models for longitudinal data were fitted to assess differences in cognitive performance across COVID-19 survivors and noninfected individuals.
ResultsThe study included 78 participants, 50 with history of mild COVID-19 and 28 without. There was a significant—likely age-related—decline in MoCA scores between the two prepandemic tests (β = −1.53, 95% confidence interval [CI] = −2.14 to −0.92, p < 0.001), which did not differ across individuals who later developed COVID-19 when compared to noninfected individuals. Six months after infection, only COVID-19 survivors had a significant decline in MoCA scores (β = −1.37, 95% CI = −2.14 to −0.61, p < 0.001), which reversed after 1 additional year of follow-up (β = 0.66, 95% CI = −0.11 to 1.42, p = 0.092). No differences were noticed among noninfected individuals when both postpandemic MoCA scores were compared.
ConclusionsStudy results suggest that long COVID-related cognitive decline may spontaneously improve over time.

Peripheral muscle fatigue limits post-COVID exercise
20 April 2022     FROM ESC PREVENTIVE CARDIOLOGY 2022
Peripheral muscle fatigue was the most common cause of exercise limitation in patients recovered from COVID-19 regardless of disease severity, in a study of nearly 300 individuals.
The source and magnitude of exercise intolerance in post–COVID-19 patients has not been well studied, said Mauricio Milani, MD, of Fitcordis Exercise Medicine Clinic, Brasilia, Brazil, in a presentation at the annual congress of the European Association of Preventive Cardiology.
To assess exercise intolerance, the researchers performed cardiopulmonary exercise testing (CPET) on 144 adults who had recovered from COVID-19 and 144 matched controls who had not had COVID-19. The average age of the participants was 43 years, and 57% were male. COVID-19 was defined as mild, moderate, or severe in 60%, 21%, and 19% of the cases, respectively.
Residual symptoms were present in 41% of cases. CPET was performed at roughly 14 weeks after disease onset.
Among the COVID-19 patients, most of the CPET limitations (92%) were caused by muscle fatigue; cardiovascular limitations were noted in 2%, and pulmonary limitations were noted in 6%.
Data from the post-COVID CPET showed differences in peak oxygen consumption, as well as the first and second ventilatory thresholds (VT1 and VT2) between COVID-19 patients and controls, and with lower values related to higher illness severities, Dr. Milani said. Heart rate also varied according to illness severity, with lower values significantly related to higher illness severities and significant differences between COVID patients and controls.
A total of 42 individuals with COVID-19 had previous CPET data for comparison (27 with mild disease and 15 with moderate or severe disease), Dr. Milani said. In the subgroup with mild disease, the only significant difference in CPET results before and after COVID-19 was peak speed. In the moderate/severe group, the researchers observed higher reductions in peak speed and also reductions in oxygen consumption at peak and thresholds.
However, peak oxygen flows were not different before and after COVID-19 in either the mild or moderate/severe subgroups, Dr. Milani said.
The study findings were limited in part by the relatively small study population; however, the results indicate that peripheral muscle fatigue is the primary etiology in exercise limitation in post–COVID-19 patients.
“Our data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components,” Dr. Milani concluded.

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Unbiased immune profiling reveals a natural killer cell-peripheral nerve  axis in fibromyalgiaVivek Verma 1, Gillian L Drury, Marc Parisien, Ayşe N Özdağ Acarli, Tho-Alfakar Al-Aubodah, Anastasia Nijnik, Xia Wen, Nicol Tugarinov, Maria Verner, Richie Klares 3rd, Alexander Linton, Emerson Krock, Carlos E Morado Urbina, Bendik Winsvold, Lars G Fritsche, Egil A Fors, Ciriaco Piccirillo, Arkady Khoutorsky, Camilla I Svensson, Mary A Fitzcharles, Pablo M Ingelmo, Nicole F Bernard, Franck P Dupuy, Nurcan Üçeyler, Claudia Sommer, Irah L King, Carolina B Meloto, Luda Diatchenko, HUNT-All In Pain

• PMID: 34913882 PMCID: PMC8942876 (available on 2023-03-24) DOI: 10.1097/j.pain.0000000000002498

AbstractThe pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.
Copyright © 2021 International Association for the Study of Pain.
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Natelson et al. Journal of Translational Medicine (2022) 20:95 https://doi.org/10.1186/s12967-022-03289-8 RESEARCH 
Physiological assessment of orthostatic intolerance in chronic fatigue syndrome Benjamin H. Natelson1*, Jin‑Mann S. Lin2 , Michelle Blate1 , Sarah Khan1 , Yang Chen2 and Elizabeth R. Unger2 
Abstract
Background: Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/ CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identifed in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormal‑ ity, followed by postural orthostatic tachycardia. 
Objective: Evaluate the physiologic response of patients with ME/CFS to a standardized OC. 
Design: Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2≤32 mmHg. Orthostatic tachycardia was heart rate increase≥30 beats per minute compared with resting or≥120 BPM. Orthostatic hypotension was decreased sys‑ tolic pressure≥20 mmHg from baseline. Tachypnea was respiratory rate of ≥20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2. Patients: 63 consecutive patients fulflling the 1994 case defnition for CFS underwent lean testing at frst visit and then annually at visit 2 (n=48) and 3 (n=29). 
Measures: Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension. 
Results: The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not difer between those with and without hypocapnia.
 Conclusions: The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormal‑ ity, hypocapnia, would be missed without capnography.

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Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients

• Natalie Eaton-Fitch, Stanley Du Preez, Hélène Cabanas, Katsuhiko Muraki, Donald Staines & Sonya Marshall-Gradisnik 

Journal of Translational Medicine volume 20, Article number: 94 (2022) Cite this article
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.
MethodsLive cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+ influx was determined.
ResultsThe amplitude (p < 0.0001) and half-time of Ca2+ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+ influx was significantly increased in ME/CFS patients (p < 0.0001).
ConclusionTRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.

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Eye movements may be key to chronic fatigue syndrome diagnosis25 March 2022  Monash University
A Monash Central Clinical School scientist has been awarded $180,000 over three years to develop a way to help diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Associate Professor Joanne Fielding, from the Department of Neuroscience, Associate Professor Fielding is working with Dr Scott Kolbe and Dr Meaghan Clough , both from the Department, and co-investigator Dr Chris Armstrong from the University of Melbourne on the project.
An enigmatic disorder, ME/CFS is characterised by extreme tiredness, pain and a range of other symptoms. Remarkably, there is currently no reliable way to diagnose it and to objectively monitor the effect of treatment in people with the disorder.
“You can’t directly measure ME/CFS at the moment. A clinician’s role is to essentially eliminate other potential causes for the constellation of symptoms,” Associate Professor Fielding said. “While there are some suggested diagnostic criteria there are no formal criteria.
“What we’re trying to do is generate a unique ME/CFS signature based on characteristic changes to eye movements, a behaviourial signature that is specific to the disorder that can be used to help diagnose it and monitor the effects of any treatments.”
Associate Professor Fielding and her team will develop the clinically useful test using ocular-motor, machine learning and neuroimaging techniques.
“We’re using video-oculography, which is basically high-powered cameras that record the eye movements in response to a set of simple stimuli on the screen.
“People with ME/CFS are typically extremely fatigued – we need something very quick that gives a snapshot of how they’re performing.”
Participants in the study can be tested in the lab or in their own homes with a portable eye-tracker – helpful to someone with such a disabling disorder.
Associate Professor Fielding said the research might also give the scientists clues about what might be happening neuropathologically in ME/CFS.
“Tentatively, what we’ve found already looks like a set of aberrant eye movements that suggest that something might be going on at the level of the brain stem – but it’s early days and that’s at best, speculative,” she said.

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Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeJessica Van Oosterwijck, Uros Marusic, [...], and Jo Nijs
AbstractAlthough autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people. Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS. This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.

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The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)Rahel S. König, Werner C. Albrich, [...], and Sofia K. Forslund
 Front Immunol. 2022 March 30; 13: 878196.
AbstractMyalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed. We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients. Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.
 
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medRxiv. Preprint. 2022 Jan 11.   doi: 10.1101/2021.06.14.21258895
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeXiaoyu Che,1,2,† Christopher R. Brydges,3,† Yuanzhi Yu,2 Adam Price,1 Shreyas Joshi,1 Ayan Roy,1 Bohyun Lee,1 Dinesh K. Barupal,4 Aaron Cheng,1 Dana March Palmer,5 Susan Levine,6 Daniel L. Peterson,7 Suzanne D. Vernon,8 Lucinda Bateman,8 Mady Hornig,5 Jose G. Montoya,9 Anthony L. Komaroff,10 Oliver Fiehn,3,* and W. Ian Lipkin1,*
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
MethodsUsing regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
ResultsIn ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
ConclusionOur findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.

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Long-Term Effects of COVID-19  Shreeya Joshee, BS    Nikhil Vatti, MD   Christopher Chang, MD, PhD, MBA Published:January 11, 2022DOI:https://doi.org/10.1016/j.mayocp.2021.12.017
AbstractCoronavirus disease 2019 (COVID-19) is the third deadly coronavirus infection of the 21st century that has proven to be significantly more lethal than its predecessors, with the number of infected patients and deaths still increasing daily. From December 2019 to July 2021, this virus has infected nearly 200 million people and led to more than 4 million deaths. Our understanding of COVID-19 is constantly progressing, giving better insight into the heterogeneous nature of its acute and long-term effects. Recent literature on the long-term health consequences of COVID-19 discusses the need for a comprehensive understanding of the multisystemic pathophysiology, clinical predictors, and epidemiology to develop and inform an evidence-based, multidisciplinary management approach. A PubMed search was completed using variations on the term post-acute COVID-19. Only peer-reviewed studies in English published by July 17, 2021 were considered for inclusion. All studies discussed in this text are from adult populations unless specified (as with multisystem inflammatory syndrome in children). The preliminary evidence on the pulmonary, cardiovascular, neurological, hematological, multisystem inflammatory, renal, endocrine, gastrointestinal, and integumentary sequelae show that COVID-19 continues after acute infection. Interdisciplinary monitoring with holistic management that considers nutrition, physical therapy, psychological management, meditation, and mindfulness in addition to medication will allow for the early detection of post-acute COVID-19 sequelae symptoms and prevent long-term systemic damage. This review serves as a guideline for effective management based on current evidence, but clinicians should modify recommendations to reflect each patient's unique needs and the most up-to-date evidence. The presence of long-term effects presents another reason for vaccination against COVID-19.

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Lancet Discovery Science:   Volume 47, May 2022, 101417
Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohortAdamHampshireaDoris A.ChatfieldbAnne ManktelowMPhilbAmyJollyaWilliamTrenderaPeter J.HellyeraMartina DelGiovaneaVirginia F.J.NewcombebJoanne G.OuttrimbBenWarnebJunaidBhattidLindaPointondAnneElmereNyarieSitholebfJohnBradleybghNathalieKingstonlStephen J.SawceriEdward T.Bullmorecdj…David K.Menonbck1
https://doi.org/10.1016/j.eclinm.2022.101417Get rights and content
Summary:BackgroundPreliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
Methods46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
FindingsCOVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
InterpretationCognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.

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Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome
Am J Respir Crit Care Med. 2022 Jan 1; 205(1): 126–129.
Published online 2021 Oct 19. doi: 10.1164/rccm.202108-1903LE
Esther de Boer, 1 , 2 Irina Petrache,  1 , 2 ,* Nir M. Goldstein, 1 J. Tod Olin, 1 Rebecca C. Keith, 1 , 2 Brian Modena, 1 Michael P. Mohning, 1 , 2 Zulma X. Yunt, 1 , 2 Inigo San-Millán, 2 , 3 , ‡ and Jeffrey J. Swigris 1 , 2 , ‡
After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (1). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (2). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (3). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (4). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.
In this study, we investigated whether patients with PASC had compromised mitochondrial function during graded exercise. Data were obtained via retrospective review of the electronic medical record from a cohort of 50 subjects with PASC (n = 50, age = 50 ± 15 yr, 35 female) that were consecutively referred to and willing to complete CPET in the Pulmonary Physiology Laboratory at National Jewish Health between June 2020 and April 2021 (Table 1). No subject was excluded. Patients were assessed on a cycle ergometer (Vmax 29; SensorMedics Corp) using a continuous ramp protocol to exhaustion. Cardiovascular, ventilatory, metabolic, and gas exchange data were collected using a metabolic cart (Ultima Cardio2 System; Med graphics) per standard protocol (5). For calculations of total FATox and carbohydrate oxidation (CHOox), we used the stoichiometric equations by Frayn and colleagues: FATox [g/min]  = 1.67 × V˙o2 [L/min] – 1.67 × V˙co2 [L/min] and CHOox [g/min] = 4.55 × V˙o2 [L/min] – 3.21 × V˙co2 [L/min] (6). Patient data were compared with results from two published cohorts that included subjects tested with CPET in Denver, Colorado (i.e., the same altitude as our cohort). The characteristics of these cohorts have been previously described (3). Statistical analyses were performed in SPSS Statistics V.27 (IBM) and graphed with Prism V.9.1.0(221) (GraphPad Software). Our study was approved by The Biomedical Research Alliance of New York (BRANY) Institutional Review Board (IRB) study # 20-12-582-528.
 
Pulmonary function testing (PFT) showed mostly normal resting airflow and gas transfer capacity. All six patients (12%) with PFT abnormalities had preexisting illnesses, including asthma (n = 3) or interstitial lung disease (n = 1). Resting transthoracic echocardiogram was obtained in 39 patients (78%) within 2 ± 3 months of CPET. Left ventricular systolic function was normal (left ventricular ejection fraction 50–70%) in all patients. Among the 50 patients who underwent CPET, the mean time from COVID-19 diagnosis to the CPET was 6 ± 4 months. V˙o2max was normal (>84% predicted) in 34 (68%; mean peak V˙o2 107 ± 22% predicted) and reduced in 16 patients (32%; mean peak V˙o2 67 ± 13% predicted). Among these 16, none had ventilatory limitation, but 9 (56%) had cardiovascular limitation (heart rate reserve <15 beats per minute at peak exercise), and 10 (63%) had a low O2 pulse value at peak exercise.
Regardless of the presence of comorbidities, among the 39 patients with PASC who had arterial catheters in place, mean lactate was significantly higher (Figures 1A and 1B); and in all 50 patients with PASC, calculated levels of FATox were significantly lower (Figures 1C and 1D) during exercise when compared with historical cohorts of subjects who are moderately active or with metabolic syndrome (3). Calculated levels of CHOox in patients with PASC were not significantly different from these published cohorts (data not shown). Average power output, oxygen consumption, and blood lactate did not differ between patients with PASC with or without comorbidities (data not shown). Correlations between post–COVID-19 symptoms, Borg score for dyspnea and leg fatigue, and time lapse from COVID-19 diagnosis to CPET with the anaerobic threshold and mitochondrial dysfunction (i.e., FATox) did not yield statistically significant relationships.
Our data suggest abnormally low FATox and altered lactate production by skeletal muscle as a putative cause of—or contributor to—the functional limitation of patients with PASC. Normally, as glycolysis increases with exercise intensity, lactate is oxidized for fuel in mitochondria, mainly in adjacent slow-twitch muscle fibers. Like FATox, lactate clearance capacity is a useful surrogate for mitochondrial function. In patients with PASC, even in those with normal pre–COVID-19 physical fitness and free of comorbidities, the metabolic disturbances of the skeletal muscle during exercise may be worse than those reported in moderately active individuals or in individuals with metabolic syndrome (3). Whereas rising blood lactate levels are expected during high exercise intensity (as glycolytic flux exceeds the rate of mitochondrial pyruvate oxidation), a high blood lactate at lower exercise levels indicates mitochondrial dysfunction (7). The inappropriately high arterial lactate levels at relatively low exercise intensity (e.g., >9 mM at 150 W) in patients with PASC indicate that the transition from FATox to CHOox occurs prematurely, suggesting metabolic reprogramming and dysfunctional mitochondria.
Dysregulated lipid oxidation and decreased mitochondrial biogenesis have been reported in acute critically ill patients admitted to the ICU (8). However, the long-term weakness in ICU survivors is associated with heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity and not solely by diminished mitochondrial content (9).
Our study has several limitations, including a small cohort size, retrospective methodology, and lack of a contemporaneous control, relying on comparisons with historical cohorts that have distinct demographics. Therefore, our findings may not be generalizable and should be considered hypothesis-generating. They should provide impetus for further investigations into the molecular mechanisms linking COVID-19 to metabolic reprogramming and mitochondrial dysfunction. Our report is consistent with that by Pleguezuelos and colleagues, who also showed that patients with PACS that followed acute COVID-19 requiring admission to the ICU suffered from reduced exercise efficiency (10) and with that of Rinaldo and colleagues showing that disease severity does not impact exercise capacity in COVID-19 survivors; however, the study focused on peak values and cardiorespiratory peak values and not on metabolic/cellular adaptations as we did in our study (11).
To our knowledge, our study provides the first evidence of mitochondrial dysfunction that advances our understanding of the pathogenesis of PACS in patients with preserved pulmonary and cardiac function. Future studies into the mechanisms of mitochondrial dysfunction in individuals with PACS will help accelerate the development of therapies to improve their functional status.
 
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Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for FibromyalgiaA Systematic Review and Network Meta-analysis
Hussein M. Farag, PharmD, MSc, PhD1; Ismaeel Yunusa, PharmD, PhD1,2; Hardik Goswami, BPharm, MSc, PhD1,3; et alIhtisham Sultan, PharmD1,4; Joanne A. Doucette, MSc, MSLIS1; Tewodros Eguale, MD, PhD1,5
JAMA Netw Open. 2022;5(5):e2212939. doi:10.1001/jamanetworkopen.2022.12939  Neurology May 19, 2022
Key Points
Question  What pharmacological treatments for adults with fibromyalgia are associated with the highest efficacy and acceptability?
Findings  In this systematic review and network meta-analysis of 36 randomized clinical trials (11 930 patients with fibromyalgia), duloxetine (120 mg) was associated with higher efficacy in treating pain and depression, while amitriptyline was associated with higher efficacy and acceptability in improving sleep, fatigue, and health-related quality of life outcomes.
Meaning  These findings suggest that with the heterogeneity of fibromyalgia symptoms, pharmacological treatments should be tailored to individual symptoms, including pain, sleep problems, depressed mood, fatigue, and health-related quality of life.
 
Abstract
Importance  Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.
Objective  To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia.
Data Sources  Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020.
Study Selection  Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs.
Data Extraction and Synthesis  This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021.
Main Outcomes and Measures  Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated.
Results  A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, −0.97; 95% CrI, −1.10 to −0.83), fatigue (SMD, −0.64; 95% CrI, −0.75 to −0.53), and improved quality of life (SMD, −0.80; 95% CrI, −0.94 to −0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, −0.33; 95% CrI, −0.36 to −0.30) and depression (SMD, −0.25; 95% CrI, −0.32 to −0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.
Conclusions and Relevance  These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.

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Environ Health Perspect . 2022 May;130(5):57001. doi: 10.1289/EHP9009. Epub 2022 May 11.
Evaluation of a Gene-Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case-Control Study Drawn from the U.S. Military Health Survey's National Population SampleRobert W Haley 1, Gerald Kramer 1, Junhui Xiao 1, Jill A Dever 2, John F Teiber 1
PMID: 35543525 PMCID: PMC9093163  DOI: 10.1289/EHP9009
Abstract
Background: Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias.
Objectives: We investigated a prestated hypothesis of the association of GWI with a gene-environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure.
Methods: A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment.
Results: The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18controls=1.18; 95% CI: 0.81, 1.73; p=0.35p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine.
Discussion: Given gene-environment independence and monotonicity, the unconfounded aRERI>0aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009

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Decreased NO production in endothelial cells exposed to plasma from ME/CFS patientsRominaBertinataRobertoVillalobos-LabrabLidijaHofmanncJenniferBlauensteinercNunoSepúlvedadeFranciscoWestermeiercf
https://doi.org/10.1016/j.vph.2022.106953Get rights and content
Highlights•
ME/CFS-plasma reduced the ability of ECs to produce NO.
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Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state.
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We provide new methodological approaches to study in vitro ED in ME/CFS.
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of plasma from either ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence and presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data showed that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma. In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.

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Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndromeArnaud Germain,1 Ludovic Giloteaux,1 Geoffrey E. Moore,2 Susan M. Levine,1 John K. Chia,3 Betsy A. Keller,2 Jared Stevens,4 Carl J. Franconi,1 Xiangling Mao,5 Dikoma C. Shungu,5 Andrew Grimson,1 and Maureen R. Hanson1
Published March 31, 2022 - Open Access | 10.1172/jci.insight.157621
Abstract
Post-exertional malaise (PEM) is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We monitored the evolution of 1157 plasma metabolites in 60 ME/CFS (45 female, 15 male) and 45 matched healthy control participants (30 female, 15 male) before and after 2 maximal cardiopulmonary exercise test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four time points allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of participants with ME/CFS compared with the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.

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Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)Joanne Hunt , Charlotte Blease , Keith J Geraghty    
First Published March 27, 22 Research Article   https://doi.org/10.1177/13591053221084494
AbstractWhilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.

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Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of PyridostigminePhillip Joseph, MD ∗Rosa Pari, MD ∗Sarah Miller, BS  Wenzhong Xiao, PhD Aaron B. Waxman, MD, PhDDavid M. Systrom, MD dcolour
Published:May 05, 2022DOI:https://doi.org/10.1016/j.chest.2022.04.146
ABSTRACTBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.
Research QuestionDoes neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?
MethodsForty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.
ResultsTwenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.
InterpretationPyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

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The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure
Front Cell Neurosci. 2022; 16: 888232.  Published online 2022 May 9. doi: 10.3389/fncel.
Herbert Renz-Polster, Marie-Eve Tremblay, Dorothee Bienzl , Joachim E Fischer
Abstract
Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking.
Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated.
Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes).
We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia.
 
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HYPOTHESIS AND THEORY  published: 25 May 2022 doi: 10.3389/fneur.2022.877772
Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to SustainDisease and Promote Relapses
Warren Tate 1,2*, Max Walker 1, Eiren Sweetman 1,3, Amber Helliwell 1, Katie Peppercorn 1,2, Christina Edgar 1, Anna Blair 4 and Aniruddha Chatterjee 5
 
1 Department of Biochemistry, University of Otago, Dunedin, New Zealand, 2 Brain Health Research Centre, University of Otago, Dunedin, New Zealand, 3 School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand,
4 Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia, 5 Department of Pathology, University of Otago, Dunedin, New Zealand
 
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented ashaving arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, withbrain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctionalblood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effectsof Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with someunique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are verysimilar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both. 
 

 Research Letter Neurology
October 22, 2021
Assessment of Cognitive Function in Patients After COVID-19 Infection
Jacqueline H. Becker, PhD1; Jenny J. Lin, MD, MPH1; Molly Doernberg, MPH1; et alKimberly Stone, MPH1; Allison Navis, MD2; Joanne R. Festa, PhD2; Juan P. Wisnivesky, MD, DrPH1,3
JAMA Netw Open. 2021;4(10):e2130645. doi:10.1001/jamanetworkopen.2021.30645
Introduction
People who have survived COVID-19 frequently complain of cognitive dysfunction, which has been described as brain fog. The prevalence of post–COVID-19 cognitive impairment and the association with disease severity are not well characterized. Previous studies on the topic have been limited by small sample sizes and suboptimal measurement of cognitive functioning.1 We investigated rates of cognitive impairment in survivors of COVID-19 who were treated in outpatient, emergency department (ED), or in hospital settings.
Methods
We analyzed data in this cross-sectional study from April 2020 through May 2021 from a cohort of patients with COVID-19 followed up through a Mount Sinai Health System registry. Study participants were 18 years or older, spoke English or Spanish, tested positive for SARS-CoV-2 or had serum antibody positivity, and had no history of dementia. Participant demographic characteristics (eg, age, race, and ethnicity) were collected via self-report. Cognitive functioning was assessed using well-validated neuropsychological measures: Number Span forward (attention) and backward (working memory), Trail Making Test Part A and Part B (processing speed and executive functioning, respectively), phonemic and category fluency (language), and the Hopkins Verbal Learning Test–Revised (memory encoding, recall, and recognition). The Mount Sinai Health System Institutional Review Board approved this study, and informed consent was obtained from study participants. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.
We calculated the frequency of impairment on each measure, defined as a z score of less than or equal to 1.5 SDs below measure-specific age-, educational level–, and sex-adjusted norms.2,3 Logistic regression assessed the association between cognitive impairment and COVID-19 care site (outpatient, ED, or hospital), adjusting for race and ethnicity, smoking, body mass index, comorbidities, and depression. The threshold for statistical significance was α = .05, and the tests were 2-tailed. Analyses were performed using SAS, version 9.4 (SAS Institute).
Results
The mean (IQR) age of 740 participants was 49 (38-59) years, 63% (n = 464) were women, and the mean (SD) time from COVID-19 diagnosis was 7.6 (2.7) months (Table 1). Participants self-identified as Black (15%), Hispanic (20%), or White (54%) or selected multiracial or other race and ethnicity (11%; other race included Asian [4.5%, n = 33)] and those who selected “other” as race). The most prominent deficits were in processing speed (18%, n = 133), executive functioning (16%, n = 118), phonemic fluency (15%, n = 111) and category fluency (20%, n = 148), memory encoding (24%, n = 178), and memory recall (23%, n = 170; Table 2).
In adjusted analyses, hospitalized patients were more likely to have impairments in attention (odds ratio [OR]: 2.8; 95% CI: 1.3-5.9), executive functioning (OR: 1.8; 95% CI: 1.0-3.4), category fluency (OR: 3.0; 95% CI: 1.7-5.2), memory encoding (OR: 2.3; 95% CI: 1.3-4.1), and memory recall (OR: 2.2; 95% CI: 1.3-3.8) than those in the outpatient group. Patients treated in the ED were more likely to have impaired category fluency (OR: 1.8; 95% CI: 1.1-3.1) and memory encoding (OR: 1.7; 95% CI: 1.0-3.0) than those treated in the outpatient setting. No significant differences in impairments in other domains were observed between groups.
Discussion
In this study, we found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients. The relative sparing of memory recognition in the context of impaired encoding and recall suggests an executive pattern. This pattern is consistent with early reports describing a dysexecutive syndrome after COVID-194 and has considerable implications for occupational, psychological, and functional outcomes. It is well known that certain populations (eg, older adults) may be particularly susceptible to cognitive impairment after critical illness5; however, in the relatively young cohort in the present study, a substantial proportion exhibited cognitive dysfunction several months after recovering from COVID-19. The findings of this study are generally consistent with those of research on other viruses (eg, influenza).6
Limitations of this study include a potential sampling bias, as some participants may have presented to Mount Sinai Health System because of health concerns. Future studies should investigate long-term post–COVID-19 cognitive trajectories and the association with neuroimaging findings to assess potential mechanisms.
Conclusions
The association of COVID-19 with executive functioning raises key questions regarding patients’ long-term treatment. Future studies are needed to identify the risk factors and mechanisms underlying cognitive dysfunction as well as options for rehabilitation.

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Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study
BMJ 2022; 376 doi: https://doi.org/10.1136/bmj-2021-068414 (Published 09 February 2022)Cite this as: BMJ 2022;376:e068414

1. Ken Cohen,Sheng Ren, Kevin Heath, Micah C Dasmariñas, Karol Giuseppe Yinglong Guo, Marc Lipsitch, Sarah E Daugherty, 
2. Correspondence to: K Cohen Ken.Cohen@optum.com

• Accepted 24 December 2021

Abstract
Objective To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection.
Design Retrospective cohort study.
Setting UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results.
Participants Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490).
Main outcome measures The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19.
Results Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae.
Conclusions The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.
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Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients
Author links open overlay panelR.BertinataR.Villalobos-LabrabL.HofmanncJ.BlauensteinercN.SepúlvedadeF.Westermeiercf
Available online 21 January 2022, 106953asculzr Vascular Pharmacology
https://doi.org/10.1016/j.vph.2022.106953Get rights and content
Highlights
•ME/CFS-plasma reduced the ability of ECs to produce NO.
Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state.
We provide new methodological approaches to study in vitro ED in ME/CFS.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of either plasma from ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence or presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data show that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma. In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.
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Multiple Early Factors Anticipate Post-Acute COVID-19 SequelaeYapeng Su 28
Dan Yuan 28Daniel G. Chen 28Mark M. Davis Jason D. Goldman James R. Heath 29
Published:January 24, 2022DOI:https://doi.org/10.1016/j.cell.2022.01.014
Highlights

• Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
• Reactivation of latent viruses during initial infection may contribute to PASC
• Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
• Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
• SUMMARY

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
DOI: https://doi.org/10.1016/j.cell.2022.01.014

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Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Jessica Van Oosterwijck 1 2, Uros Marusic 3 4, Inge De Wandele 2, Mira Meeus 2 5, Lorna Paul 6, Luc Lambrecht 7, Greta Moorkens 8, Lieven Danneels 2, Jo Nijs 1 9
J Clin Med  . 2021 Sep 30
PMID: 34640544  PMCID: PMC8509376   DOI: 10.3390/jcm10194527
Abstract
Although autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people. Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS. This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.
Keywords: autonomic function; autonomic nervous system; electrocardiogram; electrodermal activity; heart rate.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview
Undine-Sophie Deumer, Angelica Varesi, [...], and Giovanni Ricevuti
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as “brain fog”. These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient. In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.
Keywords: ME/CFS, immunity, dysbiosis, COVID-19, hormone, depression, genetics, miRNA, therapy, diagnosis
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Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients
C. (Linda) M.C. van Campen, Peter C. Rowe, and Frans C. Visser
Clinical Neurophysiology practice  2021:6
Abstract   Objective
Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients.
Methods
60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed,
using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound).
Results
End-tilt cerebral blood flow reduction was −29 (6)%, improving to −16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: −7 (2)%, moderate: −16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients.
Conclusions
During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients.
Significance
The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.
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Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19
Alexandra C. Apple,Alexis Oddi,Michael J. Peluso,Breton M. Asken,Timothy J. Henrich,J. Daniel Kelly,Samuel J. Pleasure,Steven G. Deeks,Isabel Elaine Allen,Jeffrey N. Martin … See all authors 
Annals of transational and clinical neurology
First published: 19 January 2022   https://doi.org/10.1002/acn3.51498
Abstract
Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.
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Restless legs syndrome severity in the National RLS Opioid Registry during the COVID-19 pandemic
BenjaminWipperChristopherRomero-GutierrezJohn W.Winkelman
https://doi.org/10.1016/j.sleep.2022.01.011
Abstract
Objective/background
No research has yet assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on restless legs syndrome (RLS). We hypothesized that RLS symptom severity would be increased during the COVID-19 pandemic in a sample of patients with diagnosed RLS.
Patients/methods
The National RLS Opioid Registry is a longitudinal observational study of patients using opioid medications for treatment of RLS. Questionnaires assessing RLS symptom severity, medication dosages, sleep disturbance, depression, and anxiety are administered at baseline and at recurring 6-month surveys. Survey responses from the outset of the pandemic in April/May 2020 were compared to responses completed by other participants in January/February 2020 (between-subjects analysis), as well as responses by the same participants at baseline, approximately six months later in September 2020 through February 2021, and approximately one year later in March through June 2021 (within-subjects analyses).
Results
These analyses provide evidence for higher RLS symptom severity scores at the outset of the COVID-19 pandemic in the US. Symptom severity scores were still elevated on subsequent questionnaires completed over six months into the pandemic but had returned towards baseline by the spring of 2021. Participants with increases in RLS severity were significantly more likely than others to see increases in sleep disturbance, depression, and anxiety.
Conclusions
This is the first study demonstrating increased RLS symptom severity during the earliest stage of the COVID-19 pandemic. These findings warrant similar investigations in other patient populations and suggest that clinicians should attend to RLS symptoms during times of socioeconomic and/or political uncertainty.
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COVID-19: 1 in 3 older adults will develop post-COVID-19 syndrome
Cohen K & al.. BMJ, 09 February 2022
Takeaway

• Roughly 1 in 3 older adults will develop persistent or new clinical sequelae post-acute COVID-19 infection.

Why this matters

• Consider post-acute COVID-19 risk in older adults previously hospitalized for primary infection, especially those presenting with viral lower respiratory tract illness (vLRTI).

Key results

• 132,847 matched pairs diagnosed pre-1 April 2020; median age, 74 years.
• 87,337, post-acute care: 16% (13,992) 1 sequelae, 16% (13,706) ≥2.
• Comparative group difference vs 2020: −11 (95% CI, −11.4 to −10.6); 2019: −7.9 (95% CI, −8.3 to −7.5); vLRTI: 1.4 (95% CI, 0.9-1.9).
• Most common (all P<.001 vs 2020 comparator) risk difference (RD):
  • Respiratory failure: 7.55 (95% CI, 7.18-8.01).
  • Fatigue: 5.66 (95% CI, 5.03-6.27).
  • Hypertension: 4.43 (95% CI, 2.27-6.37).
  • Mental health diagnoses: 2.5 (95% CI, 2.04-3.04).
  • Acute kidney injury: 2.74 (95% CI, 2.39-3.07).
  • Memory issues: 2.63 (95% CI, 2.23-3.13).
  • Myalgia: 2.25 (95% CI, 1.57-2.95).
  • Cardiac rhythm disorders: 2.19 (95% CI, 1.76-2.57).
  • Hypercoagulability: 1.47 (95% CI, 1.2-1.73).
• Vs vLRTI, RD:
  • Respiratory failure: 2.39 (95% CI, 1.79-2.94).
  • Dementia: 0.71 (95% CI, 0.3-1.08).
  • Postviral fatigue: 0.18 (95% CI, 0.11-0.26).

Study design

• Retrospective cohort study estimating excess risk, new clinical sequelae post-acute SARS-CoV-2 infection phase in Medicare US adults aged ≥65 years.
• Funding: Optum Laboratories.

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Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome
Nat Commun. 2022; 13: 446.
Published online 2022 Jan 25. doi: 10.1038/s41467-021-27797-1 PMCID: PMC8789854
PMID: 35078982
Carlo Cervia,1 et al
1Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
Abstract
Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.
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Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Mark A.Zinn Leonard A.Jason
International Journal of Psychophysiology Volume 170, December 2021, Pages 89-101
https://doi.org/10.1016/j.ijpsycho.2021.10.004Get rights and content
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) represents a significant public health challenge given the presence of many unexplained patient symptoms. Research has shown that many features in ME/CFS may result from a dysfunctional autonomic nervous system (ANS). We explored the role of the cortical autonomic network (CAN) involved in higher-order control of ANS functioning in 34 patients with ME/CFS and 34 healthy controls under task-free conditions. All participants underwent resting-state quantitative electroencephalographic (qEEG) scalp recordings during an eyes-closed condition. Source analysis was performed using exact low-resolution electromagnetic tomography (eLORETA), and lagged coherence was used to estimate intrinsic functional connectivity between each node across 7 frequency bands: delta (1–3 Hz), theta (4–7 Hz), alpha-1 (8–10 Hz), alpha-2 (10–12 Hz), beta-1 (13–18 Hz), beta-2 (19–21 Hz), and beta-3 (22–30 Hz). Symptom ratings were measured using the DePaul Symptom Questionnaire and the Short Form (SF-36) health survey. Graph theoretical analysis of weighted, undirected connections revealed significant group differences in baseline CAN organization. Regression results showed that cognitive, affective, and somatomotor symptom cluster ratings were associated with alteration to CAN topology in patients, depending on the frequency band. These findings provide evidence for reduced higher-order homeostatic regulation and adaptability in ME/CFS. If confirmed, these findings address the CAN as a potential therapeutic target for managing patient symptoms.
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Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping
by Jesús Castro-Marrero Mario Zacares,Eloy Almenar-Pérez, José Alegre-Martín, Elisa Oltra*
J. Clin. Med. 2021, 10(18), 4171; https://doi.org/10.3390/jcm10184171
Received: 27 August 2021 / Revised: 10 September 2021 / Accepted: 13 September 2021 / Published: 15 September 2021
Abstract
Background: 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.
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Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
C. (Linda) M. C. van Campen,Peter C. Rowe, Frans C. Visser
Stichting CardioZorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Author to whom correspondence should be addressed.
Academic Editor: Olli J. Polo
Medicina 2022, 58(1), 28; https://doi.org/10.3390/medicina58010028
Received: 18 November 2021 / Revised: 18 December 2021 / Accepted: 21 December 2021 / Published: 24 December 2021
Abstract
Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.  
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AJGP Volume 50, Issue 12, December 2021
Outcomes of COVID-19 in the community: A prospective cohort study
Stuart Tan   Lyndel Hewitt   Jose Cuenca   Dante Risi  
doi: 10.31128/AJGP-07-21-6078   
The literature indicates that patients who had previously had COVID-19 are reporting ongoing symptoms. The objective of this study was to examine ongoing symptoms, functional limitations and quality of life over time in a cohort of individuals who were deemed to have recovered.
Methods
This was a prospective observational study on biopsychosocial outcomes at enrolment and again one month later.
Results
In a cohort of 59 participants, ongoing symptoms were reported by 73% at 4.5 months (standard deviation = 1.4) post diagnosis, with 45% reporting difficulty with pre-illness activities of daily living. Of the 52 participants who completed the follow-up survey (mean 5.6 months post diagnosis), 42% reported ongoing symptoms, lower physical quality of life (12-Item Short Form Health Survey) and higher levels of anxiety, depression and stress (Depression, Anxiety and Stress Scale).
Discussion
Ongoing symptoms such as fatigue, pain and limb weakness as well as functional impairment post initial diagnosis were common. Improved understanding of this cohort can assist general practitioners in providing care.


COVID-19 is a viral infection that emerged from Wuhan, China, in December 2019. This disease has spread throughout the world (221 countries) and was declared a pandemic by the World Health Organization on 11 March 2020.1,2 Globally, by 21 June 2021, there were 178,433,377 confirmed cases, including 3,864,702 deaths (https://covid19.who.int). Of these reported cases, 163,827,935 were deemed to have recovered by various public health authorities (www.worldometers.info/coronavirus). In Australia, there had been 30,331 cases with 910 deaths at 21 June 2021, with 27,021 of these cases classified as recovered. Despite this, there have been many reports of individuals with COVID-19 experiencing debilitating symptoms long after being cleared of the acute infection.3 The term ‘long COVID’ has been used in the literature to describe the condition,4 and further studies are emerging to investigate the effects of this condition on the human body.


Various studies from other countries report ongoing morbidities of patients with COVID-19. These morbidities relate to severe pulmonary limitation,6 hepatic impairment,7 hemostatic changes8 and neurological complications.9 Carfi et al reported that in a cohort of 143 hospitalised patients who had recovered from COVID-19, 87.4% reported persistence of one symptom at a mean of 60.3 days (standard deviation [SD] = 13.6) after the onset of their first COVID-19 symptom.10 Similarly, Huang et al reported that 76% of patients hospitalised with COVID-19 (n = 1655) were symptomatic at follow-up.11 In a systematic literature review, Nasserie et al found that 72.5% of patients reported at least one symptom at 60 days or more after diagnosis, symptom onset or hospitalisation or at 30 days or more after recovery from acute illness or hospital discharge.12
The speed and ferocity of transmission of COVID-19 throughout the world has resulted in a scarcity of data on biopsychosocial and functional outcomes of survivors of COVID-19 in the community. An analysis of the clinical progress, ongoing morbidities, functional outcomes and demand on current services after a positive COVID-19 diagnosis would facilitate appropriate future resource allocation required to address these concerns and prevent their escalation before they put additional strain on the healthcare system.13 Based on Communicable Diseases Network Australia (CDNA) guidelines (version 5.1),14 an individual in the community who tested positive for COVID-19 is deemed to have recovered sufficiently to be discharged from virtual care under the following criteria: 1) 14 days after a positive polymerase chain reaction (PCR) test if asymptomatic, 2) if the patient has been afebrile for the preceding 72 hours with substantial improvement of respiratory symptoms or 3) 20 days after a positive PCR test even if still symptomatic. In April 2020, the criterion (version 2.7) was the patient being afebrile for three consecutive days in the preceding 10 days. 
It is hypothesised that individuals with a positive COVID-19 diagnosis will have ongoing health issues and needs after being classified as ‘recovered’ under current guidelines. The aim of this study was to investigate the biopsychosocial status of a cohort of individuals who had been diagnosed with COVID-19 and deemed to have recovered by health authorities, and to describe any ongoing symptoms and functional and/or mental health outcomes on enrolment to the study and one month later.
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medRxiv 2022 Jan 11;2021.06.14.21258895.  doi: 10.1101/2021.06.14.21258895. Preprint
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Xiaoyu Che, Christopher R Brydges, Yuanzhi Yu, Adam Price, Shreyas Joshi, Ayan Roy, Bohyun Lee, Dinesh K Barupal, Aaron Cheng, Dana March Palmer, Susan Levine, Daniel L Peterson, Suzanne D Vernon, Lucinda Bateman, Mady Hornig, Jose G Montoya, Anthony L Komaroff, Oliver Fiehn, W Ian Lipkin
PMID: 35043127 PMCID: PMC8764736 DOI: 10.1101/2021.06.14.21258895
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.
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Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID
 View ORCID ProfileAnne Louise Oaklander, Alexander J. Mills, Mary Kelley, Lisa S. Toran, Bryan Smith, Marinos C. Dalakas, Avindra Nath     
First published March 1, 2022, DOI:
        https://doi.org/10.1212/NXI.0000000000001146
Abstract
Background and Objectives Recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears exponential, leaving a tail of patients reporting various long COVID symptoms including unexplained fatigue/exertional intolerance and dysautonomic and sensory concerns. Indirect evidence links long COVID to incident polyneuropathy affecting the small-fiber (sensory/autonomic) axons.
Methods We analyzed cross-sectional and longitudinal data from patients with World Health Organization (WHO)-defined long COVID without prior neuropathy history or risks who were referred for peripheral neuropathy evaluations. We captured standardized symptoms, examinations, objective neurodiagnostic test results, and outcomes, tracking participants for 1.4 years on average.
Results Among 17 patients (mean age 43.3 years, 69% female, 94% Caucasian, and 19% Latino), 59% had ≥1 test interpretation confirming neuropathy. These included 63% (10/16) of skin biopsies, 17% (2/12) of electrodiagnostic tests and 50% (4/8) of autonomic function tests. One patient was diagnosed with critical illness axonal neuropathy and another with multifocal demyelinating neuropathy 3 weeks after mild COVID, and ≥10 received small-fiber neuropathy diagnoses. Longitudinal improvement averaged 52%, although none reported complete resolution. For treatment, 65% (11/17) received immunotherapies (corticosteroids and/or IV immunoglobulins).
Discussion Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause long-term disability (long COVID) with new neurologic manifestations after even mild infections.1 Reports of peripheral neuropathy include Guillain-Barré syndrome, mononeuritis multiplex, brachial plexitis, cranial neuropathies, and orthostatic intolerance, although some studies included patients with potentially contributory conditions. Various long COVID symptoms overlap with those of small-fiber polyneuropathy (SFN).2,3 Hence, we prospectively analyzed a cross-section of patients with long COVID evaluated for incident neuropathy.

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Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms
MedRxiv
Cheng Guo, Xiaoyu Che, Thomas Briese,  View ORCID ProfileOrchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March,  View ORCID ProfileMady Hornig,  View ORCID ProfileAnthony L. Komaroff, Susan Levine,  View ORCID ProfileLucinda Bateman,  View ORCID ProfileSuzanne D. Vernon,  View ORCID ProfileNancy G. Klimas, Jose G. Montoya, Daniel L. Peterson,  View ORCID ProfileW. Ian Lipkin,  View ORCID ProfileBrent L. Williams
doi: https://doi.org/10.1101/2021.10.27.21265575
Abstract
Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.
Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.
Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

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Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by  Manuela Simonato et al
PCare Laboratory, Fondazione Istituto di Ricerca Pediatrica, Citta’ della Speranza, 35127 Padova, Italy
These authors contributed equally to this work.
Academic Editors: Masaru Tanaka and Nóra Török
Biomedicines 2021, 9(11), 1724; https://doi.org/10.3390/biomedicines9111724
Received: 16 October 2021 / Revised: 14 November 2021 / Accepted: 15 November 2021 / Published: 19 November 2021
Abstract
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.
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Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis
Leonard A Jason1*, et al Emails: Leonard Jason: ljason@depaul.edu; 
Abstract
Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.
Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM.  Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students  had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM.  We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of  those who developed ME/CFS and severe ME/CFS following IM.
Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline  and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM,  were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM.
Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

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Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population
Toshimori Kitami, Sanae Fukuda, [...], and Yasuyoshi Watanabe
Scientific reports – Nature research
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
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Physiological assessment of orthostatic intolerance in chronic fatigue syndrome
Benjamin H. Natelson, Jin-Mann S. Lin, [...], and Elizabeth R. Unger
J Transl Med. 2022; 20: 95. Published online 2022 Feb 16. doi: 10.1186/s12967-022-03289-8
PMCID: PMC8849016 PMI D: 35172863
Abstract
Background
Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia.

Objective
Evaluate the physiologic response of patients with ME/CFS to a standardized OC. 
Design
Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2.
Patients
63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29).
Measures
Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension.

Results
The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia.

Conclusions
The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.
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Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
by Xia Li, Per Julin, Tie-Qiang Li
Institute of Information Engineering, China Jiliang University, 258 Xueyuan Street, Xiasha Higher 
Tomography 2021, 7(4), 675-687; https://doi.org/10.3390/tomography7040056
Received: 31 August 2021 / Revised: 13 October 2021 / Accepted: 18 October 2021 / Published: 1 November 2021
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS. In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor. In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.
Keywords: chronic fatigue syndrome; regional cerebral blood flow; pseudo-continuous arterial spin labeling; sustained attention; magnetic resonance imaging; limbic system
Front. Neurol., 13 December 2021 | https://doi.org/10.3389/fneur.2021.789784

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Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Dominic Stanculescu1, Nuno Sepúlveda2,3, Chin Leong Lim4 and Jonas Bergquist5,6*

• 1Independent Researcher, Sint Martens Latem, Belgium
• 6The ME/CFS Collaborative Research Center at Uppsala University, Uppsala, Sweden

We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS. Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences - and despite heat stroke being an acute condition - the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.
Journal of Advanced Research
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Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome
Author links open overlay panelOlga A.Sukochevaab1RebekahMaksoudbc1Narasimha M.BeerakadSabbaRao V.MadhunapantuladeMikhailSinelnikovfVladimir N.NikolenkofMargarita E.NeganovagSergey G.KlochkovgMohammadAmjad KamalhiDonald RStainesbcSonyaMarshall-Gradisnikbc
https://doi.org/10.1016/j.jare.2021.11.013Get rights and content
Abstract
Background
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Aims of Review
In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology.
Key Scientific Concepts of Review
The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

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Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts
Daniel Missailidis 1, Oana Sanislav 1, Claire Y Allan 1, Paige K Smith 2, Sarah J Annesley 1, Paul R Fisher 1
PMID: 33669532 PMCID: PMC7921983  DOI: 10.3390/ijms22042046
Int J Mol Sci. 2021 Feb 19;22(4):2046.
Abstract
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10-4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10-4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10-3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.
Keywords: ME/CFS; Myalgic Encephalomyelitis; TCA cycle; amino acid catabolism; beta-oxidation; glycolysis; metabolism; mitochondria; proteomics; transcriptomics.

Stellate ganglion block reduces symptoms of Long COVID: A case series 
Short communication – Journal of neuroimmunology
Luke D. Liu, Deborah L. Duricka * Neuroversion Inc., Anchorage, AK, USA ARTICLE INFO
 Keywords: Long COVID/PASC Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) Postural orthopedic tachycardia syndrome (POTS) Dysautonomia Stellate ganglion block Cerebral blood flow

 ABSTRACT After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble “sickness behavior,” the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to “reboot.” In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.

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Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report
Peter Novak 1
eNeurologicalSci  . 2020 Dec;21:100276.
 doi: 10.1016/j.ensci.2020.100276. Epub 2020 Sep 20.
PMID: 32984564PMCID: PMC7502253
Abstract
Coronavirus disease (COVID-19) is a novel highly contagious infectious disease caused by the coronavirus SARS-CoV2. The virus affects the human respiratory and other systems, and presents mostly as acute respiratory syndrome with fever, fatigue, dry cough, myalgia and dyspnea. The clinical manifestations vary from no symptoms to multiple organ failure. Majority of patients fully recover. Several postinfectious presumably autoimmune complications of COVID-19 affecting the brain or peripheral large nerve fibers have been reported. This report describes a post COVID-19 patient who developed chronic fatigue, orthostatic dizziness and brain fog consistent with orthostatic hypoperfusion syndrome (OCHOS), a form of orthostatic intolerance, and painful small fiber neuropathy (SFN). Initially, the patient was diagnosed with. OCHOS (detected by the tilt test with transcranial Doppler monitoring) and SFN (confirmed by skin biopsy), and both OCHOS/SFN were attributed to Post Treatment Lyme Disease Syndrome of presumed autoimmune etiology. Patient recovered on symptomatic therapy. COVID-19 triggered exacerbation of OCHOS/SFN responded to immunotherapy with intravenous immunoglobulins. This case suggests that post COVID-19 syndrome may present as an autoimmune OCHOS/SFN and that early immunotherapy may be effective. Further studies are necessary to confirm the link between OCHOS/SFN and COVID-19 disease as well as to confirm the benefit of immunotherapy.
© 2020 Published by Elsevier B.V.


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PLoS One
 2019 Feb 12;14(2):e0212222. doi: 10.1371/journal.pone.0212222. eCollection 2019.
Association of small fiber neuropathy and post treatment Lyme disease syndrome
Peter Novak 1, Donna Felsenstein 2, Charlotte Mao 3, Nadlyne R Octavien 4, Nevena Zubcevik 5
PMID: 30753241  PMCID: PMC6372188


Abstract
Objectives: To examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.
Methods: This single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.
Results: 10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.
Conclusions: SFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

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Diverse functional autoantibodies in patients with COVID-19
Eric Y Wang # 1, Tianyang Mao # 1, Jon Klein # 1, Yile Dai # 1, John D Huck 1, Jillian R Jaycox 1, Feimei Liu 1, Ting Zhou 1, Benjamin Israelow 1, Patrick Wong 1, Andreas Coppi 2, Carolina Lucas 1, Julio Silva 1, Ji Eun Oh 1, Eric Song 1, Emily S Perotti 1, Neil S Zheng 1, Suzanne Fischer 1, Melissa Campbell 3, John B Fournier 3, Anne L Wyllie 4, Chantal B F Vogels 4, Isabel M Ott 4, Chaney C Kalinich 4, Mary E Petrone 4, Anne E Watkins 4, Yale IMPACT Team; Charles Dela Cruz 5, Shelli F Farhadian 3, Wade L Schulz 2 6, Shuangge Ma 7, Nathan D Grubaugh 4, Albert I Ko 3 4, Akiko Iwasaki 8 9 10, Aaron M Ring 11 12
PMID: 34010947   DOI: 10.1038/s41586-021-03631-y
Nature   2021 Jul;595(7866):283-288.  doi: 10.1038/s41586-021-03631-y. Epub 2021 May 19
Abstract
COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

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ORIGINAL RESEARCH article
Front. Syst. Neurosci., 01 September 2021 | https://doi.org/10.3389/fnsys.2021.698240
Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett1, Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman2
Cortene Inc., Burlingame, CA, United States 2Bateman Horne Center, Salt Lake City, UT, 
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.
Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.
International Journal of Environmental Research and Public Health

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Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study 
Cassandra Balinas 1,2,3,†, Natalie Eaton-Fitch 1,2,3,†, Rebekah Maksoud 1,2,* ,† , Donald Staines 1,2 and Sonya Marshall-Gradisnik 1,2   Citation: Balinas, C.; Eaton-Fitch, N.; Maksoud, R.; Staines, D.; Marshall-Gradisnik, S. Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study. Int. J. Environ. Res. Public Health 2021, 18, 10614. https://doi.org/10.3390/ ijerph182010614 Academic Editor: Paul B. Tchounwou Received: 1 September 2021 Accepted: 6 October 2021 Published: 11 October 2021 
The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast 4215, Australia; 
Abstract: (1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multifaceted illness. The pathomechanism, severity and progression of this illness is still being investigated. Stressors have been implicated in symptom exacerbation for ME/CFS, however, there is limited information for an Australian ME/CFS cohort. The aim of this study was to assess the potential effect of life stressors including changes in work, income, or family scenario on symptom severity in an Australian ME/CFS cohort over five months; (2) Methods: Australian residents with ME/CFS responded to questions relating to work, income, living arrangement, access to healthcare and support services as well as symptoms experienced; (3) Results: thirty-six ME/CFS patients (age: 41.25 ± 12.14) completed all questionnaires (response rate 83.7%). Muscle pain and weakness, orthostatic intolerance and intolerance to extreme temperatures were experienced and fluctuated over time. Sleep disturbances were likely to present as severe. Work and household income were associated with worsened cognitive, gastrointestinal, body pain and sleep symptoms. Increased access to healthcare services was associated with improved symptom presentation; (4) Conclusions: life stressors such as work and financial disruptions may significantly contribute to exacerbation of ME/CFS symptoms. Access to support services correlates with lower symptom scores. 

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The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study
Carol L. Hodgson, Alisa M. Higgins, 
The COVID-Recovery Study Investigators and the ANZICS Clinical Trials Group
Critical Care volume 25, Article number: 382 (2021)  Published: 08 November 2021

Abstract
Background
There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months.
Methods
In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM.
Results
Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51–70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06–13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, − 0.19 [− 0.28 to − 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty.
Conclusions
At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning.
Clinical trial registration NCT04401254 May 26, 2020.

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Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Rakib U. Rayhan and James N. Baraniuk
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertiona*l malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.
Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.
Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.
Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.
Keywords: postexertional malaise, default mode network, DMN, blood oxygenation level dependent, BOLD, fibromyalgia, chronic idiopathic fatigue, submaximal exercise

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Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Emi Yamano, Yasuyoshi Watanabe, and Yosky Kataoka
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.
Keywords: ME/CFS, etiology, biomarker, metabolome, objective diagnosis

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TRYPTOPHAN METABOLITES, CYTOKINES, AND FATTY ACID BINDING PROTEIN 2 IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME –
 PROF. ALDO BARITUSSIO ET AL
Abstract
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease.
Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls.
Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine.
ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls.
Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively.
No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease.
Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism.
Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

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BACK TO THE FUTURE? IMMUNOGLOBULIN THERAPY FOR MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME
Helen Brownlie and Nigel Speight
ABSTRACT
The findings of controlled trials on use of intravenous immunoglobulin G (IV IgG) to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are generally viewed as representing mixed results. On detailed review, a clearer picture emerges, which suggests that the potential therapeutic value of this intervention has been underestimated.
Our analysis is consistent with the propositions that:
(1) IgG is highly effective for a proportion of patients with severe and well-characterised ME/CFS;
(2) responders can be predicted with a high degree of accuracy based on markers of immune dysfunction.
Rigorous steps were taken in the research trials to record adverse events, with transient symptom exacerbation commonly experienced in both intervention and placebo control groups, suggesting that this reflected the impact of participation on people with an illness characterised by post-exertional symptom exacerbation.
Worsening of certain specific symptoms, notably headache, did occur more commonly with IgG and may have been concomitant to effective treatment, being associated with clinical improvement.
The findings emerging from this review are supported by clinical observations relating to treatment of patients with severe and very severe ME/CFS, for whom intramuscular and subcutaneous administration provide alternative options.
We conclude that:  (1) there is a strong case for this area of research to be revived;
(2) pending further research, clinicians would be justified in offering a course of IgG to selected ME/CFS patients at the more severe end of the spectrum.   As the majority of trial participants had experienced an acute viral or viral-like onset, we further suggest that IgG treatment may be pertinent to the care of some patients who remain ill following infection with SARS-CoV-2 virus
Free full text: Healthcare

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A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination       published on November 24, 2021, at NEJM.org.
 William J. Murphy, Ph.D., and Dan L. Longo, M.D.


The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is incompletely understood, with its effects on multiple organ systems1 and the syndrome of “long Covid” occurring long after the resolution of infection.2 The development of multiple efficacious vaccines has been critical in the control of the pandemic, but their efficacy has been limited by the appearance of viral variants, and the vaccines can be associated with rare off-target or toxic effects, including allergic reactions, myocarditis, and immune-mediated thrombosis and thrombocytopenia in some healthy adults. Many of these phenomena are likely to be immune-mediated.3 How can we understand this diversity in immune responses in different persons?
One way of thinking about the complexity of the immune response is through the lens of anti-idiotype immune responses. The Network Hypothesis, formulated in 1974 by Niels Jerne, described a mechanism by which the antibody responses to an antigen themselves induced downstream antibody responses against the antigen-specific antibody.4 Every antibody that is induced and specific for an antigen (termed “Ab1” antibody) has immunogenic regions, particularly in their variable-region antigen-binding domains, that are unique as a result of genetic recombination of immunoglobulin variable, diversity, and joining (VDJ) genes; VDJ recombination results in new and therefore immunogenic amino acid sequences called idiotopes, which are then capable of inducing specific antibodies against Ab1 antibodies as a form of down-regulation. A similar paradigm has been proposed for T cells. However, these regulatory immune responses are also capable of doing much more. The paratopes, or antigen-binding domains, of some of the resulting anti-idiotype (or “Ab2”) antibodies that are specific for Ab1 can structurally resemble that of the original antigens themselves. Thus, the Ab2 antigen-binding region can potentially represent an exact mirror image of the initial targeted antigen in the Ab1 response, and Ab2 antibodies have even been examined for potential use as a surrogate for the antigen in vaccine studies. However, as a result of this mimicry, Ab2 antibodies also have the potential to bind the same receptor that the original antigen was targeting (Figure 1). Ab2 antibodies binding to the original receptor on normal cells therefore have the potential to mediate profound effects on the cell that could result in pathologic changes, particularly in the long term — long after the original antigen itself has disappeared.
This aspect of regulation of immune-cell responses was postulated by Plotz in 1983 as a possible cause of autoimmunity arising after viral infection5 and has since been supported experimentally by direct transfer of anti-idiotype antibodies. Ab2 antibodies generated against the enterovirus coxsackievirus B3 in mice can bind myocyte antigens, resulting in autoimmune myocarditis,6 and anti-idiotype responses can act as acetylcholine receptor agonists, leading to myasthenia gravis symptoms in rabbits.7 In addition, by displaying the mirror image of the viral antigen, Ab2 alone can even mimic the deleterious effects of the virus particle itself, as has been shown with bovine viral diarrhea virus antigen.8
For SARS-CoV-2 infection, attention centers on the spike (S) protein and its critical use of the angiotensin-converting–enzyme 2 (ACE2) receptor to gain entry into the cell. Given its critical role in regulating angiotensin responses, many physiological effects can be influenced by ACE2 engagement.9 The S protein itself has a direct effect on suppressing ACE2 signaling by a variety of mechanisms and can also directly trigger toll-like receptors and induce inflammatory cytokines.10 Anti-idiotype responses may affect ACE2 function, resulting in similar effects. However, preclinical and clinical assessments of antibody responses to SARS-CoV-2 vaccines have focused solely on Ab1 responses and virus-neutralizing efficacy. The delineation of potential anti-idiotype responses has inherent difficulties because of the polyclonal nature of responses, dynamic kinetics, and the concurrent presence of both Ab1 and Ab2 antibodies. Furthermore, ACE2 expression within cells and tissues can be variable. The different vaccine constructs (RNA, DNA, adenoviral, and protein) are also likely to have differential effects on Ab2 induction or in the mediation of vaccine effects that differ from responses to infection. Some off-target effects may not be directly linked to Ab2 responses. The association of thrombotic events with some SARS-CoV-2 vaccines in young women and the etiologic role of anti–platelet factor 4–polyanion antibodies may be the result of the adenoviral vector. However, the reported occurrence of myocarditis after vaccine administration bears striking similarities to the myocarditis associated with Ab2 antibodies induced after some viral infections.6 Ab2 antibodies could also mediate neurologic effects of SARS-CoV-2 infection or vaccines, given the expression of ACE2 on neuronal tissues, the specific neuropathologic effects of SARS-CoV-2 infection,11 and the similarity of these effects to Ab2-mediated neurologic effects observed in other viral models.
It would therefore be prudent to fully characterize all antibody and T-cell responses to the virus and the vaccines, including Ab2 responses over time. Using huACE2 transgenic mice and crossing them with strains that are predisposed to autoimmunity or other human pathologic conditions can also provide important insights. An understanding of potential Ab2 responses may also provide insights into Ab1 maintenance and efficacy and into the application of antibody-based therapeutic agents. However, much more basic science research is needed to determine the potential role idiotype-based immunoregulation of both humoral and cell-mediated responses may play both in antiviral efficacy and in unwanted side effects of both SARS-CoV-2 infection and the vaccines that protect us from it.

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Graded exercise therapy for ME/CFS: finding consensus between the royal colleges, patients, and researchers
BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n3026 (Published 08 December 2021)Cite this as: BMJ 2021;375:n3026
The BMJ reports the royal colleges’ discontent with the new National Institute for Health and Care Excellence guideline on myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS), particularly regarding graded exercise therapy (GET).12 The quality of the evidence and the rigour of its assessment are contested by the colleges, patient representatives, and researchers.34 In summary, the colleges emphasise the potential benefits of exercise for patients with ME/CFS, the patient community emphasises the potential harm that exercise can cause, and both communities quote research supporting their hypotheses, the quality of which is contested. Is there any agreement on the guideline?
Consider a patient with ME/CFS who, after attempting a therapy based on exercise, reports a worsening of their symptoms, sequelae which they regard as harmful. Should the treating physician interpret this as “the bodies [sic] normal response” and press on? Or should they defer to the NICE assertion that “treatment programmes that result in symptom exacerbation are not recommended” and abandon exercise based approaches?5
The guideline is quite clear: “Health and social care professionals should take time to build supportive, trusting, and empathetic relationships.” Trust cannot be achieved if a patient believes the prescribed treatment is causing them harm. Surely royal colleges, researchers, and patients can all agree on this?

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SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19
Lize M. Grobbelaar, Sample analysis, Visualization, Writing—original draft, Chantelle Venter, Data curation, Project administration, [...], and Etheresia Pretorius, 
Bioscience reports Volume 41, Issue 8 – August 2021
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation.
Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to β and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.
Keywords: COVID-19, electron microscopy, Fibrin(ogen), fluorescence microscopy, Microclot, Spike protein Sa

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MEDICAL NEWS: New metabolic phenotype of long COVID identified
Heather Mason   |   18 January 2022
A potential new cluster phenotype for patients with post-acute COVID syndrome (PACS) is described in an article published in Open Forum Infectious Diseases, which reports on the prevalence of this metabolic-associated fatty liver disease (MAFLD) phenotype.
The analysis included 235 patients who were followed at a single university outpatient clinic. The primary outcome was the prevalence of MAFLD, detected by transient elastography, during the first post-discharge follow-up visit, compared with the MAFLD prevalence at the time of hospital admission. Figures were calculated retrospectively using the hepatic steatosis index.
The results showed that the prevalence of MAFLD was 55.3 per cent at follow-up and 37.3 per cent on admission. Among the independent predictors of MAFLD were insulin resistance (odds ratio [OR] 1.5), body mass index (OR 1.14), and metabolic syndrome (OR 2.54).
Regarding a possible link with other clusters, the researchers found that MAFLD had weak or very weak associations, indicating that it may represent an independent PACS cluster, with potential metabolic and cardiovascular health consequences in the long-COVID-19.
The authors highlight the importance of careful follow-up of patients with MAFLD in the context of PACS since it is necessary to understand the clinical implications of this syndrome.

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Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis
KJETIL BJORNEVIK HTTPS://ORCID.ORG/0000-0002-2892-6986MARIANNA CORTESE HTTPS://ORCID.ORG/0000-0002-3665-2006BRIAN C. HEALY HTTPS://ORCID.ORG/0000-0001-5272-2425JENS KUHLEMICHAEL J. MINA HTTPS://ORCID.ORG/0000-0002-0674-5762YUMEI LENG HTTPS://ORCID.ORG/0000-0003-2512-9284STEPHEN J. ELLEDGE HTTPS://ORCID.ORG/0000-0001-7923-6283DAVID W. NIEBUHRANN I. SCHER[...]ALBERTO ASCHERIO  
SCIENCE • 13 Jan 2022 • Vol 375, Issue 6578 • pp. 296-301 • DOI: 10.1126/science.abj8222
Stronger evidence for viral connection
Multiple sclerosis is a chronic demyelinating disease of the central nervous system. The underlying cause of this disease is not known, but Epstein-Barr virus is thought to be a possible culprit. However, most people infected with this common virus do not develop multiple sclerosis, and it is not feasible to directly demonstrate causation of this disease in humans. Using data from millions of US military recruits monitored over a 20-year period, Bjornevik et al. determined that Epstein-Barr virus infection greatly increased the risk of subsequent multiple sclerosis and that it preceded the development of disease, supporting its potential role in the pathogenesis of multiple sclerosis (see the Perspective by Robinson and Steinman). —YN
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

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FDA OKs New Adult Insomnia Med  - Medscape medical news
Erik Greb
January 10, 2022
The US Food and Drug Administration (FDA) has approved the dual orexin receptor antagonist daridorexant (Quviviq) for the treatment of insomnia in adults, the drug's manufacturer, Idorsia, has announced.
The FDA's decision was based partly on a phase 3 trial of adults with moderate-to-severe insomnia who were randomly assigned to receive 25 or 50 mg of daridorexant or matching placebo. Daridorexant was associated with dose-dependent improvements in wake after sleep onset, total sleep time, and latency to persistent sleep.
Whereas the overall results are very positive, the improvements in daytime functioning are especially "exciting," Thomas Roth, PhD, director of the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, Michigan, told Medscape Medical News.
"That's sort of a big deal. For me, that's the biggest deal there is," said Roth, who was a consultant on the design of the phase 3 trial and on the interpretation of the data.
The drug will be available in doses of 25 mg and 50 mg, and the FDA has recommended that it be classified as a controlled substance. After it is scheduled by the US Drug Enforcement Administration, daridorexant is expected to be made available in May.


Favorable Safety Profile
Insomnia is a common disorder characterized by difficulty falling asleep or staying asleep and by early morning awakenings. Patients with insomnia often report fatigue, irritability, and difficulty with concentration. The condition can also result in significant problems with work and social activities, thus contributing to anxiety or depression.
As with other dual orexin receptor antagonists, daridorexant competitively binds with both orexin receptors in the lateral hypothalamus to block the activity of orexin in a reversible way. This approach decreases the downstream action of the wake-promoting neurotransmitters that are overactive in patients with insomnia.
The phase 3 trial measured daytime functioning using the new Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a patient-reported outcome instrument. Daridorexant was associated with significant improvements in daytime function, particularly in sleepiness and mood.
Previous trials of other dual orexin receptor antagonists did not use the IDSIQ as an outcome, so it is not possible to compare daridorexant with those drugs in this respect, Roth noted. Researchers also have not conducted head-to-head trials of the drug with other dual orexin receptor antagonists.
Daridorexant also had a favorable safety profile and was not associated with rebound insomnia or withdrawal effects. The most common adverse events were headache and somnolence or fatigue.
"They had no effect on sleep stage distribution [and] they had no significant effects on sleep and breathing in people with mild to moderate sleep apnea," said Roth, who presented the phase 3 findings at SLEEP 2020. 

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The Lancet: ARTICLES| VOLUME 21, ISSUE 2, P125-139, FEBRUARY 01, 2022
Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials

• Prof Emmanuel Mignot, MD  David Mayleben, PhD Prof Ingo Fietze, MD Damien Leger, MD Gary Zammit, PhD Claudio L A Bassetti, MD et al.

Published:February, 2022DOI:https://doi.org/10.1016/S1474-4422(21)00436-1
Summary
Background
Daytime functioning is impaired in people with insomnia disorder. Currently available dual orexin receptor antagonists have shown efficacy in insomnia disorder, but do not address all aspects of this disease. We aimed to assess safety and efficacy of daridorexant, a novel orexin receptor antagonist, on night-time and daytime symptoms of insomnia.
Methods
We did two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials at 156 sites in 17 countries. Adults (aged ≥18 years) with insomnia disorder were randomly assigned using interactive response technology (1:1:1) to receive daridorexant 50 mg, 25 mg, or placebo (study 1) or daridorexant 25 mg, 10 mg, or placebo (study 2) every evening for 3 months. Participants, investigators, and site personnel were masked to treatment allocation. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. The secondary endpoints were change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3. Study-wise type I error rate (5%) was controlled for all pairwise comparisons. Efficacy was analysed in all randomly assigned participants, and safety in all participants who received at least one dose of treatment. The studies are registered at ClinicalTrials.gov, NCT03545191 (study 1) and NCT03575104 (study 2).
Findings
Between June 4, 2018 and Feb 25, 2020, 930 participants were randomly assigned to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310) in study 1. Between May 29, 2018, and May 14, 2020, 924 participants were randomly assigned to receive daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) in study 2. In study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group compared with participants in the placebo group at month 1 (least squares mean [LSM] difference −22·8 min [95% CI −28·0 to −17·6], p<0·0001 for WASO; –11·4 min [−16·0 to −6·7], p<0·0001 for LPS) and month 3 (−18·3 min [−23·9 to −12·7], p<0·0001 for WASO; −11·7 min [−16·3 to −7·0], p<0·0001 for LPS). WASO and LPS were significantly reduced among participants in the daridorexant 25 mg group compared with the placebo group at month 1 (LSM difference −12·2 min [−17·4 to −7·0], p<0·0001 for WASO; –8·3 min [−13·0 to −3·6], p=0·0005 for LPS) and month 3 (−11·9 min [−17·5 to −6·2], p<0·0001 for WASO; −7·6 min [−12·3 to −2·9], p=0·0015 for LPS). Compared with placebo, participants in the daridorexant 50 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 22·1 min [14·4 to 29·7], p<0·0001) and month 3 (19·8 min [10·6 to 28·9], p<0·0001), and IDSIQ sleepiness domain scores at month 1 (–1·8 [–2·5 to –1·0], p<0·0001) and month 3 (–1·9 [–2·9 to –0·9], p=0·0002). Compared with the placebo group, participants in the daridorexant 25 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 12·6 min [5·0 to 20·3], p=0·0013) and month 3 (9·9 min [0·8 to 19·1], p=0·033), but not IDSIQ sleepiness domain scores (–0·8 [–1·5 to 0·01], p=0·055 at month 1; –1·0 [–2·0 to 0·01], p=0·053 at month 3). In study 2, WASO was significantly reduced among participants in the daridorexant 25 mg group compared with participants in the placebo group at month 1 (LSM difference −11·6 min [−17·6 to −5·6], p=0·0001) and month 3 (−10·3 min [−17·0 to −3·5], p=0·0028), whereas no significant differences in LPS were observed at month 1 (–6·5 min [–12·3 to –0·6], p=0·030) or month 3 (–9·0 [–15·3 to –2·7], p=0·0053). Compared with the placebo group, participants in the daridorexant 25 mg group had significant improvement in self-reported total sleep time at month 1 (LSM difference 16·1 min [8·2 to 24·0], p<0·0001) and month 3 (19·1 [10·1 to 28·0], p<0·0001), but not in IDSIQ sleepiness domain scores (–0·8 [–1·6 to 0·1], p=0·073 at month 1; –1·3 [–2·2 to –0·3], p=0·012 at month 3). Compared with the placebo group, no significant differences were observed among participants in the daridorexant 10 mg group for WASO (LSM difference –2·7 min [–8·7 to 3·2], p=0·37 at month 1; –2·0 [–8·7 to 4·8], p=0·57 at month 3), LPS (–2·6 min [–8·4 to 3·2], p=0·38 at month 1; –3·2 min [–9·5 to 3·1], p=0·32 at month 3), self-reported total sleep time (13·4 min [5·5 to 21·2], p=0·0009 at month 1; 13·6 min [4·7 to 22·5], p=0·0028 at month 3), nor IDSIQ sleepiness domain scores (–0·4 [–1·3 to 0·4], p=0·30 at month 1; –0·7 [–1·7 to 0·2], p=0·14 at month 3). Overall incidence of adverse events was comparable between treatment groups (116 [38%] of 308 participants in the daridorexant 50 mg group, 117 [38%] of 310 in the daridorexant 25 mg group, and 105 [34%] of 309 in the placebo group in study 1; 121 [39%] of 308 participants in the daridorexant 25 mg group, 117 [38%] of 306 in the daridorexant 10 mg group, and 100 [33%] of 306 in the placebo group). Nasopharyngitis and headache were the most common adverse events in all groups. One death (cardiac arrest) occurred in the daridorexant 25 mg group in study 1, which was not deemed to be treatment-related.
Interpretation
Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favourable safety profile.

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Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae
Yapeng Su et al
Published in Cell: Accepted: January 19, 2022 Received in revised form: December 14, 2021Received: September 29, 2021
Highlights

• Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
• Reactivation of latent viruses during initial infection may contribute to PASC
• Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
• Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells

SUMMARY
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Current status of fecal microbiota transplantation for irritable bowel syndrome
Magdy El-Salhy,Trygve Hausken,Jan Gunnar Hatlebakk,
First published: 08 July 2021 https://doi.org/10.1111/nmo.14157
Neurogastroenterology and motility
Abstract
Background
Irritable bowel syndrome (IBS) is a common gastrointestinal functional disorder. Although IBS is a benign condition, it reduces the quality of life considerably. While there is currently no effective treatment for this disorder, fecal microbiota (FMT) seems to be promising.
Purpose
The aim of this review was to analysis possible factors affecting the success or failure of the randomized controlled trials (RCTs) of FMT for IBS and highlighting the gaps in our knowledge that need to be filled and of sketching a possible model for successful FMT in IBS patients.
MethodsA systematic search was conducted of literature published in English from January 2015 to December 2020 using the keywords: fecal microbiota transplantation, randomized trials, and IBS.
Key Results
Seven randomized controlled trials (RCTs) on the efficacy of FMT for IBS were found in the literature. Four of the seven RCTs found various positive effects, while the other three did not find any effect.
Conclusions and Inferences
The efficacy of FMT for IBS appears to be donor-dependent. The effective (super) donor would need to have a favorable microbiota signature, and 11 clinical criteria that are known to be associated with a favorable microbiota have been suggested for selecting FMT donors for IBS. Comparing the microbiota of the effective donors with those of healthy subjects would reveal the favorable microbiota signature required for a super-donor. However, the studies reviewed were not designed to compare efficacy of different donor types. The dose of the fecal transplant is also an important factor influencing the outcome of FMT for IBS. However, further studies designed to test the effect of fecal transplant dose are needed to answer this question. Administering the fecal transplant to either the small or large intestine seems to be effective, but the optimal route of administration remains to be determined. Moreover, whether single or repeated FMT is more effective is also still unclear. A 1-year follow-up of IBS patients who received FMT showed that adverse events of abdominal pain, diarrhea, and constipation were both mild and self-limiting.
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Research Letter Neurology    October 22, 2021
Assessment of Cognitive Function in Patients After COVID-19 Infection
Jacqueline H. Becker, PhD1; Jenny J. Lin, MD, MPH1; Molly Doernberg, MPH1; et alKimberly Stone, MPH1; Allison Navis, MD2; Joanne R. Festa, PhD2; Juan P. Wisnivesky, MD, DrPH1,3
JAMA Netw Open. 2021;4(10):e2130645. doi:10.1001/jamanetworkopen.2021.30645
COVID-19 Resource Center
Introduction
People who have survived COVID-19 frequently complain of cognitive dysfunction, which has been described as brain fog. The prevalence of post–COVID-19 cognitive impairment and the association with disease severity are not well characterized. Previous studies on the topic have been limited by small sample sizes and suboptimal measurement of cognitive functioning.1 We investigated rates of cognitive impairment in survivors of COVID-19 who were treated in outpatient, emergency department (ED), or inpatient hospital settings.
Methods
We analyzed data in this cross-sectional study from April 2020 through May 2021 from a cohort of patients with COVID-19 followed up through a Mount Sinai Health System registry. Study participants were 18 years or older, spoke English or Spanish, tested positive for SARS-CoV-2 or had serum antibody positivity, and had no history of dementia. Participant demographic characteristics (eg, age, race, and ethnicity) were collected via self-report. Cognitive functioning was assessed using well-validated neuropsychological measures: Number Span forward (attention) and backward (working memory), Trail Making Test Part A and Part B (processing speed and executive functioning, respectively), phonemic and category fluency (language), and the Hopkins Verbal Learning Test–Revised (memory encoding, recall, and recognition). The Mount Sinai Health System Institutional Review Board approved this study, and informed consent was obtained from study participants. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We calculated the frequency of impairment on each measure, defined as a z score of less than or equal to 1.5 SDs below measure-specific age-, educational level–, and sex-adjusted norms.2,3 Logistic regression assessed the association between cognitive impairment and COVID-19 care site (outpatient, ED, or hospital), adjusting for race and ethnicity, smoking, body mass index, comorbidities, and depression. The threshold for statistical significance was α = .05, and the tests were 2-tailed. Analyses were performed using SAS, version 9.4 (SAS Institute).
Results
The mean (IQR) age of 740 participants was 49 (38-59) years, 63% (n = 464) were women, and the mean (SD) time from COVID-19 diagnosis was 7.6 (2.7) months (Table 1). Participants self-identified as Black (15%), Hispanic (20%), or White (54%) or selected multiracial or other race and ethnicity (11%; other race included Asian [4.5%, n = 33)] and those who selected “other” as race). The most prominent deficits were in processing speed (18%, n = 133), executive functioning (16%, n = 118), phonemic fluency (15%, n = 111) and category fluency (20%, n = 148), memory encoding (24%, n = 178), and memory recall (23%, n = 170; Table 2).
In adjusted analyses, hospitalized patients were more likely to have impairments in attention (odds ratio [OR]: 2.8; 95% CI: 1.3-5.9), executive functioning (OR: 1.8; 95% CI: 1.0-3.4), category fluency (OR: 3.0; 95% CI: 1.7-5.2), memory encoding (OR: 2.3; 95% CI: 1.3-4.1), and memory recall (OR: 2.2; 95% CI: 1.3-3.8) than those in the outpatient group. Patients treated in the ED were more likely to have impaired category fluency (OR: 1.8; 95% CI: 1.1-3.1) and memory encoding (OR: 1.7; 95% CI: 1.0-3.0) than those treated in the outpatient setting. No significant differences in impairments in other domains were observed between groups.
Discussion
In this study, we found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients. The relative sparing of memory recognition in the context of impaired encoding and recall suggests an executive pattern. This pattern is consistent with early reports describing a dysexecutive syndrome after COVID-194 and has considerable implications for occupational, psychological, and functional outcomes. It is well known that certain populations (eg, older adults) may be particularly susceptible to cognitive impairment after critical illness5; however, in the relatively young cohort in the present study, a substantial proportion exhibited cognitive dysfunction several months after recovering from COVID-19. The findings of this study are generally consistent with those of research on other viruses (eg, influenza).6
Limitations of this study include a potential sampling bias, as some participants may have presented to Mount Sinai Health System because of health concerns. Future studies should investigate long-term post–COVID-19 cognitive trajectories and the association with neuroimaging findings to assess potential mechanisms.
Conclusions
The association of COVID-19 with executive functioning raises key questions regarding patients’ long-term treatment. Future studies are needed to identify the risk factors and mechanisms underlying cognitive dysfunction as well as options for rehabilitation.


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Heliyon:     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
João Malato, Franziska Sotzny, [...], and Nuno Sepúlveda
Abstract
People 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.
Keywords: Myalgic encephalomyelitis/chronic fatigue syndrome, SARS-CoV-2, ACE2, Gene expression, DNA methylation


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An Audit of UK Hospital Doctors’ Knowledge and Experience of Myalgic Encephalomyelitis
Keng Ngee Hng,  Keith Geraghty,  Derek F. H. Pheby
 Medicina 2021, 57(9), 885; https://doi.org/10.3390/medicina57090885
Received: 21 July 2021 / Revised: 13 August 2021 / Accepted: 24 August 2021 / Published: 27 August 2021
Abstract
Background and Objectives: There is some evidence that knowledge and understanding of ME among doctors is limited. Consequently, an audit study was carried out on a group of hospital doctors attending a training event to establish how much they knew about ME and their attitudes towards it. Materials and Methods: Participants at the training event were asked to complete a questionnaire, enquiring about prior knowledge and experience of ME and their approaches to diagnosis and treatment. A total of 44 completed questionnaires were returned. Responses were tabulated, proportions selecting available options determined, 95% confidence limits calculated, and the significance of associations determined by Fisher’s exact test. Results: Few respondents had any formal teaching on ME, though most had some experience of it. Few knew how to diagnose it and most lacked confidence in managing it. None of the respondents who had had teaching or prior experience of ME considered it a purely physical illness. Overall, 91% of participants believed ME was at least in part psychological. Most participants responded correctly to a series of propositions about the general epidemiology and chronicity of ME. There was little knowledge of definitions of ME, diagnosis, or of clinical manifestations. Understanding about appropriate management was very deficient. Similarly, there was little appreciation of the impact of the disease on daily living or quality of life. Where some doctors expressed confidence diagnosing or managing ME, this was misplaced as they were incorrect on the nature of ME, its diagnostic criteria and its treatment. Conclusion: This audit demonstrates that most doctors lack training and clinical expertise in ME. Nevertheless, participants recognised a need for further training and indicated a wish to participate in this. It is strongly recommended that factually correct and up-to-date medical education on ME be made a priority at undergraduate and postgraduate levels. It is also recommended that this audit be repeated following a period of medical education.
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; ME/CFS; ME; medical education; postgraduate education



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The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients
J of translational medicine

Natalie Eaton-Fitch, Hélène Cabanas, [...], and Sonya Marshall-Gradisnik
Abstract:       Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated.
Methods
NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured.
Results
Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients.
Conclusion
Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.
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ME/CFS: Exercise goals should be set by patients and not driven by treatment plan, says NICE
BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2643 (Published 29 October 2021)Cite this as: BMJ 2021;375:n2643
Graded exercise therapy (GET) should no longer be used to treat patients with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS), says the National Institute for Health and Care Excellence in long awaited updated guidance.1
Patients may still be offered exercise programmes provided they are not based on fixed incremental increases in physical activity or exercise. Instead, programmes should be based around person centred energy management, which is a self-management strategy led by the patient with support from a healthcare professional in an ME/CFS specialist team, the guideline advises.
Energy management should consider all types of activity (cognitive, physical, emotional, and social) that help patients learn to use the amount of energy they have, while reducing their risk of post-exertional malaise or worsening their symptoms by exceeding their limits.
Cognitive behavioural therapy has sometimes been assumed to be a cure for ME/CFS, the guideline acknowledges. Now it should be offered only to help people manage their symptoms, improve their functioning, and reduce the distress associated with having a chronic illness.


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Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic
Joane Matta, PhD1; Emmanuel Wiernik, PhD1; Olivier Robineau, MD, PhD2,3; et alFabrice Carrat, MD, PhD3; Mathilde Touvier, PhD4; Gianluca Severi, PhD5,6; Xavier de Lamballerie, MD, PhD7; Hélène Blanché, PhD8; Jean-François Deleuze, PhD8; Clément Gouraud, MD, MSc9; Nicolas Hoertel, MD, PhD10; Brigitte Ranque, MD, PhD11; Marcel Goldberg, MD, PhD1; Marie Zins, MD, PhD1; Cédric Lemogne, MD, PhD12; for the Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Group
JAMA Intern Med. Published online November 8, 2021. doi:10.1001/jamainternmed.2021.6454
Key Points
Question  Are the belief in having had COVID-19 infection and actually having had the infection as verified by SARS-CoV-2 serology testing associated with persistent physical symptoms during the COVID-19 pandemic?
Findings  In this cross-sectional analysis of 26 823 adults from the population-based French CONSTANCES cohort during the COVID-19 pandemic, self-reported COVID-19 infection was associated with most persistent physical symptoms, whereas laboratory-confirmed COVID-19 infection was associated only with anosmia. Those associations were independent from self-rated health or depressive symptoms.
Meaning  Findings suggest that persistent physical symptoms after COVID-19 infection should not be automatically ascribed to SARS-CoV-2; a complete medical evaluation may be needed to prevent erroneously attributing symptoms to the virus.
Abstract
Importance  After an infection by SARS-CoV-2, many patients present with persistent physical symptoms that may impair their quality of life. Beliefs regarding the causes of these symptoms may influence their perception and promote maladaptive health behaviors.
Objective  To examine the associations of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms (eg, fatigue, breathlessness, or impaired attention) in the general population during the COVID-19 pandemic.
Design, Setting, and Participants  Participants in this cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks. Participants who reported having an initial COVID-19 infection only after completing the serology test were excluded.
Main Outcomes and Measures  Logistic regressions for each persistent symptom as the outcome were computed in models including both self-reported COVID-19 infection and serology test results and adjusting for age, sex, income, and educational level.
Results  Of 35 852 volunteers invited to participate in the study, 26 823 (74.8%) with complete data were included in the present study (mean [SD] age, 49.4 [12.9] years; 13 731 women [51.2%]). Self-reported infection was positively associated with persistent physical symptoms, with odds ratios ranging from 1.39 (95% CI, 1.03-1.86) to 16.37 (95% CI, 10.21-26.24) except for hearing impairment (odds ratio, 1.45; 95% CI, 0.82-2.55) and sleep problems (odds ratio, 1.14; 95% CI, 0.89-1.46). A serology test result positive for SARS-COV-2 was positively associated only with persistent anosmia (odds ratio, 2.72; 95% CI, 1.66-4.46), even when restricting the analyses to participants who attributed their symptoms to COVID-19 infection. Further adjusting for self-rated health or depressive symptoms yielded similar results. There was no significant interaction between belief and serology test results.
Conclusions and Relevance  The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection. Further research in this area should consider underlying mechanisms that may not be specific to the SARS-CoV-2 virus. A medical evaluation of these patients may be needed to prevent symptoms due to another disease being erroneously attributed to “long COVID.”
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Local immune response to food antigens drives meal-induced abdominal pain
Javier Aguilera-Lizarraga, Morgane V. Florens, Guy E. Boeckxstaens 
Nature volume 590, pages151–156 (2021) 
Abstract
Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.


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Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms
Cheng Guo, Xiaoyu Che, Thomas Briese,  View ORCID ProfileOrchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March,  View ORCID ProfileMady Hornig,  View ORCID ProfileAnthony L. Komaroff, Susan Levine,  View ORCID ProfileLucinda Bateman,  View ORCID ProfileSuzanne D. Vernon,  View ORCID ProfileNancy G. Klimas, Jose G. Montoya, Daniel L. Peterson,  View ORCID ProfileW. Ian Lipkin,  View ORCID ProfileBrent L. Williams
doi:  https://doi.org/10.1101/2021.10.27.21265575  BMJ Yale
Abstract
Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.
Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.
Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.
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Front. Med., 05 July 2021 | https://doi.org/10.3389/fmed.2021.686736
Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank
Tiago Dias Domingues1,2, Anna D. Grabowska3, Ji-Sook Lee4, Jose Ameijeiras-Alonso5, Francisco Westermeier6,7, Carmen Scheibenbogen8, Jacqueline M. Cliff4, Luis Nacul9,10, Eliana M. Lacerda9, Helena Mouriño1,11 and Nuno Sepúlveda2,4,8*
The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.


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A Comprehensive Examination of Severely Ill ME/CFS Patients
Chia-Jung Chang,Li-Yuan Hung, Andreas M. Kogelnik, David KaufmanRaeka, S. Aiyar,Angela M. Chu,Julie Wilhelmy,Peng Li,,l Tannenbaum, Wenzhong Xiao, and Ronald W. Davis
 ME/CFS Collaborative Research Center at Stanford, Stanford University School of Medicine, Palo Alto, CA 94305, USA
These authors have contributed equally to this work and share first authorship.
Academic Editors: Kenneth J. Friedman, Lucinda Bateman and Kenny Leo De Meirleir
Healthcare 2021, 9(10), 1290; https://doi.org/10.3390/healthcare9101290
Received: 1 September 2021 / Revised: 20 September 2021 / Accepted: 22 September 2021 / Published: 29 September 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls. The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments. Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS. In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.
Keywords: severe ME/CFS; quality of life; clinical symptoms; sleep; cognitive tests; laboratory tests; viral infection; antibody and antigen; long COVID; post-acute sequelae SARS-CoV-2 infection (PASC)


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PERSPECTIVE 
Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome 
Bindu D. Paula,b,c,1, Marian D. Lemled , Anthony L. Komaroffe , and Solomon H. Snydera,b,c,1 
Edited by Maureen R. Hanson, Cornell University, Ithaca, NY, and accepted by Editorial Board Member Philippa Marrack June 25, 2021
 (received for review February 28, 2021) 
Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics. COVID-19 | chronic fatigue syndrome | myalgic encephalomyelitis 


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 Health, Wellbeing, and Prognosis of Australian Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Case-Controlled Follow-Up Study
Elisha K. Josev,Adam Scheinberg,Katherine Rowe,Lionel Lubitz and,,Sarah J. Knight
Neurodisability and Rehabilitation, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne 3052, Australia
J. Clin. Med. 2021, 10(16), 3603; https://doi.org/10.3390/jcm10163603
Received: 30 June 2021 / Revised: 1 August 2021 / Accepted: 9 August 2021 / Published: 16 August 2021
Abstract
Background: The purpose of this study was to follow-up an Australian cohort of adolescents newly-diagnosed with ME/CFS at a tertiary paediatric ME/CFS clinic and healthy controls over a mean period of two years (range 1–5 years) from diagnosis. Objectives were to (a) examine changes over time in health and psychological wellbeing, (b) track ME/CFS symptomatology and fulfillment of paediatric ME/CFS diagnostic criteria over time, and (c) determine baseline predictors of ME/CFS criteria fulfilment at follow-up. Methods: 34 participants aged 13–18 years (25 ME/CFS, 23 controls) completed standardised questionnaires at diagnosis (baseline) and follow-up assessing fatigue, sleep quality and hygiene, pain, anxiety, depression, and health-related quality of life. ME/CFS symptomatology and diagnostic criteria fulfilment was also recorded. Results: ME/CFS patients showed significant improvement in most health and psychological wellbeing domains over time, compared with controls who remained relatively stable. However, fatigue, pain, and health-related quality of life remained significantly poorer amongst ME/CFS patients compared with controls at follow-up. Sixty-five percent of ME/CFS patients at baseline continued to fulfil ME/CFS diagnostic criteria at follow-up, with pain the most frequently experienced symptom. Eighty-two percent of patients at follow-up self-reported that they still had ME/CFS, with 79% of these patients fulfilling criteria. No significant baseline predictors of ME/CFS criteria fulfilment at follow-up were observed, although pain experienced at baseline was significantly associated with criteria fulfilment at follow-up (R = 0.6, p = 0.02). Conclusions: The majority of Australian adolescents with ME/CFS continue to fulfil diagnostic criteria at follow-up, with fatigue, pain, and health-related quality of life representing domains particularly relevant to perpetuation of ME/CFS symptoms in the early years following diagnosis. This has direct clinical impact for treating clinicians in providing a more realistic prognosis and highlighting the need for intervention with young people with ME/CFS at the initial diagnosis and start of treatment.
Keywords: chronic fatigue syndrome; myalgic encephalomyelitis; follow-up; adolescence; health; wellbeing; diagnostic criteria

Chronic fatigue syndrome and long covid: individualisation, not compartmentalisation
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1863 (Published 28 July 2021)Cite this as: BMJ 2021;374:n1863

1. Russell S Malcolm, specialty doctor

Newman’s investigation of chronic fatigue syndrome and long covid supports the development of specialised multidisciplinary support for patients with long covid.1 But compartmentalisation of a problem like chronic fatigue syndrome can sometimes miss the point.
Dysregulated systems, by their nature, cannot be manipulated into functionality, so the clinical modelling of a system disturbance is often best undertaken by a clinician with dedicated expertise in multisystem assessment who can pull the “hard” and “soft” data together.
Specialised teams, such as the fatigue clinic at the Royal London Hospital for Integrated Medicine, routinely individualise chronic fatigue syndrome cases to a high level of detail. In the absence of objective data, the use of advanced and holistic history taking can explore the factors that perpetuate the clinical state.
The “forensic” part of the inquiry searches for the symptomatic features of pathophysiological change, hypothalamic dysregulation, or ongoing immunological disturbance. The physical and functional inquiry is then contextualised by an empathic and holistic psychosocial survey.
Each patient has a unique combination of perpetuating factors in chronic fatigue syndrome and long covid, so treatment approaches should also be individualised to a high degree. This level of individualisation is not always possible using a compartmentalised method of assessment.

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Long covid: reshaping conversations about medically unexplained symptoms
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1859 (Published 28 July 2021)Cite this as: BMJ 2021;374:n1859

1. Sean L Davidson, psychiatry registrar1,  
2. David B Menkes, academic psychiatrist2
3. sean.davidso@waikatodhb.health.co.nz

Newman’s article, a linked patient commentary, and the tranche of rapid responses show how “long covid” has reignited debate about the causes and management of chronic fatigue syndrome.1 Rather than moving beyond the controversy, most of the ensuing arguments have fallen back into familiar grooves deepened by confirmation bias and dualistic thinking.123 On a more positive note, the intense media attention on and public interest in long covid present a golden opportunity to reshape and extend discussions about medically unexplained symptoms.
Patients presenting with symptoms in the presence of normal diagnostic tests account for 26-35% of consultations in primary care.4 The banner of medically unexplained symptoms encompasses heterogeneous issues—simple transient problems, recognised symptom complexes such as chronic fatigue syndrome, and emerging phenomena like long covid. All present challenges to the doctor-patient relationship, confer risks of overdiagnosis and overtreatment, and can provoke frustration and anxiety in junior and experienced clinicians alike.25
These common clinical scenarios emphasise the pressing need for a framework to aid communication with patients who are frustrated by the mismatch of disabling symptoms and normal investigations. The contrasting societal and medical narratives that Newman outlines regarding chronic fatigue exemplify the challenges that doctors and patients face together in coming to a shared understanding of diagnosis and management options.12 These consultations often carry the weight of decades of power imbalance, psychological stigma, and bitter dualistic debate, leaving both doctor and patient dissatisfied.13
In contrast to most medical specialties, neurologists have made remarkable progress in establishing a patient led terminology and common framework to positively identify and manage functional disorders.6 Other disciplines should strive to match this example but recognise that complex and undifferentiated presentations will doubtless persist and require skill and judgment to investigate appropriately and to constructively manage uncertainty. Crucially, this approach must leave room for an evolving evidence base because “unexplained” does not mean “unexplainable.” Long covid provides an opportunity for the medical profession to move beyond stale controversies and to reconsider how we discuss symptoms lacking clear cause with patients, students, and colleagues.
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Exclusive: Four members of NICE’s guideline committee on ME/CFS stand down
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1937 (Published 03 August 2021)Cite this as: BMJ 2021;374:n1937

1. Ingrid Torjesen

Four members of the NICE guideline development committee for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) left the group just weeks before the final guideline was due to be published, The BMJ has learnt.
The departures suggest divisions within the committee over the guideline’s final content, which is an update on 2007 guidance on diagnosing and managing ME/CFS. Three have resigned, and one has been removed by NICE.
The draft guidance, published in November 2020,1 included significant changes to the 2007 recommendations2 and raised questions about how the evidence could have shifted so substantially.
In 2007 NICE recommended interventions such as cognitive behavioural therapy and graded exercise therapy for people with mild or moderate ME/CFS, whereas the draft update cites a “lack of evidence for the effectiveness of these interventions.” …
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Nutrients. 2021 May; 13(5): 1397.
Published online 2021 Apr 21. doi: 10.3390/nu13051397 PMCID: PMC8143286 PMID: 33919346
Véronique Morel,1 Marie-Eva Pickering,2 Jonathan Goubayon,1 Marguérite Djobo,1 Nicolas Macian,1 and Gisèle Pickering1,*
Maria Perticone, Academic Editor


Clinical Investigation Center, Inserm CIC 1405, Bat 3C, University Hospital Clermont-Ferrand, F-63000 Clermont-Ferrand, France; rf.dnarreftnomrelc-uhc@lerom_v (V.M.); rf.dnarreftnomrelc-uhc@noyabuogj (J.G.); rf.dnarreftnomrelc-uhc@obojdm (M.D.); rf.dnarreftnomrelc-uhc@naicamn (N.M.)
Abstract
Background: Magnesium (Mg) is commonly used in clinical practice for acute and chronic pain and has been reported to reduce pain intensity and analgesics consumption in a number of studies. Results are, however, contested. 
Objectives: This review aims to investigate randomised clinical trials (RCTs) on the effectiveness of Mg treatment on pain and analgesics consumption in situations including post-operative pain, migraine, renal pain, chronic pain, neuropathic pain and fibromyalgia. 
Results: The literature search identified 81 RCTs (n = 5447 patients) on Mg treatment in pain (50 RCTs in post-operative pain, 18 RCTs in migraine, 5 RCTs in renal pain, 6 RCTs in chronic/neuropathic pain, 2 RCTs in fibromyalgia). 
Conclusion: The level of evidence for the efficacy of Mg in reducing pain and analgesics consumption is globally modest and studies are not very numerous in chronic pain. A number of gaps have been identified in the literature that need to be addressed especially in methodology, rheumatic disease, and cancer. Additional clinical trials are needed to achieve a sufficient level of evidence and to better optimize the use of Mg for pain and pain comorbidities in order to improve the quality of life of patients who are in pain.

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Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
by C (Linda) M.C. van Campen,Peter C. Rowe, Frans C. Visser
 Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Healthcare 2020, 8(2), 169; https://doi.org/10.3390/healthcare8020169
Received: 5 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m2 and BMI was 24.0(5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS. 
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Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy, Shaun Bhatia, Mohammed Islam, Leonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
*Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.  

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The Lonely, Isolating, and Alienating Implications of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Samir Boulazreg, Ami Rokach
Faculty of Education, University of Western Ontario, London, ON N6A 3K7, Canada
Department of Psychology, York University, Toronto, ON M3J 1P3, Canada
*Healthcare 2020, 8(4), 413; https://doi.org/10.3390/healthcare8040413
Received: 17 July 2020 / Revised: 27 September 2020 / Accepted: 11 October 2020 / Published: 20 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
This article provides a narrative review on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through a psychosocial lens and examines how this impairment affects its sufferers during adolescence and adulthood, as well as how it impacts family caregivers and healthcare professionals’ mental health. Since there has been a lack of investigation in the literature, the primary psychosocial stressor that this review focuses on is loneliness. As such, and in an attempt to help establish a theoretical framework regarding how loneliness may impact ME/CFS, loneliness is comprehensively reviewed, and its relation to chronic illness is described. We conclude by discussing a variety of coping strategies that may be employed by ME/CFS individuals to address their loneliness. Future directions and ways with which the literature may investigate loneliness and ME/CFS are discussed.
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Heliyon. 2021 Aug;7(8):e07665.
 doi: 10.1016/j.heliyon.2021.e07665. Epub 2021 Jul 29.
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
João Malato 1 2, Franziska Sotzny 3, Sandra Bauer 3, Helma Freitag 3, André Fonseca 4, Anna D Grabowska 5, Luís Graça 1, Clara Cordeiro 2 4, Luís Nacul 6 7, Eliana M Lacerda 6, Jesus Castro-Marrero 8, Carmen Scheibenbogen 3, Francisco Westermeier 9 10, Nuno Sepúlveda 2 3 11
PMID: 34341773   PMCID: PMC8320404   DOI: 10.1016/j.heliyon.2021.e07665
Abstract
People 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.
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Orthostatic stress testing in myalgic encephalomyelitis/chronic fatigue syndrome patients with or without concomitant fibromyalgia: effects on pressure pain thresholds and temporal summation
 C.(L.)M.C. van Campen1 , P.C. Rowe2 , F.W.A. Verheugt3 , F.C. Visser
ABSTRACT 
Objective. Muscle pain and fibromyalgia (FM) are common among individuals with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). We recently demonstrated that during orthostatic stress testing, adults with ME/CFS reported increased pain. In the current study, we hypothesised that pain pressure thresholds (PPT) would decrease and temporal summation (windup) would increase after head-up tilt testing (HUT), and that the presence of co-morbid FM would be associated with greater change in both measures. 
Methods. We studied adult ME/CFS patients undergoing HUT. PPT and temporal summation (or windup) measurements were obtained pre- and post-HUT at the finger and shoulder. 
Conclusion. Pressure pain threshold decreased in ME/CFS patients with or without fibromyalgia after head-up tilt test (HUT), but did not change postHUT in healthy controls. Windup preand post-HUT was significantly higher compared to healthy controls, but did not change from pre- to post-HUT. These results demonstrate that, like exercise, orthostatic stress can negatively influence the physiology of pain perception in ME/CFS. Furthermore, the physiology of pain perception is even more negatively influenced by concomitant fibromyalgia. 
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Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome
Annamaria De Bellis, Giuseppe Bellastella, Vlenia Pernice, Paolo Cirillo, Miriam Longo, Antonietta Maio, Lorenzo Scappaticcio, Maria Ida Maiorino, Antonio Bellastella, Katherine Esposito ... Show more
The Journal of Clinical Endocrinology & Metabolism, dgab429, https://doi.org/10.1210/clinem/dgab429     Published:13 July 2021
 Context
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.
Objective
This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Methods
This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results
Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients).
Conclusion
Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

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Front. Med., 18 June 2021 | https://doi.org/10.3389/fmed.2021.688486
The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Adam J. O'Neal and Maureen R. Hanson*

• Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, United States

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
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GPs need awareness about post-covid ME/CFS
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1995 (Published 12 August 2021)Cite this as: BMJ 2021;374:n1995

1. Caroline Kamau-Mitchell, senior lecturer
2. C.kamau@bbk.ac.uk

Wise reports that general practitioners might be under-reporting long covid in patient records.1 Approximately 25% of people infected with SARS-CoV-1 developed debilitating fatigue and other symptoms that met diagnostic criteria for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) that continued for more than four years.2 So patients with long covid who have had chronic fatigue for six or more months, together with other mandatory symptoms, are likely to be diagnosed as having ME/CFS.
A recent inquiry report for the House of Lords discussed the need for GPs to follow-up patients with suspected long covid and to determine whether those still experiencing severe fatigue after six months meet the other diagnostic criteria for ME/CFS.3 Although there is no known cure, viruses are known to be one of the possible causes of ME/CFS,4 so recognising the chronic fatigue reported by many patients with long covid can help GPs direct them to appropriate support.3 Without enough awareness, patients presenting with long covid symptoms might not be believed by some GPs or might receive misdiagnoses for mental conditions. Not all patients with long covid have ME/CFS but, for those who do, GPs must identify the need for appropriate support, including referrals to occupational rehabilitation support services.3
Data are needed to clarify rates of ME/CFS after covid-19, and GPs can help by conducting six month follow-up of patients who report long covid.
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Long covid—mechanisms, risk factors, and management
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1648 (Published 26 July 2021)Cite this as: BMJ 2021;374:n1648
Harry Crook, research assistant1,  Sanara Raza, research assistant1,  Joseph Nowell, research assistant1,  Megan Young, clinical research officer1,  Paul Edison, clinical senior lecturer, honorary professor12

1. Correspondence to P Edison paul.edison@imperial.ac.uk

Abstract
Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
Lucinda Bateman, MD,Alison C. Bested, MD,Hector F. Bonilla, MD,Ilene S. Ruhoy, MD, PhD, Maria A. Vera-Nunez, MD, MSBI, Brayden P. Yellman, MD
Open Access Published:August 25, 2021DOI:https://doi.org/10.1016/j.mayocp.2021.07.004
Abstract
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
CBT (cognitive behavioral therapy), GET (graded exercise therapy), ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), NAM (National Academy of Medicine), PEM (post-exertional malaise)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multi-system disease affecting millions of people worldwide. Despite its high prevalence and disabling nature, medical education programs rarely cover ME/CFS and guidance for practicing clinicians is often outdated and inappropriate. 
 Standard tests typically return normal results, and some clinicians are wholly unaware of or question the legitimacy of ME/CFS.
 Consequently, up to 91% of affected people are undiagnosed or misdiagnosed with other conditions, such as depression.
 To obtain a diagnosis, patients frequently have had to see multiple clinicians over a number of years. Even after diagnosis, patients struggle to obtain appropriate care and have often been prescribed treatments, such as cognitive-behavioral therapy (CBT) and graded exercise therapy (GET), that could worsen their condition.
In 2015, the US National Academy of Medicine (NAM, previously the Institute of Medicine) created new ME/CFS clinical diagnostic criteria that required the hallmark symptom of post-exertional malaise (PEM).
 The US Centers for Disease Control and Prevention have adopted these new criteria, have removed recommendations for CBT and GET, and have begun to incorporate the best clinical practices of ME/CFS experts. These steps will help improve the speed and accuracy of diagnosis and the quality of clinical care.
Lingering symptoms including fatigue follow various types of infectious illnesses.
 These “postinfectious” fatigue syndromes resemble ME/CFS.
 Moreover, ME/CFS itself often follows an infectious-like illness.
 On occasion, the infectious illness preceding ME/CFS, such as infectious mononucleosis,
 Coxiella burnetii infection,
 giardiasis,
 or severe acute respiratory syndrome (caused by a coronavirus similar to the etiologic agent of COVID-19), has been well documented, but often, no attempt has been made to diagnose the infectious agent.
Following acute COVID-19, whether hospitalized or not, many patients continue to experience debility and symptoms for many months.
 Some of these “long haulers” may have symptoms reflecting organ damage, such as to the lungs or heart, from the acute disease.
 Other long haulers are symptomatic despite having no clear evidence of such organ damage.
 A study of patients ill 6 months after mild or moderate acute COVID-19 found that about half met criteria for ME/CFS.
 One review suggested that the number of cases of ME/CFS could double as a result of the pandemic.
 Like ME/CFS patients, those with post-COVID conditions have recounted being dismissed by health care professionals.
This article provides essential information about how to diagnose and care for adults with ME/CFS and echoes other recent ME/CFS guidance
 Accurately and expeditiously diagnosing ME/CFS is important. There are many steps a clinician can take to improve the health, function, and quality of life of these patients. Even if they do not go on to develop ME/CFS, some patients with post-COVID conditions may also benefit from approaches such as pacing.
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Front. Syst. Neurosci., 01 September 2021 | https://doi.org/10.3389/fnsys.2021.698240
Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
 Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman2Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett
1Cortene Inc., Burlingame, CA, United States
Bateman Horne Center, Salt Lake City, UT, United States

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.
Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

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Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study
Michela Antonelli et al-based,
Published:September 01, 2021 DOI:https://doi.org/10.1016/S1473-3099(21)00460-6 nested, Summary
Background
COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.
Methods
This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status.
Findings
Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.
Interpretation
To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.

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2021 Jul 13;12:687806.Frontiers in Immunology  doi: 10.3389/fimmu.2021.687806. eCollection 2021.
Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment
Helene Cabanas 1 2, Katsuhiko Muraki 2 3, Natalie Eaton-Fitch 1 2, Donald Ross Staines 1 2, Sonya Marshall-Gradisnik 1 2 PMID: 34326841 PMCID: PMC8313851  
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder. The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0-5.0 mg/day) treatment seems to offer some potential benefit suggesting that its effect may be targeted towards the pathomechanism of ME/CFS. As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. TRPM3 ion channel activity was measured after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls using whole-cell patch-clamp technique. We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, in NK cells from ME/CFS patients taking LDN. These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells. Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.
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Published by De Gruyter April 22, 2020
Diagnosis of mast cell activation syndrome: a global “consensus-2”
Lawrence B. Afrin , Mary B. Ackerley, Linda S. Bluestein, Joseph H. Brewer, Jill B. Brook, Ariana D. Buchanan, Jill R. Cuni, William P. Davey, Tania T. Dempsey , Shanda R. Dorff, Martin S. Dubravec, Alena G. Guggenheim, Kimberly J. Hindman, Bruce Hoffman, David L. Kaufman, Stephanie J. Kratzer, Theodore M. Lee, Mindy S. Marantz, Andrew J. Maxwell, Kelly K. McCann, Dwight L. McKee, Laurie Menk Otto, Laura A. Pace, Dahra D. Perkins, Laurie Radovsky, Mary S. Raleigh, Sonia A. Rapaport, Emma J. Reinhold, Mark L. Renneker, William A. Robinson, Aaron M. Roland, E. Scott Rosenbloom, Peter C. Rowe, Ilene S. Ruhoy, David S. Saperstein, David A. Schlosser, Jill R. Schofield, Janet E. Settle, Leonard B. Weinstock, Martina Wengenroth, Mark Westaway, Shijun Cindy Xi and Gerhard J. Molderings
From the journal Diagnosis   https://doi.org/10.1515/dx-2020-0005
Abstract
The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of “mast cell activation syndrome” (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a “consensus” (re-termed here as “consensus-1”). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as “consensus-2”), resembling “consensus-1” in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by “consensus-2” criteria has potential to be problematic, but underdiagnosis by “consensus-1” criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.
Keywords: chronic illness; mast cell activation disease; mast cell activation syndrome; medical controversies; medically unexplained symptoms; misdiagnosis

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Long COVID: low prevalence in SARS-CoV-2 infected children
Radtke T & al.. JAMA, 15 July 2021 Miriam Davis, PhD   |   16 September 2021
Takeaway

• Long-term symptoms after SARS-CoV-2 infection (so-called long COVID) affect 4% of children and adolescents vs 2% of uninfected control participants, according to a longitudinal cohort study.

Why this matters

• This is the first report of long COVID prevalence in a population-based cohort of children and adolescents with the use of an uninfected control group.

Study design

• Population-based longitudinal cohort study of children from randomly selected classes in 55 randomly selected schools in the canton of Zurich, Switzerland.
• SARS-CoV-2 infection was determined by serology testing at 2 points and long COVID was assessed by online symptom questionnaires.
• 109 seropositive children were compared with 1246 seronegative children (between October 2020 and March/April 2021).
• Funding: Swiss Federal Office of Public Health; University of Zurich Foundation; private funders.

Key results

• Median age, 11 years; interquartile range, 9-13 years; 54% girls.
• Age and sex patterns were similar between seropositive and seronegative children.
• Long COVID prevalence: 4% of 109 seropositive children vs 2% of seronegative control participants reported ≥1 symptom lasting >12 weeks.
• Most frequently reported symptoms in seropositive vs seronegative children were:
  • Tiredness (3% vs 1%).
  • Difficulty in concentrating (2% vs 1%).
  • Increased need for sleep (2% vs 0%).

Limitations

• Small number of seropositive children.
• Lack of information regarding exact time of SARS-CoV-2 infection.
• Potential misclassification because of false seropositive results.

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Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset
Sophie Steiner, Sonya C. Becker, [...], and Carmen Scheibenbogen
Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p= 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.
Keywords: single nucleotide polymorphism (SNP), tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interferon regulatory factor 5 (IRF5), tumor necrosis factor (TNF), myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), autoimmunity
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MEDICAL NEWS   Rates of persistent COVID-19 symptoms a year after hospital discharge    Dawn O'Shea   |   30 August 2021
Half of hospitalised COVID-19 survivors experience at least one persistent symptom a year after discharge, suggests a study published in The Lancet.
The study assessed 1276 COVID-19 survivors at six and 12 months following discharge from Jin Yin-tan Hospital in Wuhan, China, between January 7 and May 29, 2020.
At six months, 68 per cent had at least one sequelae symptom, decreasing to 49 per cent at 12 months (P<.0001). The proportion of patients with dyspnoea, characterised by a modified British Medical Research Council (mMRC) score of ≥1, was 26 per cent at six months and 30 per cent at 12 months (P=.014). Additionally, more patients had anxiety or depression at 12 months (26%) than at six months (23%). There was no significant change in distance walked in 6 min (6MWD).
Eighty-eight per cent of patients who were employed before COVID-19 had returned to their original work at 12 months.
Compared with men, women had an odds ratio (OR) for fatigue or muscle weakness (1.43; 95% CI 1.04-1.96), anxiety or depression (OR 2.00; 95% CI 1.48-2.69), and impaired diffusion (OR 2.97; 95% CI 1.50-5.88).
At 12 months, COVID-19 survivors had more problems with mobility, pain or discomfort, and anxiety or depression, and had more prevalent symptoms than controls.

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Front. Med., 07 May 2021 | https://doi.org/10.3389/fmed.2021.672370
Theory: Treatments for Prolonged ICU Patients May Provide New Therapeutic Avenues for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*

• 1Independent Researcher, Sint Martens Latem, Belgium
• 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
• 3Analytical Chemistry and Neurochemistry, Department of Chemistry–Biomedical Center, Uppsala University, Uppsala, Sweden
• 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

We here provide an overview of treatment trials for prolonged intensive care unit (ICU) patients and theorize about their relevance for potential treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these treatment trials generally target: (a) the correction of suppressed endocrine axes, notably through a “reactivation” of the pituitary gland's pulsatile secretion of tropic hormones, or (b) the interruption of the “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. There are significant parallels in the treatment trials for prolonged critical illness and ME/CFS; this is consistent with the hypothesis of an overlap in the mechanisms that prevent recovery in both conditions. Early successes in the simultaneous reactivation of pulsatile pituitary secretions in ICU patients—and the resulting positive metabolic effects—could indicate an avenue for treating ME/CFS. The therapeutic effects of thyroid hormones—including in mitigating O&NS and inflammation and in stimulating the adreno-cortical axis—also merit further studies. Collaborative research projects should further investigate the lessons from treatment trials for prolonged critical illness for solving ME/CFS.

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Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116546/#
Lindsay S. Petracek, Stacy J. Suskauer, [...], and Peter C. Rowe
Abstract
Introduction: Fatigue is a common acute symptom following SARS-CoV-2 infection (COVID-19). The presence of persistent fatigue and impaired daily physical and cognitive function has led to speculation that like SARS-CoV-1 infection, COVID-19 will be followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods and Results: We describe three adolescent and young adult patients who had confirmed or probable COVID-19 infections early on during the pandemic and were referred for evaluation to the Chronic Fatigue Clinic at the Johns Hopkins Children's Center. All patients reported orthostatic intolerance symptoms within the first 2 weeks of illness, and 10-min passive standing tests were consistent with postural tachycardia syndrome. After 6 months of illness, all three patients met criteria for ME/CFS. Clinical features of interest included strong histories of allergies in all three patients, two of whom had elevations in 
plasma histamine. Each demonstrated limitations in symptom-free range of motion of the limbs and spine and two presented with pathological Hoffman reflexes. These comorbid features have been reported in adolescents and young adults with ME/CFS.
Conclusion: ME/CFS can be triggered by COVID-19 in adolescents and young adults. Further work is needed to determine the pathogenesis of ME/CFS after COVID-19 and optimal methods of treating these patients. Our preliminary study calls attention to several comorbid features that deserve further attention as potential targets for intervention. These include neuromuscular limitations that could be treated with manual forms of therapy, orthostatic intolerance and POTS for which there are multiple medications and non-pharmacologic therapies, treatable allergic and mast cell phenomena, and neurologic abnormalities that may require specific treatment. Larger studies will need to ascertain the prevalence of these abnormalities.

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Post-acute sequelae of COVID-19 in a non-hospitalized cohort: Results from the Arizona CoVHORT
Melanie L. Bell , Collin J. Catalfamo,Leslie V. Farland,Kacey C. Ernst,Elizabeth T. Jacobs,Yann C. Klimentidis, 
Megan Jehn, Kristen Pogreba-Brown

Published: August 4, 2021    https://doi.org/10.1371/journal.pone.0254347

Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as long COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of PASC, defined as experiencing at least one symptom 30 days or longer, and prevalence of individual symptoms. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30–250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95% confidence interval: 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress/anxiety (30.8%). The median number of symptoms was 3 (range 1–20). Amongst 157 participants with longer follow-up (≥60 days), PASC prevalence was 77.1%.

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Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study 
Linda W G Luijten, Sonja E Leonhard, Annemiek A van der Eijk, Alex Y Doets, Luise Appeltshauser, Samuel Arends, Shahram Attarian, Luana Benedetti, Chiara Briani, Carlos Casasnovas  
Brain, awab279, https://doi.org/10.1093/brain/awab279  Published: 23 September 2021

Abstract
In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12–22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not.
*
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Exploring Symptom Fluctuations and Triggers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Novel Patient-Centred N-of-1 Observational Designs: A Protocol for a Feasibility and Acceptability Study
Suzanne McDonald, Smuel X. Tan, Shamima Banu, Mieke van Driel, James M. McGree, Geoffrey Mitchell & Jane Nikles 
The Patient - Patient-Centered Outcomes Research (2021)Published: 09 August 2021


Abstract Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition of unknown aetiology associated with a range of disabling symptoms, including post-exertional malaise, chronic fatigue, musculoskeletal pain, orthostatic intolerance, unrefreshing sleep, and cognitive dysfunction. ME/CFS is a heterogeneous disorder, with significant variation in symptom type and severity between individuals, as well as within individuals over time. The diversity of ME/CFS symptom presentation makes management challenging; treatments supported by data from randomised controlled trials may not work for all individuals due to the variability in experienced symptoms. Studies using quantitative N-of-1 observational designs involve repeated outcome measurements in an individual over time and can generate rigorous individual-specific conclusions about symptom patterns and triggers in individuals with ME/CFS. This study aims to explore the feasibility and acceptability of using novel patient-centred N-of-1 observational designs to explore symptom fluctuations and triggers in ME/CFS at the individual level.
Methods and Analysis
Individuals with a medical diagnosis of ME/CFS will be recruited through ME/CFS patient organisations to participate in a series of patient-centred N-of-1 observational studies. Using a wrist-worn electronic diary, participants will complete ecological momentary assessments of fatigue, stress, mood, and cognitive demand, three times per day for a period of 6–12 weeks. Personally relevant symptoms and triggers will also be incorporated into the questionnaire design. Physical activity will be objectively measured via an integrated accelerometer. Feasibility and acceptability outcomes will be assessed including the percentage of diary entries completed, as well as recruitment and retention rate, feasibility of analysing and interpreting the data collected, and participant views about participation elicited via a post-study semi-structured interview.
Discussion
This study will assess the feasibility and acceptability of patient-centred N-of-1 observational studies to assess diseases with complex presentations such as ME/CFS, as well as provide individual-level evidence about fluctuations and triggers of ME/CFS symptoms that may aid self-management.

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Causal attributions and perceived stigma for myalgic encephalomyelitis/chronic fatigue syndrome
Laura Froehlich, Daniel BR Hattesohl, Joseph Cotler, .First Published July 9, 2021 Research Article   https://doi.org/10.1177/13591053211027631  J of Health Psychology

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with the hallmark symptom of post-exertional malaise. Evidence for physiological causes is converging, however, currently no diagnostic test or biomarker is available. People with ME/CFS experience stigmatization, including the perception that the disease is psychosomatic. In a sample of 499 participants with self-diagnosed ME/CFS, we investigated perceived stigma as a pathway through which perceived others’ causal attributions relate to lower satisfaction with social roles and activities and functional status. Higher perceived attributions by others to controllable and unstable causes predicted lower health-related and social outcomes via higher perceived stigma.

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Mayo Clinic Proceedings
Available online 25 August 2021
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
Author links open overlay panelLucindaBatemanMDaAlison C.BestedMDbHector F.BonillaMDdBela V.ChhedaMDeLilyChuMD, MSHSfJennifer M.CurtinMDeTania T.DempseyMDgMary E.DimmockBAhTheresa G.DowellDNP, MPTiDonnaFelsensteinMDjDavid L.KaufmanMDeNancy G.KlimasMDcAnthony L.KomaroffMDkCharles W.LappMBME, MDlSusan M.LevineMDmJose G.MontoyaMDnBenjamin H.NatelsonMDoDaniel L.PetersonMDp…Brayden P.YellmanMDa
https://doi.org/10.1016/j.mayocp.2021.07.004Get rights and content
Under a Creative Commons license
Abstract
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
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Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
International Journal of environmental research and public health.
Joshua Bond, Tessa Nielsen, and Lynette Hodges
Abstract
Background: Evidence is emerging that individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may suffer from chronic vascular dysfunction as a result of illness-related oxidative stress and vascular inflammation. The study aimed to examine the impact of maximal-intensity aerobic exercise on vascular function 48 and 72 h into recovery. Methods:ME/CFS (n = 11) with gender and age-matched controls (n = 11) were randomly assigned to either a 48 h or 72 h protocol. Each participant had measures of brachial blood pressure, augmentation index (AIx75, standardized to 75 bpm) and carotid-radial pulse wave velocity (crPWV) taken. This was followed by a maximal incremental cycle exercise test. Resting measures were repeated 48 or 72 h later (depending on group allocation). Results: No significant differences were found when ME/CFS were directly compared to controls at baseline. During recovery, the 48 h control group experienced a significant 7.2% reduction in AIx75 from baseline measures (p < 0.05), while the matched ME/CFS experienced no change in AIx75. The 72 h ME/CFS group experienced a non-significant increase of 1.4% from baseline measures. The 48 h and 72 h ME/CFS groups both experienced non-significant improvements in crPWV (0.56 ms−1 and 1.55 ms−1, respectively). Conclusions: The findings suggest that those with ME/CFS may not experience exercise-induced vasodilation due to chronic vascular damage, which may be a contributor to the onset of post-exertional malaise (PEM).
Keywords: myalgic encephalomyelitis, chronic fatigue syndrome, arterial stiffness, post-exertional malaise
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Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register 
Emmert Roberts, Simon Wessely, Trudie Chalder, Chin-Kuo Chang*, Matthew Hotopf*
Lancet 2016; 387: 1638–43
Summary 
Background 
Mortality associated with chronic fatigue syndrome is uncertain. We investigated mortality in individuals diagnosed with chronic fatigue syndrome in secondary and tertiary care using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register. 
Methods We calculated standardised mortality ratios (SMRs) for all-cause, suicide-specific, and cancer-specific mortality for a 7-year observation period using the number of deaths observed in SLaM records compared with age specific and sex-specific mortality statistics for England and Wales. Study participants were included if they had had contact with the chronic fatigue service (referral, discharge, or case note entry) and received a diagnosis of chronic fatigue syndrome.
 Findings 
We identified 2147 cases of chronic fatigue syndrome from CRIS and 17 deaths from Jan 1, 2007, to Dec 31, 2013. 1533 patients were women of whom 11 died, and 614 were men of whom six died. There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65–1·85; p=0·67) or cancer-specific mortality (1·39, 0·60–2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. This remained the case when deaths from suicide were removed from the analysis. There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22–15·98; p=0·002).
 Interpretation
 We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide. This highlights the need for clinicians to be aware of the increased risk of completed suicide and to assess suicidality adequately in patients with chronic fatigue syndrome. 
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 2021 Mar 22;8:642710.Front. Med. Lausanne.
 doi: 10.3389/fmed.2021.642710. eCollection 2021.
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study
Kari Sørland 1 2, Miriam Kristine Sandvik 3, Ingrid Gurvin Rekeland 1 4, Lis Ribu 2, Milada Cvancarova Småstuen 2, Olav Mella 1 4, Øystein Fluge 1 4
PMID: 33829023 PMCID: PMC8019750 DOI: 10.3389/fmed.2021.642710
Abstract
Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide. Methods: This substudy to the open-label phase II trial "Cyclophosphamide in ME/CFS" included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30). Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343-4,334) vs. healthy individuals 1,886 p.u. (range 808-8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls. 


Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
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Intramuscular Pressure Is Almost Three Times Higher in Fibromyalgia Patients: A Possible Mechanism for Understanding the Muscle Pain and Tenderness
Robert S. Katz, Frank Leavitt, Alexandra Katz Small and Ben J. Small
The Journal of Rheumatology April 2021, 48 (4) 598-602; DOI: https://doi.org/10.3899/jrheum.191068
Abstract
Objective Widespread pain in fibromyalgia syndrome (FMS) is conventionally viewed as arising from disordered central processing. This study examines intramuscular pressure in the trapezius as an alternative mechanism for understanding FMS pain.
Methods One hundred eight patients who satisfied the American College of Rheumatology criteria for FMS and 30 patients who met the ACR criteria for another rheumatic disease comprised the study groups. Muscle pressure was measured in mmHg using a pressure gauge attached to a no. 22 needle inserted into the mid-portion of the trapezius muscle. In addition, patients with FMS and rheumatic disease controls had dolorimetry testing, digital palpation, and reported pain scores.
Results Muscle pressure was substantially higher in patients with FMS with a mean value of 33.48 ± 5.90 mmHg. Only 2 of 108 patients had muscle pressure of < 23 mmHg. The mean pressure in rheumatic disease controls was 12.23 ± 3.75 mmHg, with a range from 3–22 mmHg. Patients with FMS were more tender than controls based on both dolorimetry (P < 0.001) and digital palpation (P < 0.001). The mean pain score in patients with FMS and controls was 6.68 ± 1.91 and 1.43 ± 1.79, respectively (P < 0.001).
Conclusion Pressure in the trapezius muscle of patients with FMS is remarkably elevated and may be an intrinsic feature of FMS that could be monitored as part of the diagnostic evaluation. The burden of the pressure abnormality may help explain the diffuse muscle pain of FMS. Therefore, FMS as a disorder of exclusively central pain processing should be revisited. Therapeutically, the reduction of muscle pressure may change the clinical picture significantly.
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021 Apr 12;archdischild-2020-320196.
Recovery from chronic fatigue syndrome: a systematic review-heterogeneity of definition limits study comparison
Yasmin Moore 1, Teona Serafimova 1, Nina Anderson 1 2, Hayley King 1, Alison Richards 1 3, Amberly Brigden 1, Parisa Sinai 1, Julian Higgins 1, Caitlin Ascough 1, Philippa Clery 1, Esther M Crawley 4 5
PMID: 33846138   DOI: 10.1136/archdischild-2020-320196
Abstract
Background: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a common illness with a major impact on quality of life. Recovery is poorly understood. Our aim was to describe definitions of recovery in paediatric CFS/ME, the rate of recovery and the time to recovery.
Methods: This systematic review included a detailed search of MEDLINE, EMBASE, PsycInfo and Cochrane Library between 1994 and July 2018. Inclusion criteria were (1) clinical trials and observational studies, (2) participants aged <19 years with CFS/ME, (3) conducted in Western Healthcare systems and (4) studies including a measure of recovery and time taken to recover.
Results: Twelve papers (10 studies) were identified, involving 826 patients (range 23-135). Recovery rates were highly varied, ranging between 4.5% and 83%.Eleven distinct definitions of recovery were used; six were composite outcomes while five used unidimensional outcomes. Outcome measures used to define recovery were highly heterogeneous. School attendance (n=8), fatigue (n=6) and physical functioning (n=4) were the most common outcomes included in definition of recovery. Only five definitions included a personal measure of recovery.
Implications: Definitions of recovery are highly variable, likely secondary to differences in study design, outcomes used, follow-up and study populations. Heterogeneous definitions of recovery limit meaningful comparison between studies, highlighting the need for a consensus definition going forward. Recovery is probably best defined from the child's own perspective with a single self-reported measure. If composite measures are used for research, there should be agreement on the core outcome set used.

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Journal of the Neurological Sciences Volume 422, 15 March 2021, 117326
Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study
RiccardoMancaa1KatijaKhanb1MicaelaMitolocMatteo De MarcoaLynseyGrievesondRosemaryVarleyeIain D.WilkinsonfAnnalenaVenneria
https://doi.org/10.1016/j.jns.2021.117326 
Highlights
Cognitive effort can induce PEM and worsening of ME/CFS symptoms.
PEM is associated with changes in functional connectivity of the salience network.
Increased right insular FC with frontal areas is associated with symptom worsening.
Abstract
Background
A common symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM). Various brain abnormalities have been observed in patients with ME/CFS, especially in insular and limbic areas, but their link with ME/CFS symptoms is still unclear. This pilot study aimed at investigating the association between PEM in ME/CFS and changes in functional connectivity (FC) of two main networks: the salience network (SN) and the default-mode network (DMN).
Methods
A total of 16 women, 6 with and 10 without ME/CFS, underwent clinical and MRI assessment before and after cognitive exertion. Resting-state FC maps of 7 seeds (3 for the SN and 4 for the DMN) and clinical measures of fatigue, pain and cognition were analysed with repeated-measure models. FC-symptom change associations were also investigated.
Results
Exertion induced increases in fatigue and pain in patients with ME/CFS compared to the control group, while no changes were found in cognitive performance. At baseline, patients showed altered FC between some DMN seeds and frontal areas and stronger FC between all SN seeds and left temporal areas and the medulla. Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms.
Conclusions
Cognitive exertion can induce worsening of ME/CFS-related symptoms. These changes were here associated with strengthening of FC of the right insula with areas involved in reward processing and cognitive control.
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Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts 
Daniel Missailidis,Oana Sanislav,Claire Y. Allan,Paige K. Smith,Sarah J. Annesley,Paul R. Fisher
Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia
Monash Health, Melbourne, VIC 3186, Australia
Int. J. Mol. Sci. 2021, 22(4), 2046; https://doi.org/10.3390/ijms22042046
Received: 16 January 2021 / Revised: 8 February 2021 / Accepted: 15 February 2021 / Published: 19 February 2021
Abstract
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10−4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10−4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10−3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates. View Full-Text
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Front Med (Lausanne) . 2021 Mar 22;8:642710. doi: 10.3389/fmed.2021.642710. eCollection 2021.
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study
Kari Sørland 1 2, Miriam Kristine Sandvik 3, Ingrid Gurvin Rekeland 1 4, Lis Ribu 2, Milada Cvancarova Småstuen 2, Olav Mella 1 4, Øystein Fluge 1 4
PMID: 33829023 PMCID: PMC8019750  DOI: 10.3389/fmed.2021.642710
Abstract
Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide. Methods: This substudy to the open-label phase II trial "Cyclophosphamide in ME/CFS" included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30). Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343-4,334) vs. healthy individuals 1,886 p.u. (range 808-8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls. Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
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 Aliment Pharmacol Ther  2021 Jan;53(1):79-86.  doi: 10.1111/apt.16166. Epub 2020 Nov 18.
Randomised clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease
Palle Bager 1, Christian Lodberg Hvas 1, Charlotte Lock Rud 1, Jens Frederik Dahlerup 1
PMID: 33210299
Abstract
Background: Fatigue is a burdensome symptom for patients with inflammatory bowel disease (IBD). Few pharmacological interventions have documented effect on fatigue in patients with IBD. A pilot study indicated a 20-day effect with high-dose thiamine.
Aims: To investigate the effect and safety of high-dose oral thiamine (600-1800 mg/d) based on gender and weight on chronic fatigue in patients with quiescent IBD.
Methods: This was a randomised, double-blinded, placebo-controlled crossover trial. Patients had quiescent IBD, severe chronic fatigue and no other explanation for fatigue. Patients were allocated 1:1 to either 1) high-dose oral thiamine for 4 weeks, 4 weeks of washout, 4 weeks of oral placebo or 2) oral placebo for 4 weeks, 4 weeks of washout, 4 weeks of high-dose oral thiamine. Fatigue was measured using the Inflammatory Bowel Disease-Fatigue Questionnaire. The primary outcome was improvement (≥3 points) of fatigue after 4 weeks on thiamine.
Results: Forty patients were enrolled between November 2018 and October 2019. Crossover analysis showed a mean reduction of 4.5 points (95% CI 2.6-6.2) in fatigue after thiamine compared with a mean increase of 0.75 point (95% CI -1.3-2.8; P = 0.0003) after placebo. Furthermore, 55% of group 1 and 75% of group 2 showed an improvement ≥ 3 points while on thiamine compared with 25% of group 1 and 35% of group 2 while on placebo. Only mild side effects were detected.
Conclusion: We showed a significant beneficial effect of high-dose oral thiamine on chronic fatigue in IBD. The treatment was well tolerated.
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Mysterious Ailment, Mysterious Relief: Vaccines Help Some COVID Long Haulers 
Will Stone – Kaiser Health News
April 16, 2021
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An estimated 10% to 30% of people who get covid-19 suffer from lingering symptoms of the disease, or what's known as "long covid."
Judy Dodd, who lives in New York City, is one of them. She spent nearly a year plagued by headaches, shortness of breath, extreme fatigue and problems with her sense of smell, among other symptoms.
She said she worried that this "slog through life" was going to be her new normal.
Everything changed after she got her covid vaccine.
"I was like a new person. It was the craziest thing ever," said Dodd, referring to how many of her health problems subsided significantly after her second shot.
As the U.S. pushes to get people vaccinated, a curious benefit is emerging for those with this post-illness syndrome: Their symptoms are easing and, in some cases, fully resolving after vaccination.
It's the latest clue in the immunological puzzle of long covid, a still poorly understood condition that leaves some who get infected with wide-ranging symptoms months after the initial illness.
The notion that a vaccine aimed at preventing the disease may also treat it has sparked optimism among patients, and scientists who study the post-illness syndrome are taking a close look at these stories.
"I didn't expect the vaccine to make people feel better," said Akiko Iwasaki, an immunologist at the Yale School of Medicine who's researching long covid.
"More and more, I started hearing from people with long covid having their symptoms reduced or completely recovering, and that's when I started to get excited because this might be a potential cure for some people."
While promising, it's still too early to know just how many people with long covid feel better as a result of being vaccinated and whether that amounts to a statistically meaningful difference.
In the meantime, Iwasaki and other researchers are beginning to incorporate this question into ongoing studies of long haulers by monitoring their symptoms pre- and post-vaccination and collecting blood samples to study their immune response.
There are several leading theories for why vaccines could alleviate the symptoms of long covid: It's possible the vaccines clear up leftover virus or fragments, interrupt a damaging autoimmune response or in some other way "reset" the immune system.
"It's all biologically plausible and, importantly, should be easy to test," said Dr. Steven Deeks of the University of California-San Francisco, who is also studying the long-term impacts of the coronavirus on patients.
"
Among the patients of Dr. Daniel Griffin at Columbia University Medical Center in New York, "brain fog" and gastrointestinal problems are two of the most common symptoms that seem to resolve post-vaccination.
Griffin, who is running a long-term study of post-covid illness, initially estimated that about 30% to 40% of his patients felt better. Now, he believes the number may be higher, as more patients receive their second dose and see further improvements.
"We've been sort of chipping away at this [long covid] by treating each symptom," he said. "If it's really true that at least 40% of people have significant recovery with a therapeutic vaccination, then, to date, this is the most effective intervention we have for long covid."
A small U.K. study, not yet peer-reviewed, found about 23% of long-covid patients had an "increase in symptom resolution" post-vaccination, compared with about 15% of those who were unvaccinated.
But not all clinicians are seeing the same level of improvement.
Clinicians at post-covid clinics at the University of Washington in Seattle, Oregon Health & Science University in Portland, National Jewish Health in Denver and the University of Pittsburgh Medical Center told NPR and KHN that, so far, a small number of patients — or none at all — have reported feeling better after vaccination, but it wasn't a widespread phenomenon.
"I've heard anecdotes of people feeling worse, and you can scientifically come up with an explanation for it going in either direction," said UCSF's Deeks.

Why Are Patients Feeling Better?
There are several theories for why vaccines could help some patients — each relying on different physiological understandings of long covid, which manifests in a variety of ways.
"The clear story is that long covid isn't just one issue," said Dr. Eric Topol, director of the Scripps Research Translational Institute, which is also studying long covid and the possible therapeutic effects of vaccination.
Some people have fast resting heart rates and can't tolerate exercise. Others suffer primarily from cognitive problems, or some combination of symptoms like exhaustion, trouble sleeping and issues with smell and taste, he said.
As a result, it's likely that different therapies will work better for some versions of long covid than others, said Deeks.
One theory is that people who are infected never fully clear the coronavirus, and a viral "reservoir," or fragments of the virus, persist in parts of the body and cause inflammation and long-term symptoms, said Iwasaki, the Yale immunologist.
According to that explanation, the vaccine might induce an immune response that gives the body extra firepower to beat back the residual infection.
"That would actually be the most straightforward way of getting rid of the disease, because you're getting rid of the source of inflammation," Iwasaki said.
Griffin at Columbia Medical Center said this "viral persistence" idea is supported by what he's seeing in his patients and hearing from other researchers and clinicians. He said patients seem to be improving after receiving any of the covid vaccines, generally about "two weeks later, when it looks like they're having what would be an effective, protective response."
Another possible reason that some patients improve comes from the understanding of long covid as an autoimmune condition, in which the body's immune cells end up damaging its own tissues.
A vaccine could hypothetically kick into gear the "innate immune system" and "dampen the symptoms," but only temporarily, said Iwasaki, who has studied the role of harmful proteins, called autoantibodies, in covid.
This self-destructive immune response happens in a subset of covid patients while they are ill, and the autoantibodies produced can circulate for months later. But it's not yet clear how that may contribute to long covid, said John Wherry, director of the Institute for Immunology at the University of Pennsylvania.
Another theory is that the infection has "miswired" the immune system in some other way and caused chronic inflammation, perhaps like chronic fatigue syndrome, Wherry said. In that scenario, the vaccination might somehow "reset" the immune system.
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BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n693 (Published 31 March 2021)Cite this as: BMJ 2021;372:n693
Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study
Daniel Ayoubkhani, principal statistician1,  Kamlesh Khunti, professor of primary care diabetes and vascular medicine2,  Vahé Nafilyan, principal statistician1, Thomas Maddox, statistician1,  Ben Humberstone, deputy director of health analysis and life events division1,  Ian Diamond, UK national statistician1,  Amitava Banerjee, associate professor of clinical data science and honorary consultant cardiologist
Accepted 15 March 2021
Abstract
Objective To quantify rates of organ specific dysfunction in individuals with covid-19 after discharge from hospital compared with a matched control group from the general population.
Design Retrospective cohort study.
Setting NHS hospitals in England.
Participants 47 780 individuals (mean age 65, 55% men) in hospital with covid-19 and discharged alive by 31 August 2020, exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics from 10 years of electronic health records.
Main outcome measures Rates of hospital readmission (or any admission for controls), all cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity.
Results Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals).
Conclusions Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.
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Neural therapy for fibromyalgia: Myth or improving quality of life?
Elif Balevi Batur   Tuğba Atan      First published: 21 September 2020  https://doi.org/10.1111/ijcp.13719    International Journal of Clinical practice
Abstract
Background
Fibromyalgia is a common rheumatic disease, which is thought to be a neuroendocrine dysregulation disorder. Patients’ quality of life (QOL) is severely affected by this disease. Though neural therapy, as a treatment option, attempts to correct the underlying neuroendocrine dysfunction, yet there is no proven evidence of its effect on this disease. The present study aimed to evaluate the effectiveness of neural therapy on pain and functionality in patients with fibromyalgia.
Methods
The study was a 1‐year retrospective cohort study and held in physical medicine and rehabilitation clinics. A total of 60 female patients diagnosed with fibromyalgia were included. Sixty female patients with fibromyalgia were included in this study. Patients were divided into two groups; the first group (n = 30) received neural therapy, the second group (n = 30) received conventional physical therapy and each of the two groups received the same home exercise (stretching, strengthening and aerobic exercises) programme for four weeks. The primer outcomes were visual analogue scale (VAS), Short Form‐36 (SF‐36) and Fibromyalgia Impact Questionnaire (FIQ) scores after the treatment.
Results
The social functioning score exhibited a significant improvement only in the intra‐group comparison of the neural therapy group (P < .001). However, after treatment, the VAS, FIQ and all the SF‐36 parameters, except role limitations because of physical health, were detected to be significantly improved in the neural therapy group compared with the exercise group (P < .001).
Conclusions
Neural therapy may be an effective alternative treatment for improving the QOL in patients with fibromyalgia.
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Pharmacological Research
Volume 165, March 2021, 105465
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from?
Peter L.ToogoodabDaniel J.ClauwcSameerPhadkebDavidHoffmand
https://doi.org/10.1016/j.phrs.2021.105465Get rights and content
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5–1.5 % and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.


Graphical abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from? P. Toogood, D. Clauw, S. Phadke, D. Hoffman.

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Antibody-dependent cell-mediated cytotoxicity (ADCC) in familial myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Alexander P. Sung,Jennifer J.-J. Tang,Michael J. Guglielmo,Julie Smith-Gagen,Lucinda Bateman ,Lydia Navarrete-Galvan, show all
Pages 226-244 | Received 17 Nov 2020, Accepted 12 Jan 2021, Published online: 02 Feb 2021
 ABSTRACT
Background
Chronic fatigue syndrome (CFS) is an illness of unknown origin that may have familial risks. Low natural killer (NK) lymphocyte activity was proposed as a risk for familial CFS in 1998. Since then, there have been many studies of NK lymphocytes in CFS in general populations but few in familial CFS. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK lymphocytes helps control viral infections. ADCC is affected by variant CD16A receptors for antibody that are genetically encoded by FCGR3A.
Methods
This report characterizes ADCC effector NK cell numbers, ADCC activities, and FCGR3A variants of five families each with 2–5 CFS patients, their family members without CFS and unrelated controls. The patients met the Fukuda diagnostic criteria. We determined: CD16Apositive blood NK cell counts; EC50s for NK cell recognition of antibody; ADCC lytic capacity; FCGR3A alleles encoding CD16A variants, ROC tests for biomarkers, and synergistic risks.
Results
CFS patients and their family members had fewer CD16Apositive NK cells, required more antibody, and had ADCC that was lower than the unrelated controls. CFS family members were predominantly genetically CD16A F/F s for the variant with low affinity for antibodies. ROC tests indicated unsuitability of ADCC as a biomarker for CFS because of the low ADCC of family members without CFS. Familial synergistic risk vs. controls was evident for the combination of CD16Apositive NK cell counts with ADCC capacity.
Conclusions
Low ADCC may be a risk factor for familial CFS. Furthermore, characterization of familial CFS represents an opportunity to identify pathogenic mechanisms of CFS.
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Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME)
Giuseppe Francesco Damiano Lupo,Gabriele Rocchetti, Luigi Lucini,  Lorenzo Lorusso, Elena Manara, Matteo Bertelli, Edoardo Puglisi & Enrica Capelli 
Scientific Reports volume 11, Article number: 7043 (2021)  
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidences suggest strong correlations between dysbiosis and pathological condition. The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS. The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.
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Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE)
John Cullinan 1, Derek F H Pheby 2, Diana Araja 3, Uldis Berkis 3, Elenka Brenna 4, Jean-Dominique de Korwin 5 6, Lara Gitto 7, Dyfrig A Hughes 8, Rachael M Hunter 9, Dominic Trepel 10 11, Xia Wang-Steverding 12    PMID: 33652747   PMCID: PMC7996783  DOI: 10.3390/medicina57030208
Abstract
Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs' knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.
Keywords: GP knowledge and understanding; ME/CFS; chronic fatigue syndrome; myalgic encephalomyelitis; primary care.
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 Clin Med. 2020 Oct 31;9(11):3527.    doi: 10.3390/jcm9113527.
Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance
Björn Gerdle 1 2, Bijar Ghafouri 1, Eva Lund 3, Ann Bengtsson 1, Peter Lundberg 2 4, Helene van Ettinger-Veenstra 1 2, Olof Dahlqvist Leinhard 2 4 5, Mikael Fredrik Forsgren 2 4 5
Affiliations expand PMID: 33142767  PMCID: PMC7693920  DOI: 10.3390/jcm9113527
Abstract
In fibromyalgia (FM) muscle metabolism, studies are sparse and conflicting associations have been found between muscle metabolism and pain aspects. This study compared alterations in metabolic substances and blood flow in erector spinae and trapezius of FM patients and healthy controls. FM patients (n = 33) and healthy controls (n = 31) underwent a clinical examination that included pressure pain thresholds and physical tests, completion of a health questionnaire, participation in microdialysis investigations of the etrapezius and erector spinae muscles, and also underwent phosphorus-31 magnetic resonance spectroscopy of the erector spinae muscle. At the baseline, FM had significantly higher levels of pyruvate in both muscles. Significantly lower concentrations of phosphocreatine (PCr) and nucleotide triphosphate (mainly adenosine triphosphate) in erector spinae were found in FM. Blood flow in erector spinae was significantly lower in FM. Significant associations between metabolic variables and pain aspects (pain intensity and pressure pain threshold PPT) were found in FM. Our results suggest that FM has mitochondrial dysfunction, although it is unclear whether inactivity, obesity, aging, and pain are causes of, the results of, or coincidental to the mitochondrial dysfunction. The significant regressions of pain intensity and PPT in FM agree with other studies reporting associations between peripheral biological factors and pain aspects.
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Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029
Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*

• 1Independent Researcher, Sint Martens Latem, Belgium
• 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
• 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
• 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.
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Chest: 2021 Feb 10;S0012-3692(21)00256-7.  doi: 10.1016/j.chest.2021.01.082. 
Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Phillip Joseph 1, Carlo Arevalo 2, Rudolf K F Oliveira 3, Mariana Faria-Urbina 4, Donna Felsenstein 5, Anne Louise Oaklander 6, David M Systrom 4    PMID: 33577778
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.
Research question: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?
Study design and methods: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles.
Results: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.
Interpretation: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.
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Healthcare (Basel)  . 2020 Jun 30;8(3):192.    doi: 10.3390/healthcare8030192.
Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease
C Linda Mc van Campen 1, Peter C Rowe 2, Frans C Visser 1    PMID: 32629923    PMCID: PMC7551790
Abstract
Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients.
Methods and results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO2), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO2, VO2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 (p-Value between 0.003 and <0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients (p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (-19 (11) %).
Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group.

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The impact of tryptophan supplementation on sleep quality: a systematic review, meta-analysis, and meta-regression
Clarinda N Sutanto, Wen Wei Loh, Jung Eun Kim
Nutrition Reviews, nuab027, https://doi.org/10.1093/nutrit/nuab027 Published: 03 May 2021
Abstract
Context
L-tryptophan (Trp) has been documented to aid sleep, but a systematic compilation of its effect on sleep quality is still limited.
Objective
We assessed the effect of Trp supplementation on sleep quality via meta-analysis and meta-regression. The effects of daily Trp dose (<1 g and ≥1 g) were also assessed.
Data sources
A database search was done in PubMed, Medline (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane and a total of 18 articles were collected.
Data extraction
Extracted data from 4 articles were also analyzed using random-effect meta-analysis and meta-regression. Standardized mean difference (SMD) was used in meta-analysis.
Data analysis
Results from the study suggested that Trp supplementation can shorten wake after sleep onset (−81.03 min/g, P = 0.017; SMD, −1.08 min [95%CI, −1.89 to −0.28]). In addition, the group receiving ≥1 g Trp supplementation had a shorter wake after sleep onset than the group with Trp < 1g supplementation (Trp <1 g vs Trp ≥1 g: 56.55 vs 28.91 min; P = 0.001). However, Trp supplementation did not affect other sleep components.
Conclusion
Trp supplementation, especially at ≥1 g can help improve sleep quality.

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COVID-19 symptoms over time: comparing long-haulers to ME/CFS
Leonard A. Jason,Mohammed F. Islam,Karl Conroy,Joseph Cotler,Chelsea Torres,Mady Johnson & show all
Received 21 Apr 2021, Accepted 22 Apr 2021, Published online: 05 May 2021  
Fatigue,Biomedicine, Health and Behaviouir

ABSTRACT
Introduction
Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods
278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
Results
Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
Conclusions
These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
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Sci Rep . 2021 Feb 25;11(1):4541.  doi: 10.1038/s41598-021-83660-9.
Recursive ensemble feature selection provides a robust mRNA expression signature for myalgic encephalomyelitis/chronic fatigue syndrome
Paula I Metselaar 1, Lucero Mendoza-Maldonado 2, Andrew Yung Fong Li Yim 3, Ilias Abarkan 4, Peter Henneman 3, Anje A Te Velde 1, Alexander Schönhuth 5, Jos A Bosch 6 7, Aletta D Kraneveld 4, Alejandro Lopez-Rincon 8 9
Affiliations expand PMID: 33633136  PMCID: PMC7907358
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disorder characterized by disabling fatigue. Several studies have sought to identify diagnostic biomarkers, with varying results. Here, we innovate this process by combining both mRNA expression and DNA methylation data. We performed recursive ensemble feature selection (REFS) on publicly available mRNA expression data in peripheral blood mononuclear cells (PBMCs) of 93 ME/CFS patients and 25 healthy controls, and found a signature of 23 genes capable of distinguishing cases and controls. REFS highly outperformed other methods, with an AUC of 0.92. We validated the results on a different platform (AUC of 0.95) and in DNA methylation data obtained from four public studies on ME/CFS (99 patients and 50 controls), identifying 48 gene-associated CpGs that predicted disease status as well (AUC of 0.97). Finally, ten of the 23 genes could be interpreted in the context of the derailed immune system of ME/CFS.
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Cytokine networks analysis uncovers further differences between those who develop myalgic encephalomyelitis/chronic fatigue syndrome following infectious mononucleosis
Leonard A. Jason,Joseph Cotler,Mohammed F. Islam,Jacob Furst,Matthew Sorenson &Ben Z. Katz
Pages 45-57 | Received 24 Feb 2021, Accepted 07 Apr 2021, Published online: 18 Apr 2021 
https://doi.org/10.1080/21641846.2021.1915131
ABSTRACT
Background
We followed college students before, during, and after infectious mononucleosis (IM) for the development of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Aim
We used network analysis to study relationships between pre-illness cytokine data amongst three groups of participants: those 30 who went on to develop ME/CFS following IM (and met one case definition), those 18 who went on to develop severe ME/CFS (S-ME-CFS) following IM (and met greater than one case definition), and those 58 who recovered following IM (controls).
Methods
We recruited 4501 college students; approximately 5% developed IM during their enrollment at university. Those who developed IM were evaluated at a 6-month follow-up to determine whether they recovered or met criteria for ME/CFS; those who met >1 set of criteria for ME/CFS were termed S-ME/CFS. Patterns of pre-illness cytokine networks were then classified according to the following characteristics: membership, modularity, Eigen centrality, Total centrality, and mean degree. Network statistics were compared across groups using a one-way analysis of variance (ANOVA).
Results
Those with S-ME/CFS had a more interconnected network of cytokines, whereas recovered controls had more differentiated networks and more subgroupings of cytokine connections. Those with ME/CFS had a network that was denser than the controls, but less dense than those with severe ME/CFS.
Conclusions
The distinct network differences between these three groups implies that there may be biological differences between our three groups of study participants at baseline.
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Front. Med., 22 March 2021 | https://doi.org/10.3389/fmed.2021.642710
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study
Kari Sørland1,2*, Miriam Kristine Sandvik3, Ingrid Gurvin Rekeland1,4, Lis Ribu2, Milada Cvancarova Småstuen2, Olav Mella1,4 and Øystein Fluge1,4

• 1Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
• 2Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
• 3Porsgrunn District Psychiatric Centre, Telemark Hospital Trust, Porsgrunn, Norway
• 4Department of Clinical Science, Institute of Medicine, University of Bergen, Bergen, Norway

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.
Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18–65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).
Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5–13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7–21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343–4,334) vs. healthy individuals 1,886 p.u. (range 808–8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.
Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
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Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy   Shaun Bhatia  Mohammed Islam and Leonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.
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In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
Arnaud Germain Susan M. Levine and Maureen R. Hanson *
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Proteomes 2021, 9(1), 6; https://doi.org/10.3390/proteomes9010006
Received: 1 January 2021 / Revised: 24 January 2021 / Accepted: 25 January 2021 / Published: 29 January 2021
(This article belongs to the Special Issue Functional Proteomics 2020)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.
Brain and Behavior
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ORIGINAL RESEARCH
Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
Sara Haghighi, Sara Forsmark, Olof Zachrisson, Arvid Carlsson, Marie K. L. Nilsson, Maria L. Carlsson, Robert C. Schuit, Carl-Gerhard Gottfries
First published: 02 February 2021    https://doi.org/10.1002/brb3.2040
Abstract
Objectives
The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales.
Materials and Methods
In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks.
Results
Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.
Conclusions
(-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.
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UK Moves to Revise Guidelines for Treatment of Chronic Fatigue Syndrome
AJN, American Journal of Nursing: March 2021 - Volume 121 - Issue 3 - p 16
doi: 10.1097/01.NAJ.0000737248.67484.2e
Abstract
Advocates hail rejection of debunked exercise and cognitive behavior therapies.
Proposed guidelines for management of myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS), from the United Kingdom's National Institute for Health and Care Excellence (NICE) are being hailed for their rejection of graded exercise therapy and cognitive behavior therapy (CBT) as routine treatment. Major medical organizations, advocacy groups, and patients have strongly advocated for NICE to align guidelines with scientific evidence.
The U.S. Centers for Disease Control and Prevention (CDC) in 2017 eliminated these largely useless and, in some cases, harmful therapies from its recommendations. That NICE is now following suit is good news, though many say it is long overdue. Moreover, patients are unlikely to see immediate results as new science can take years to reach clinical practice.
The illness is characterized by debilitating fatigue and difficulty with concentration and memory. An estimated 2.5 million Americans are diagnosed with ME/CFS, most of them women. Because symptoms can range widely and standard laboratory tests yield little insight as to cause, ME/CFS has been viewed as a stress-induced disorder in some women.
Graded exercise therapy and CBT became the go-to therapies for ME/CFS based on findings of a 2011 study, known as PACE, published in the Lancet. According to the study investigators, these treatments produced a sustained improvement in patients' levels of fatigue and physical function, even leading to recovery for some. Top researchers who reviewed the study, however, found major flaws. Patients also reacted negatively, saying the study's results did not reflect their experiences and reinforced inaccurate and stigmatizing beliefs about the illness as a psychological and behavioral disorder. Eventually, over 100 academics, patient groups, and others called for an independent reanalysis of the data. Despite this forceful opposition, the study remained influential with clinicians and continued to underpin treatment recommendations of major medical organizations, including the CDC and NICE.
Perceptions began to change with the 2015 release of the Institute of Medicine's landmark report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, in which the authors described ME/CFS as a “serious, chronic, complex, systemic disease” and cited newly identified biomarkers indicating immunological and neurological dysfunction. The report and continuing pressure from scientists, clinicians, and patients led the CDC to remove recommendations for graded exercise therapy and CBT as its British counterpart, NICE, now proposes to do.--Karen Roush, PhD, RN, FNP-BC, news director

Unpacking post-covid symptoms
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1173 (Published 19 May 2021)Cite this as: BMJ 2021;373:n1173     Elaine.maxwell@nihr.ac.uk
Common, burdensome, and highly variable
Our understanding of long covid (also known as post-covid syndrome) has progressed considerably since the first follow-up of people discharged from hospital in 2020 after SARS-CoV-2 infection.12 People who were not admitted to hospital with their covid-19 infection but who have enduring symptoms have driven the wider recognition of long covid symptoms, including organ impairment.3 Much evidence comes from small, observational studies or surveys using different case definitions and sampling frames, resulting in a wide range of prevalence estimates.4 Larger surveys found that enduring symptoms were more often reported among people who had had covid-19 than among controls who had not,56 including reporting of cognitive deficits.7 However, reliance on self-reporting in many studies has been criticised by some commentators.
In a linked paper, Daugherty and colleagues (doi:10.1136/bmj.n1098) used a large electronic records dataset to describe the prevalence and risks of post-covid sequelae in patients both admitted to hospital and in the community in the United States.8 Several studies have retrospectively reviewed ICD-10 (international classification of diseases, 10th revision) codes in electronic health records, including a large study reporting that people admitted to hospital with covid-19 were 3.5 times more likely to be readmitted and 7.7 times more likely to die within five months of discharge than controls admitted to hospital without covid-19.9 Researchers using US Department of Veterans Affairs databases found increased use of analgesics, antidepressants, antihypertensives, and oral hypoglycaemics in the six months after confirmed covid-19 compared with controls,10 and data from the US TriNetX electronic health records network showed that nearly 34% of people testing positive for SARS-CoV-2 had a neurological or psychiatric diagnosis in the following six months.11
Daugherty and colleagues found that certain conditions were more commonly diagnosed after covid-19 than after other viral lower respiratory tract infections.8 The estimated 14% incidence of new diagnoses up to six months after SARS-CoV-2 infection is strikingly similar to the 13.7% incidence of self-reported symptoms lasting more than 12 weeks found by the UK Office for National Statistics.6 While both studies report higher incidence in people admitted to hospital, new symptoms and diagnoses were also seen in those who remained at home.6810 The absolute number of people reporting long covid symptoms will be higher in the community owing to the (at least) 10-fold difference in the numbers admitted to hospital and those who stayed at home.12 Primary care clinicians should expect patients with mild initial infections to report long covid or post-covid symptoms just as frequently as those who were critically ill.
In common with most studies, Daugherty and colleagues report that enduring symptoms are more common in women, those living with social deprivation, and those with pre-existing comorbidities.8 Importantly, they found that 10% of people developed new diagnoses requiring medical attention more than three weeks after the initial infection, with 4% developing more than one new diagnosis. This feature is well described by people with real life experience, who call it the “corona-coaster.” People who present with late onset symptoms (particularly those not admitted to hospital) report that some healthcare professionals do not associate symptoms with covid-19 and do not provide appropriate assessment and treatment.4
It is too early to predict how long clinical sequelae will persist after covid-19, but these symptoms clearly create a major personal burden for many people, with some individuals experiencing difficulty returning to work and some unable to care for dependents.4 Long covid is also putting a strain on healthcare services, which have been already decimated by the pandemic. Identifying risk factors would facilitate triage and faster access to specialist care. However, one of the peculiarities of long covid is its non-linear progression, hampering attempts to predict who will develop particular symptoms and when. Risk factors differ for different new diagnoses, suggesting that a variety of mechanisms could be at play.81011 Applying these risk factors to clinical practice will probably need long covid to be subdivided into more specific phenotypes.
Daugherty and colleagues’ analyses included people aged 18-65, and although symptom reporting is less common outside this age band,6 evidence is growing that children also experience long covid.1314 In older adults, symptoms could be under-reported because of assumptions that they are due to aging or comorbidities. Healthcare professionals should be alert to the possibility of long covid in anyone with confirmed or suspected covid-19. How to treat these longer term consequences is now an urgent research priority.
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Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1098 (Published 19 May 2021)Cite this as: BMJ 2021;373:n1098
Sarah E Daugherty, senior researcher1,  Yinglong Guo, director1,  Kevin Heath, national medical director for clinical intelligence and physician2 ,  Micah C Dasmariñas, data scientist1,  Karol Giuseppe Jubilo, data scientist1,  Jirapat Samranvedhya, principal data scientist1,  Marc Lipsitch, professor3,  Ken Cohen, executive director of translational research and clinician2 4 

• Accepted 26 April 2021

Abstract
Objective To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65.
Design Retrospective cohort study.
Setting Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database.
Participants Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness.
Main outcome measures More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated.
Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.
Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

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Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome
WakiroSatoabHirohikoOnoaTakajiMatsutanicMasakazuNakamuraaIsuShindKeikoAmanoeRyujiSuzukicTakashiYamamuraab
https://doi.org/10.1016/j.bbi.2021.03.023Get rights and content
Brain, Behavior, and Immunity    Volume 95, July 2021, Pages 245-255
Highlights
ME/CFS is characterized by skewed B cell receptor gene usage.
Upregulation of specific IGHV genes correlated to infection-related episodes at onset.
Plasmablasts of ME/CFS patients upregulated interferon response genes.
B cell receptor repertoire analysis can provide a useful diagnostic marker in ME/CFS.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.

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Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)

• C. (Linda) M. C. van Campen, Peter C. Rowe & Frans C. Visser 

Journal of Translational Medicine volume 19, Article number: 193 (2021)  
Abstract
Background
Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).
Methods and results
In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.
Conclusion
This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.

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Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Klaus J. Wirth & Carmen Scheibenbogen 
Journal of Translational Medicine volume 19, Article number: 162 (2021) 
Abstract
Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

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Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS
Bianka Jäkel, Claudia Kedor, Patricia Grabowski, Kirsten Wittke, Silvia Thiel, Nadja Scherbakov, Wolfram Doehner, Carmen Scheibenbogen & Helma Freitag 
Journal of Translational Medicine volume 19, Article number: 159 (2021)  
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease accompanied by muscular fatigue and pain. A functional measure to assess muscle fatigability of ME/CFS patients is, however, not established in clinical routine. The aim of this study is to evaluate by assessing repeat maximum handgrip strength (HGS), muscle fatigability as a diagnostic tool and its correlation with clinical parameters.
Methods
We assessed the HGS of 105 patients with ME/CFS, 18 patients with Cancer related fatigue (CRF) and 66 healthy controls (HC) using an electric dynamometer assessing maximal (Fmax) and mean force (Fmean) of ten repetitive measurements. Results were correlated with clinical parameters, creatinine kinase (CK) and lactate dehydrogenase (LDH). Further, maximum isometric quadriceps strength measurement was conducted in eight ME/CFS patients and eight HC.
Results
ME/CFS patients have a significantly lower Fmax and Fmean HGS compared to HC (p < 0.0001). Further, Fatigue Ratio assessing decline in strength during repeat maximal HGS measurement (Fmax/Fmean) was higher (p ≤ 0.0012). The Recovery Ratio after an identical second testing 60 min later was significantly lower in ME/CFS compared to HC (Fmean2/Fmean1; p ≤ 0.0020). Lower HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and with higher CK and LDH levels after exertion.
Conclusion
Repeat HGS assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS.
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J Clin Med 2020 Oct 11;9(10):3246. doi: 10.3390/jcm9103246.
Mindfulness-Based Program Plus Amygdala and Insula Retraining (MAIR) for the Treatment of Women with Fibromyalgia: A Pilot Randomized Controlled Trial
Juan P Sanabria-Mazo 1 2 3 4, Jesus Montero-Marin 5, Albert Feliu-Soler 1 2 3, Virginia Gasión 6, Mayte Navarro-Gil 6 7, Héctor Morillo-Sarto 8, Ariadna Colomer-Carbonell 1 2 3, Xavier Borràs 3, Mattie Tops 9, Juan V Luciano 1 2, Javier García-Campayo 6 7
PMID: 33050630   PMCID: PMC7599726
Abstract
The lack of highly effective treatments for fibromyalgia (FM) represents a great challenge for public health. The objective of this parallel, pilot randomized controlled trial (RCT) was two-fold: (1) to analyze the clinical effects of mindfulness plus amygdala and insula retraining (MAIR) compared to a structurally equivalent active control group of relaxation therapy (RT) in the treatment of FM; and (2) to evaluate its impact on immune-inflammatory markers and brain-derived neurotrophic factor (BDNF) in serum. A total of 41 FM patients were randomized into two study arms: MAIR (intervention group) and RT (active control group), both as add-ons of treatment as usual. MAIR demonstrated significantly greater reductions in functional impairment, anxiety, and depression, as well as higher improvements in mindfulness, and self-compassion at post-treatment and follow-up, with moderate to large effect sizes. Significant decreases in pain catastrophizing and psychological inflexibility and improvements in clinical severity and health-related quality of life were found at follow-up, but not at post-treatment, showing large effect sizes. The number needed to treat was three based on the criteria of ≥50% Fibromyalgia Impact Questionnaire (FIQ) reduction post-treatment. Compared to RT, the MAIR showed significant decreases in BDNF. No effect of MAIR was observed in immune-inflammatory biomarkers (i.e., TNF-α, IL-6, IL-10, and hs-CRP). In conclusion, these results suggest that MAIR, as an adjuvant of treatment-as-usual (TAU), appears to be effective for the management of FM symptoms and for reducing BDNF levels in serum.

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Trends in Molecuar medicine    Available online 7 June 2021
Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome
Anthony L.Komaroff1W. IanLipkin2 https://doi.org/10.1016/j.molmed.2021.06.002Get rights and content
Highlights
In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”.
Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.
ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome.
The US and other developed nations have committed considerable support for research on post-COVID illnesses.
Abstract
SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.
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Integr Med Res . 2021 Jun;10(2):100664.  doi: 10.1016/j.imr.2020.100664. Epub 2020 Sep 22.
Effectiveness a herbal medicine ( Sipjeondaebo-tang) on adults with chronic fatigue syndrome: A randomized, double-blind, placebo-controlled trial
Seungwon Shin 1 2, Soo Jung Park 3, Minwoo Hwang 4 
PMID: 33101925 PMCID: PMC7578262
Abstract
Background: Sipjeondaebo-tang (SJDBT, Shi-quan-da-bu-tang in Chinese) is a widely prescribed herbal medicine in traditional Korean medicine. This study aimed to evaluate the effectiveness and safety of SJDBT for treating chronic fatigue syndrome (CFS).
Methods: Ninety-six eligible participants were randomly allocated to either the SJDBT or placebo groups in a 1:1 ratio. Nine grams of SJDBT or placebo granules were administered to the patients for 8 weeks. The primary outcome was the response rate, defined as the proportion of participants with a score of 76 or higher in the Checklist Individual Strength assessment. Other measurements for fatigue severity, quality of life, and qi/blood/yin/yang deficiency were included. Safety was assessed throughout the trial.
Results: At week 8, the response rate did not significantly differ between the groups (SJDBT: 35.4%; placebo: 54.2%; P = 0.101, effect size [95% confidence interval] = 0.021 [-0.177, 0.218]). However, the scores of the visual analogue scale (P = 0.001, -0.327 [-0.506, -0.128]), Fatigue Severity Scale (P = 0.020, 0.480 [0.066, 0.889]), and Chalder fatigue scale (P = 0.004, -0.292 [-0.479, -0.101]) for the SJDBT group showed significant improvements in fatigue severity at the endpoint. Quality of life was not significantly different. Furthermore, SJDBT significantly ameliorated the severity of qi deficiency compared to that in the placebo group. No serious adverse events were observed.
Conclusion: This trial failed to show a significant improvement in fatigue severity, as assessed by the CIS-deprived response rate. It merely showed that SJDBT could alleviate the severity of fatigue and qi deficiency in patients with CFS. However, the further study is needed to confirm the details.

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Postdengue chronic fatigue syndrome in an adolescent boy 
Thadchanamoorthy V and Dayasiri K.
BMJ Case Reports. 2021 Jun 7;14(6):e238605 
Abstract 
Chronic fatigue syndrome (CFS) is often preceded by a viral illness and has recurrent ‘flulike’ symptoms which include a wide spectrum of musculoskeletal and neurological clinical features. The condition is also known as myalgic encephalomyelitis and systemic exertional intolerance syndrome.
CFS has been reported following dengue among adult patients. We report the case of an 11-year-old boy who developed CFS following recovery of dengue haemorrhagic fever (DHF). The reported child was initially managed as for DHF and was clinically asymptomatic on post-discharge day 3. He was re-admitted after 3 weeks with severe joint pains, myalgia and unbearable headache.
As his symptoms persisted, he was investigated in-depth. All investigations were normal except mild elevation of liver functions. The diagnosis of CFS secondary to DHF was made by exclusion of differential diagnosis. At 1-year follow-up, patient continues to have symptoms after treatment with physiotherapy and nutrition counselling. 

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Front. Immunol., 06 April 2021 | https://doi.org/10.3389/fimmu.2021.644548
Delineating the Association Between Soluble CD26 and Autoantibodies Against G-Protein Coupled Receptors, Immunological and Cardiovascular Parameters Identifies Distinct Patterns in Post-Infectious vs. Non-Infection-Triggered Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Marvin Szklarski1*, Helma Freitag1, Sebastian Lorenz1, Sonya C. Becker1, Franziska Sotzny1, Sandra Bauer1, Jelka Hartwig1, Harald Heidecke2, Kirsten Wittke1, Claudia Kedor1, Leif G. Hanitsch1, Patricia Grabowski1, Nuno Sepúlveda1 and Carmen Scheibenbogen1

• 1Institute of Medical Immunology, Charité –Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
• 2CellTrend, Luckenwalde, Germany

Soluble cluster of differentiation 26 (sCD26) has a wide range of enzymatic functions affecting immunological, metabolic and vascular regulation. Diminished sCD26 concentrations have been reported in various autoimmune diseases and also in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). Here we re-evaluate sCD26 as a diagnostic marker and perform a comprehensive correlation analysis of sCD26 concentrations with clinical and paraclinical parameters in ME/CFS patients. Though this study did find significantly lower concentrations of sCD26 only in the female cohort and could not confirm diagnostic suitability, results from correlation analyses provide striking pathomechanistic insights. In patients with infection-triggered onset, the associations of low sCD26 with elevated autoantibodies (AAB) against alpha1 adrenergic (AR) and M3 muscarinic acetylcholine receptors (mAChR) point to a pathomechanism of infection-triggered autoimmune-mediated vascular and immunological dysregulation. sCD26 concentrations in infection-triggered ME/CFS were found to be associated with activated T cells, liver enzymes, creatin kinase (CK) and lactate dehydrogenase (LDH) and inversely with Interleukin-1 beta (IL-1b). Most associations are in line with the known effects of sCD26/DPP-4 inhibition. Remarkably, in non-infection-triggered ME/CFS lower sCD26 in patients with higher heart rate after orthostatic challenge and postural orthostatic tachycardia syndrome (POTS) suggest an association with orthostatic regulation. These findings provide evidence that the key enzyme sCD26 is linked to immunological alterations in infection-triggered ME/CFS and delineate a different pathomechanism in the non-infectious ME/CFS subset.

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Analysis of Gender Differences in HRV of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Mobile-Health Technology
Lluis Capdevila  Jesús Castro-Marrero José Alegre Juan Ramos-Castro 3 and Rosa M Escorihuela
Departament de Psicologia Bàsica, Sport Research Institute, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Sensors 2021, 21(11), 3746; https://doi.org/10.3390/s21113746
Received: 20 April 2021 / Revised: 20 May 2021 / Accepted: 22 May 2021 / Published: 28 May 2021
(This article belongs to the Special Issue Smartphones and Wearable Sensors for Monitoring Heart Rate and Heart Rate Variability)
Abstract
In 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.
Keywords: mHealth; heart rate variability; HRV; ME/CFS; myalgic encephalomyelitis; chronic fatigue syndrome; gender differences
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settings
Post-Exertional Malaise May Be Related to Central Blood Pressure, Sympathetic Activity and Mental Fatigue in Chronic Fatigue Syndrome Patients
Sławomir Kujawski Joanna Słomko Lynette Hodges Derek F. H. Pheby Modra Murovska  
Julia L. Newton Paweł Zalewski
J. Clin. Med. 2021, 10(11), 2327; https://doi.org/10.3390/jcm10112327
Received: 25 March 2021 / Revised: 21 May 2021 / Accepted: 23 May 2021 / Published: 26 May 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Abstract
Post-exertional malaise (PEM) is regarded as the hallmark symptom in chronic fatigue syndrome (CFS). The aim of the current study is to explore differences in CFS patients with and without PEM in indicators of aortic stiffness, autonomic nervous system function, and severity of fatigue. One-hundred and one patients met the Fukuda criteria. A Chronic Fatigue Questionnaire (CFQ) and Fatigue Impact Scale (FIS) were used to assess the level of mental and physical fatigue. Aortic systolic blood pressure (sBPaortic) and the autonomic nervous system were measured with the arteriograph and Task Force Monitor, respectively. Eighty-two patients suffered prolonged PEM according to the Fukuda criteria, while 19 did not. Patients with PEM had higher FIS scores (p = 0.02), lower central systolic blood pressure (p = 0.02) and higher mental fatigue (p = 0.03). For a one-point increase in the mental fatigue component of the CFQ scale, the risk of PEM increases by 34%. For an sBPaortic increase of 1 mmHg, the risk of PEM decreases by 5%. For a one unit increase in sympathovagal balance, the risk of PEM increases by 330%. Higher mental fatigue and sympathetic activity in rest are related to an increased risk of PEM, while higher central systolic blood pressure is related to a reduced risk of PEM. However, none of the between group differences were significant after FDR correction, and therefore conclusions should be treated with caution and replicated in further studies.
Keywords: PEM; myalgic encephalomyelitis; brain fog; vascular stiffness

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Front. Med., 07 May 2021 | https://doi.org/10.3389/fmed.2021.672370
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*

• 1Independent Researcher, Sint Martens Latem, Belgium
• 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
• 3Analytical Chemistry and Neurochemistry, Department of Chemistry–Biomedical Center, Uppsala University, Uppsala, Sweden
• 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

We here provide an overview of treatment trials for prolonged intensive care unit (ICU) patients and theorize about their relevance for potential treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these treatment trials generally target: (a) the correction of suppressed endocrine axes, notably through a “reactivation” of the pituitary gland's pulsatile secretion of tropic hormones, or (b) the interruption of the “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. There are significant parallels in the treatment trials for prolonged critical illness and ME/CFS; this is consistent with the hypothesis of an overlap in the mechanisms that prevent recovery in both conditions. Early successes in the simultaneous reactivation of pulsatile pituitary secretions in ICU patients—and the resulting positive metabolic effects—could indicate an avenue for treating ME/CFS. The therapeutic effects of thyroid hormones—including in mitigating O&NS and inflammation and in stimulating the adreno-cortical axis—also merit further studies. Collaborative research projects should further investigate the lessons from treatment trials for prolonged critical illness for solving ME/CFS.

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COVID-19 symptoms over time: comparing long-haulers to ME/CFS
Leonard A. Jason,Mohammed F. Islam,Karl Conroy,Joseph Cotler,Chelsea Torres,Mady Johnson  
Received 21 Apr 2021, Accepted 22 Apr 2021, Published online: 05 May 2021
https://doi.org/10.1080/21641846.2021.1922140 
ABSTRACT
Introduction
Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods
278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
Results
Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
Conclusions
These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
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How can we manage covid fatigue?
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1610 (Published 24 June 2021)Cite this as: BMJ 2021;373:n1610               Fiona Godlee, editor in chief
What’s the long term outlook after covid? And what’s the prognosis for health systems and staff struggling with covid pressures, waiting lists, and stretched resources?
Most people make a good recovery, but the wide range of covid related illness and organ damage weave a complex prognostic picture. Of patients discharged from hospital, more than one in 10 will die within six months, writes Emily Fraser (doi:10.1136/bmj.n1565).1 Some patients with lung damage will have persisting respiratory symptoms, but for those who were previously fit and without other complications the outlook is good, with functional recovery better than expected from the radiological evidence.
Up to 376 000 people in the UK have reported ongoing symptoms more than 12 months after contracting the virus, with persistent mental and physical fatigue a troubling reality for many (doi:10.1136/bmj.n1559).2 This presents clinicians with a range of challenges. Should patients with fatigue follow the dominant advice of the CFS/ME communities: that pacing rather than graded exercise therapy is the safest route, as is now also recommended in controversial draft guidance from the UK National Institute for Health and Care Excellence? Or does this risk sentencing patients to a lifetime of symptom monitoring and long term disability? What of the researchers braving this often toxic academic terrain?
Promisingly, away from the “fire and fury” of debate, doctors and others are quietly working out how best to treat each patient without causing harm (doi:10.1136/bmj.n1559).2 Careful screening for post-exertional malaise and individualised treatment plans seem to be the way forward. But it’s also crucial to tackle endemic power imbalances between patients and professionals and to co-produce knowledge and services (https://blogs.bmj.com/bmj/2021/06/23/how-power-imbalances-in-the-narratives-research-and-publications-around-long-covid-can-harm-patients).3
The needs of patients with long covid are just one of many calls on stretched healthcare resources. We also need a primary care led vaccine infrastructure (doi:10.1136/bmj.n1578) and a full recovery plan for the NHS (https://blogs.bmj.com/bmj/2021/06/18/chris-ham-the-governments-response-to-the-nhs-backlog-has-fallen-short).45 We can’t recoup the vast sums squandered on test and trace, but perhaps a rethink will soon be in order after the US Food and Drug Administration’s warning against using the Innova rapid test (doi:10.1136/bmj.n1582).6 This comes on top of continuing grave concerns about the test’s reliability and evaluation (doi:10.1136/bmj.n1058) and now a call for trials in schools to be suspended (https://blogs.bmj.com/bmj/2021/06/17/daily-contact-testing-trials-in-schools-are-unethical-and-extending-them-to-include-the-delta-variant-puts-everyone-at-risk).78 Despite all this, the UK regulator has extended authorisation for two more months (doi:10.1136/bmj.n1582),6 so it will be worth brushing up your understanding of how to interpret lateral flow tests (doi:10.1136/bmj.n1411).9 In case you need reminding, context and pre-test probability are everything (https://blogs.bmj.com/bmj/2021/06/15/sheila-bird-diagnostic-tests-must-be-more-rigorously-regulated).10
Sadly, the pressure on healthcare systems and staff is causing moral distress and injury (doi:10.1136/bmj.n1543),11 which won’t be helped by doctors in the UK retiring in greater numbers and at a younger age (doi:10.1136/bmj.n1594).12 Tax rules on pensions are a major factor (doi:10.1136/bmj.n1517).13 The government has changed the rules for judges and must do the same for doctors if this haemorrhaging of vital talent and experience is to be stemmed.
This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
https://bmj.com/coronavirus/usage

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Neurological and psychiatric complications in patients with COVID-19
Heather Mason   |   23 June 2021
A study published in Brain Communications has found an 11 per cent prevalence of neuropsychiatric symptoms among hospitalised COVID-19 patients, with a wide range of associated neurological and psychiatric complications.
The researchers analysed 245 adult COVID-19 patients with a de novo neurological or psychiatric manifestation to better understand the detailed spectrum of neuropsychiatric disorders.
The results show that the most frequent neuropsychiatric symptoms were motor weakness, cognitive disturbances, impaired consciousness, psychiatric disturbance, headache, and behavioural disturbance. Some symptoms appeared soon after COVID-19 onset, such as myalgia, headache, or anosmia, while others had a delayed onset, such as sensory symptoms and psychiatric disturbances.
The most frequent neuropsychiatric syndromes were encephalopathy, critical illness polyneuropathy and myopathy, psychiatric disturbances, and cerebrovascular complications.
Other syndromes, such as isolated disabling headache, seizures, isolated movement disorders, and encephalitis, were much rarer. Guillain-Barré syndrome was observed in five patients.
The most commonly observed psychiatric disorders in the context of COVID-19 infection were anxiety disorders, depression, acute psychosis, adjustment disorders and acute stress, although some of the patients had a pre-existing condition.
The study described a wide range of neuropsychiatric complications, and further studies are needed to understand their underlying mechanisms and potential long-term problems, the authors concluded.

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Dysregulation of brain and choroid plexus cell types in severe COVID-19
Andrew C. Yang, Fabian Kern, Patricia M. Losada, Maayan R. Agam, Christina A. Maat, Georges P. Schmartz, Tobias Fehlmann, Julian A. Stein, Nicholas Schaum, Davis P. Lee, Kruti Calcuttawala, Ryan T. Vest, Daniela Berdnik, Nannan Lu, Oliver Hahn, David Gate, M. Windy McNerney, Divya Channappa, Inma Cobos, Nicole Ludwig, Walter J. Schulz-Schaeffer, Andreas Keller & Tony Wyss-Coray 
Nature  Published: 21 June 2021
Abstract
Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1–3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4–6. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans7 and linked to cognitive function8—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.
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BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1626 (Published 24 June 2021)Cite this as: BMJ 2021;373:n1626
Adrian O’Dowd
Around a third of people in England who developed covid-19 went on to experience long term symptoms sometimes called “long covid,” a UK study has found and experts believe that more than two million people could have been affected in this way.
Findings from the React-2 (Real-time Assessment of Community Transmission) study from Imperial College London used self-reported data from 508 707 adults aged 18 or older who took part in three rounds of surveys that were carried out between September 2020 and February 2021, in which they were asked about 29 different symptoms.
The study, published as a preprint and not yet peer reviewed,1 found that around a fifth (19.2%) of those surveyed reported having had contracted covid-19 previously, with more than a third (37.7%) reporting at least one persistent symptom and 14.8% experiencing three or more symptoms lasting at least 12 weeks.
Almost a third of people (30.5%) with at least one symptom lasting 12 weeks or more reported having had severe covid-19 symptoms that had a “significant effect on my daily life” at the time of their illness.
Overall, 5.8% of the study population had one or more persistent symptoms for 12 weeks or more, a proportion that could translate to more than two million people in England. The most common persistent symptoms included tiredness, shortness of breath, muscle aches, and difficulty sleeping.
In addition, the researchers found that long covid was more common among women than men (1.5 times as likely) and in people who were overweight or obese, who smoked, lived in deprived areas, or had been admitted to hospital. In contrast, persistent covid-19 symptoms were lower in people of Asian ethnicity.
The findings also indicated that prevalence of persistent symptoms increased with age, with a 3.5% increase in likelihood for each decade of life.
At a press briefing to launch the study, Paul Elliott, director of the REACT programme and chair in epidemiology and public health medicine at Imperial, was asked how long “long” covid may be for some people.
“For some people, I think they will have very long term consequences of having had the infection,” said Elliott. “There are certainly people who have got organ damage, so if they have that they will continue to have the consequences.
“Long covid is still poorly understood, but we hope through our research that we can contribute to better identification and management of this condition, which our data and others’ suggest may ultimately affect millions of people in the UK alone.”
The authors suggested various possible reasons why women seemed to be more likely to have long covid symptoms. Fellow report author Helen Ward, professor of public health at Imperial, told The BMJ, “There are a lot of theories. It may be that it is to do with a more active immune response in women that reduces symptoms initially but then produces prolonged symptoms.”
After the briefing the government said that covid-19 was still a relatively new disease and that it was providing scientists with £50m (€60m; $70m) of research funding to better understand its long term effects.
Similar themes to the React-2 study’s findings emerged in another study, led by researchers at University College London and King’s College London.2 It found that a sixth (17%) of middle aged people who reported being infected with SARS-CoV-2 also reported long covid symptoms but that this proportion fell to 7.8% in younger adults.

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A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
KlausWirthaCarmenScheibenbogenb
https://doi.org/10.1016/j.autrev.2020.102527Get rights and content
Autoimmunity Reviews  Volume 19, Issue 6, June 2020, 102527
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.
We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.
Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.

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Wirth and Scheibenbogen J Transl Med (2021) 19:162 https://doi.org/10.1186/s12967-021-02833-2 
REVIEW Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS)
 Klaus J. Wirth1 and Carmen Scheibenbogen2* 
Abstract Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The fnding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor infuences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the frst hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufcient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload afects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronifcation. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. 
Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease. 

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Tolerability and Efficacy of s.c. IgG Self-Treatment in ME/CFS Patients with IgG/IgG Subclass Deficiency: A Proof-of-Concept Study
Carmen Scheibenbogen  Franziska Sotzny   Jelka Hartwig  Sandra Bauer  Helma Freitag ,
Kirsten Wittke  Wolfram Doehner  Nadja Scherbakov  Madlen Loebel  Patricia Grabowski


Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
2
Academic Editors: Giovanni Ricevuti and Lorenzo Lorusso
J. Clin. Med. 2021, 10(11), 2420; https://doi.org/10.3390/jcm10112420
Received: 19 April 2021 / Revised: 26 May 2021 / Accepted: 27 May 2021 / Published: 29 May 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Abstract
Background: Chronic fatigue syndrome (ME/CFS) is a complex disease frequently triggered by infections. IgG substitution may have therapeutic effect both by ameliorating susceptibility to infections and due to immunomodulatory effects. Methods: We conducted a proof of concept open trial with s.c. IgG in 17 ME/CFS patients suffering from recurrent infections and mild IgG or IgG subclass deficiency to assess tolerability and efficacy. Patients received s.c. IgG therapy of 0.8 g/kg/month for 12 months with an initial 2 months dose escalation phase of 0.2 g and 0.4 g/kg/month. Results: Primary outcome was improvement of fatigue assessed by Chalder Fatigue Scale (CFQ; decrease ≥ 6 points) and of physical functioning assessed by SF-36 (increase ≥ 25 points) at month 12. Of 12 patients receiving treatment per protocol 5 had a clinical response at month 12. Two additional patients had an improvement according to this definition at months 6 and 9. In four patients treatment was ceased due to adverse events and in one patient due to disease worsening. We identified LDH and soluble IL-2 receptor as potential biomarker for response. Conclusion: Our data indicate that self-administered s.c. IgG treatment is feasible and led to clinical improvement in a subset of ME/CFS patients.
Keywords: chronic fatigue syndrome; myalgic encephalomyelitis; autoimmunity; immunology; IgG replacement; IgG deficiency; biomarker

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Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients
J. Blauensteiner, R. Bertinat, L. E. León, M. Riederer, N. Sepúlveda & F. Westermeier 
Scientific Reports volume 11, Article number: 10604 (2021)  
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by unexplained debilitating fatigue. Although the etiology is unknown, evidence supports immunological abnormalities, such as persistent inflammation and immune-cell activation, in a subset of patients. Since the interplay between inflammation and vascular alterations is well-established in other diseases, endothelial dysfunction has emerged as another player in ME/CFS pathogenesis. Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO) that maintains endothelial homeostasis. eNOS is activated by silent information regulator 1 (Sirt1), an anti-inflammatory protein. Despite its relevance, no study has addressed the Sirt1/eNOS axis in ME/CFS. The interest in circulating microRNAs (miRs) as potential biomarkers in ME/CFS has increased in recent years. Accordingly, we analyze a set of miRs reported to modulate the Sirt1/eNOS axis using plasma from ME/CFS patients. Our results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are jointly increased in ME/CFS patients compared to healthy controls. A similar finding was obtained when analyzing public miR data on peripheral blood mononuclear cells. Bioinformatics analysis shows that endothelial function-related signaling pathways are associated with these miRs, including oxidative stress and oxygen regulation. Interestingly, histone deacetylase 1, a protein responsible for epigenetic regulations, represented the most relevant node within the network. In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS.

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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
by 
Luis Nacul  et al
London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London WC1E 7HT, UK
Academic Editor: Tibor Hortobágyi
Medicina 2021, 57(5), 510; https://doi.org/10.3390/medicina57050510
Received: 11 April 2021 / Revised: 13 May 2021 / Accepted: 13 May 2021 / Published: 19 May 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Designed 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.
Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; diagnosis; health services; care
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Front. Immunol., 31 October 2019 | https://doi.org/10.3389/fimmu.2019.02545
Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Helene Cabanas1,2,3*, Katsuhiko Muraki3,4, Donald Staines1,2,3 and Sonya Marshall-Gradisnik1,2,3

• 1School of Medical Science, Griffith University, Gold Coast, QLD, Australia

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions. Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin. We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

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The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE)
by 
Derek F. H. Pheby, Diana Araja, Uldis Berkis, Elenka Brenna, John Cullinan, Jean-Dominique de Korwin,Lara Gitto,Dyfrig A. Hughes,Rachael M. Hunter,Dominic Trepel, Xia Wang-Steverding
Academic Editor: Edgaras Stankevičius
Medicina 2021, 57(4), 388; https://doi.org/10.3390/medicina57040388
Received: 13 March 2021 / Revised: 12 April 2021 / Accepted: 13 April 2021 / Published: 16 April 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.
Keywords: prevention; economic impact; chronic fatigue syndrome; myalgic encephalomyelitis; ME/CFS
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settings
Open AccessReview
Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders
by  Sarah Jane Annesley        Paul Robert Fisher
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Academic Editors: Anna Atlante and Daniela Valenti
Int. J. Mol. Sci. 2021, 22(9), 4536; https://doi.org/10.3390/ijms22094536
Received: 1 April 2021 / Revised: 23 April 2021 / Accepted: 24 April 2021 / Published: 26 April 2021
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions)
Abstract
Neurological disorders, including neurodegenerative diseases, are collectively a major cause of death and disability worldwide. Whilst the underlying disease mechanisms remain elusive, altered mitochondrial function has been clearly implicated and is a key area of study in these disorders. Studying mitochondrial function in these disorders is difficult due to the inaccessibility of brain tissue, which is the key tissue affected in these diseases. To overcome this issue, numerous cell models have been used, each providing unique benefits and limitations. Here, we focussed on the use of lymphoblastoid cell lines (LCLs) to study mitochondrial function in neurological disorders. LCLs have long been used as tools for genomic analyses, but here we described their use in functional studies specifically in regard to mitochondrial function. These models have enabled characterisation of the underlying mitochondrial defect, identification of altered signalling pathways and proteins, differences in mitochondrial function between subsets of particular disorders and identification of biomarkers of the disease. The examples provided here suggest that these cells will be useful for development of diagnostic tests (which in most cases do not exist), identification of drug targets and testing of pharmacological agents, and are a worthwhile model for studying mitochondrial function in neurological disorders.

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Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol
by C. (Linda) M. C. van Campen  * and Frans C. Visser
Stichting Cardiozorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
Academic Editors: Filipe Manuel Clemente and Parisi Attilio
Healthcare 2021, 9(6), 682; https://doi.org/10.3390/healthcare9060682
Received: 11 April 2021 / Revised: 1 May 2021 / Accepted: 3 June 21 / Published: 5 June 2021 
Abstract
Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. Methods: Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. Results: Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.
Keywords: chronic fatigue syndrome; cardiopulmonary exercise testing; VO2 peak; ventilatory threshold; VO2AT; RER; myalgic encephalitis; workload; idiopathic chronic fatigue
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settingsOpen AccessReview
Identifying and Managing Suicidality in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Lily Chu  , Meghan Elliott,Eleanor Stein   3 and  Leonard A. Jason
Academic Editors: Kenneth J. Friedman, Lucinda Bateman and Kenny Leo De Meirleir
Healthcare 2021, 9(6), 629; https://doi.org/10.3390/healthcare9060629
Received: 30 March 2021 / Revised: 14 May 2021 / Accepted: 16 May 2021 / Published: 25 May 2021
(This article belongs to the Collection ME/CFS – the Severely and Very Severely Affected)
Abstract
Adult patients affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are at an increased risk of death by suicide. Based on the scientific literature and our clinical/research experiences, we identify risk and protective factors and provide a guide to assessing and managing suicidality in an outpatient medical setting. A clinical case is used to illustrate how information from this article can be applied. Characteristics of ME/CFS that make addressing suicidality challenging include absence of any disease-modifying treatments, severe functional limitations, and symptoms which limit therapies. Decades-long misattribution of ME/CFS to physical deconditioning or psychiatric disorders have resulted in undereducated healthcare professionals, public stigma, and unsupportive social interactions. Consequently, some patients may be reluctant to engage with mental health care. Outpatient medical professionals play a vital role in mitigating these effects. By combining evidence-based interventions aimed at all suicidal patients with those adapted to individual patients’ circumstances, suffering and suicidality can be alleviated in ME/CFS. Increased access to newer virtual or asynchronous modalities of psychiatric/psychological care, especially for severely ill patients, may be a silver lining of the COVID-19 pandemic.

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Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection
Bruce K. Patterson, Edgar B. Francisco, Ram Yogendra, Emily Long, Amruta Pise, Hallison Rodrigues, Eric Hall, Monica Herrara, Purvi Parikh, Jose Guevara-Coto, Xaiolan Chang, Jonah B Sacha, Rodrigo A Mora-Rodríguez, Javier Mora
doi: https://doi.org/10.1101/2021.06.25.449905
This article is a preprint and has not been certified by peer review [what does this mean?].
200011406
ABSTRACT
The recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 also contained SARS-CoV-2 RNA. Non-classical monocytes are capable of causing inflammation throughout the body in response to fractalkine/CX3CL1 and RANTES/CCR5.
Summary SARS CoV-2 S1 Protein in CD16+ Monocytes In PASC
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Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Bruce K Patterson 1, Jose Guevara-Coto 2, Ram Yogendra 3, Edgar B Francisco 1, Emily Long 1, Amruta Pise 1, Hallison Rodrigues 1, Purvi Parikh 4, Javier Mora 3, Rodrigo A Mora-Rodríguez 3
Affiliations expand  PMID: 34262570  PMCID: PMC8273732 : 10.3389/fimmu.2021.700782
Abstract
Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.

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2021 Jun 28;12:700782.
 doi: 10.3389/fimmu.2021.700782. eCollection 2021.
Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Bruce K Patterson 1, Jose Guevara-Coto 2, Ram Yogendra 3, Edgar B Francisco 1, Emily Long 1, Amruta Pise 1, Hallison Rodrigues 1, Purvi Parikh 4, Javier Mora 3, Rodrigo A Mora-Rodríguez 3

• PMID: 34262570 PMCID: PMC8273732  DOI: 10.3389/fimmu.2021.700782

Abstract
Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.
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A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome
Diego Garcia-Borreguero MD, PhD, Celia Garcia-Malo MD, Juan José Granizo MD, Sergi Ferré MD, PhD
First published: 17 June 2021 Movement Disorders   
https://doi.org/10.1002/mds.28668
ABSTRACT
Background
New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role.
Objective
The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment.
Methods
A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response.
Results
Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%).
Conclusions
Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Adam J. O'Neal and Maureen R. Hanson
Front. Med. 2021:8:688486
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
Keywords: myalgic encephalomyelitis, chronic fatigue syndrome, enterovirus, chronic infection, RT-PCR, serology, immunohistochemistry, cell culture

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MEDICAL NEWS
COVID-19 linked to reactivation of Epstein-Barr virus
Dawn O'Shea   |   26 July 2021
Two recently published studies suggest that Epstein-Barr virus (EBV) reactivation may play a role in the development of long COVID-19 symptoms and severe disease.
In the first study, researchers ran EBV serological tests on COVID-19 patients at least 90 days after testing positive for SARS-CoV-2, comparing EBV reactivation rates of those with long COVID symptoms to those who did not. They found that over 73 per cent of patients with long COVID-19 symptoms were positive for EBV reactivation.
The second study found EBV reactivation may also be associated with COVID-19 severity.
This retrospective single-centre study included 67 COVID-19 patients divided into an EBV/SARS-CoV-2 coinfection group and a SARS-CoV-2 infection alone group.
Among COVID-19 patients, 37 (55.2%) were seropositive for EBV viral capsid antigen (VCA) IgM antibody.
Coinfected patients had a 3.09-fold risk of fever (P=.03). C-reactive protein (P=.02) and aspartate aminotransferase (P=.04) were also higher in this group, along with higher corticosteroid use (P=.03).
The authors speculate that EBV reactivation may be associated with the severity of COVID-19.
The relationships described in these studies open up new possibilities for the diagnosis and treatment of initial COVID-19 infection and long COVID.
References  
Chen T, Song J, Liu H, Zheng H, Chen C. Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep. 2021 May 25;11(1):10902. doi: 10.1038/s41598-021-90351-y. PMID: 34035353; PMCID: PMC8149409.
Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens. 2021 Jun 17;10(6):763. doi: 10.3390/pathogens10060763. PMID: 34204243; PMCID: PMC8233978.
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Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis
Adonis Sfera, Carolina Osorio, [...], and Zisis Kozlakidis
Frontiers in neurovascular science
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality. In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.
Keywords: endothelial cells, cellular senescence, gut microbial community, endotoxin tolerance, microbial translocation

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Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis
Adonis Sfera 1, Carolina Osorio 2, Nyla Jafri 1, Eddie Lee Diaz 1, Jose E Campo Maldonado 3
Front Immunol2020 Jun 19;11:1472.   doi: 10.3389/fimmu.2020.01472. eCollection 2020.PMID: 32655579  PMCID: PMC7325923   DOI: 10.3389/fimmu.2020.01472
Abstract
Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).

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Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Rebekah Maksoud   Natalie Eaton-Fitch   Michael Matula   Hélène Cabanas   Donald Staines
Sonya Marshall-Gradisnik
National Centre for Neuroimmunology and Emerging Diseases (NCNED), Menzies Health Institute Queensland, Griffith University, Gold Coast 4222, Australia
Healthcare 2021, 9(5), 568; https://doi.org/10.3390/healthcare9050568
Received: 13 April 2021 / Revised: 1 May 2021 / Accepted: 7 May 2021 / Published: 11 May 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
(1) Background—Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifaceted illness characterized by profound and persistent fatigue unrelieved by rest along with a range of other debilitating symptoms. Experiences of unrefreshing and disturbed sleep are frequently described by ME/CFS patients. This is the first systematic review assessing sleep characteristics in ME/CFS. The aim of this review is to determine whether there are clinical characteristics of sleep in ME/CFS patients compared to healthy controls using objective measures such as polysomnography and multiple sleep latency testing. (2) Methods—the following databases—Pubmed, Embase, Medline (EBSCO host) and Web of Science, were systematically searched for journal articles published between January 1994 to 19 February 2021. Articles that referred to polysomnography or multiple sleep latency testing and ME/CFS patients were selected, and further refined through use of specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute checklist. (3) Results—twenty observational studies were included in this review. The studies investigated objective measures of sleep quality in ME/CFS. Subjective measures including perceived sleep quality and other quality of life factors were also described. (4) Conclusions—Many of the parameters measured including slow- wave sleep, apnea- hypopnea index, spectral activity and multiple sleep latency testing were inconsistent across the studies. The available research on sleep quality in ME/CFS was also limited by recruitment decisions, confounding factors, small sample sizes and non-replicated findings. Future well-designed studies are required to understand sleep quality in ME/CFS patients.
Keywords: Myalgic Encephalomyelitis; chronic fatigue syndrome; sleep; polysomnography; multiple sleep latency testing

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Effect of Melatonin Plus Zinc Supple mentation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Jesús Castro-Marrero Maria-Cleofé Zaragozá Irene López-Vílchez José Luis Galmés Begoña Cordobilla, Sara Maurel, Joan Carles Domingo, José Alegre-Martín
Antioxidants 2021, 10(7), 1010; https://doi.org/10.3390/antiox10071010
Received: 30 May 2021 / Revised: 14 June 2021 / Accepted: 21 June 2021 / Published: 23 June 2021
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating condition, probably of multifactorial etiology. No effective approved drugs are currently available for its treatment. Several studies have proposed symptomatic treatment with melatonin and zinc supplementation in chronic illnesses; however, little is known about the synergistic effect of this treatment on fatigue-related symptoms in ME/CFS. The primary endpoint of the study was to assess the effect of oral melatonin plus zinc supplementation on fatigue in ME/CFS. Secondary measures included participants’ sleep disturbances, anxiety/depression and health-related quality of life. A proof-of-concept, 16-week, randomized, placebo-controlled, double-blind trial was conducted in 50 ME/CFS patients assigned to receive either oral melatonin (1 mg) plus zinc (10 mg) supplementation (n = 24) or matching placebo (n = 26) once daily. Endpoint outcomes were evaluated at baseline, and then reassessed at 8 and 16 weeks of treatment and 4 weeks after treatment cessation, using self-reported outcome measures. The most relevant results were the significant reduction in the perception of physical fatigue in the Mel-Zinc group at the final treatment follow-up versus placebo (p < 0.05), and the significant improvement in the physical component summary at all follow-up visits in the experimental group. Urinary 6-sulfatoxymelatonin levels were significantly elevated though the treatment in experimental group vs. placebo (p < 0.0001); however, no significantly differences were observed for zinc concentration among participants. Our findings suggest that oral melatonin plus zinc supplementation for 16 weeks is safe and potentially effective in reducing fatigue and improving the quality of life in ME/CFS. This clinical study was registered on ClinicalTrials.gov (NCT03000777).
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Open AccessArticle
Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol
C. (Linda) M. C. van Campen       Frans C. Visser
Stichting Cardiozorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
ealthcare 2021, 9(6), 683; https://doi.org/10.3390/healthcare9060683
Received: 22 April 2021 / Revised: 3 June 2021 / Accepted: 3 June 2021 / Published: 5 June 2021
Abstract
(1) Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS )patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfill the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. (2) Methods: We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. (3) Results: Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration. A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. (4) Conclusion: This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a second-day CPET. These results are similar to published results in male ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.
 Free access | 10.1172/JCI150377

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Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Øystein Fluge,1,2 Karl J. Tronstad,3 and Olav Mella1,2
Published July 15, 2021 -
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with unknown etiology, no validated specific and sensitive biomarker, and no standard approved effective treatment. ME/CFS has a profound impact on the quality of life of both patients and caregivers and entails high costs for society. The severity varies among patients who are able to participate to some extent in social life (mild), those who are mainly housebound (moderate) or bedridden (severe), and the very severely ill who are completely dependent on assistance for all daily living tasks, such as feeding or turning around in bed.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often starts in previously healthy individuals after an infection, the most common being infectious mononucleosis (EBV). It is more frequent in women and influenced by genetic predisposition. The main symptoms are postexertional malaise (PEM), fatigue, orthostatic intolerance, cognitive disturbances, sleep problems with inadequate restitution after rest, sensory hypersensitivity with pain, and symptoms related to autonomic and immune dysfunction. The prevalence is 0.1% to 0.8%, and ME/CFS must be distinguished from general fatigue, which is much more common in the population.
Historically, there has been limited scientific interest in ME/CFS. However, research efforts have increased in the last decade. Although this has led to different hypotheses, a firmly established pathomechanism is lacking.
Herein, we suggest a framework model for the initiation and maintenance of ME/CFS consisting of three principal steps: (a) an initial aberrant immune response; (b) an effector system for symptom generation and maintenance; and (c) compensatory adaptations. 
The model and possible therapeutic opportunities are summarized in Figure 1.
 Figure 1
Proposed model for ME/CFS pathomechanisms. We suggest three principal steps underlie the initiation and maintenance of ME/CFS. (i) Immune response after infection serves as a triggering event, with a role for B cells/plasma cells and autoantibodies in the underlying pathology. (ii) The vascular system and possibly GPCRs are potential targets for autoantibodies, which may affect endothelium or neurovascular control and autonomic small nerve fibers. The autoantibodies could be pathogenic IgGs or functional autoantibodies that normally occur after infection, but persist and fail to resolve over time. This disturbed homeostasis involves endothelial dysfunction in large and small arteries, impaired venous return and preload failure, and arteriovenous shunting, presumed to result in impaired autoregulation of blood flow and tissue hypoxia on exertion. (iii) Secondary compensatory efforts may add to the clinical presentation and symptoms. They include autonomic adaptations, often with increased sympathetic tone, and metabolic adaptations aiming to restore energy supply. Possible strategies for clinical trials targeting these pathways are also indicated.


Our proposed pathomechanistic model (Figure 1) is compatible with the lack of obvious histologic inflammation in tissue samples from ME/CFS, lack of overt organ damage, and the potential for recovery — sometimes spontaneous and without sequelae. Future research should focus on the natural course of ME/CFS over time to identify the mechanisms that induce and maintain disease, find targets for intervention, and specifically aim to elucidate immune dysregulation and patterns of autoantibodies with mechanisms for circulatory disturbances.
In our model, clinical symptoms of ME/CFS are related primarily to the inadequate autoregulation of blood flow yielding tissue hypoxia on exertion, but are also influenced by the compensatory adaptations from increased sympathetic output and from metabolic shifts. We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output. If so, one would expect a greater benefit for patients with less ongoing immune activation and less vascular dysregulation, but with main symptom contributions from the secondary autonomic adaptations. Conversely, patients with active immune disturbance and ongoing vascular dysregulation as the main symptom generators would have less impact from cognitive intervention, although psychosocial support and coping strategies may still have a beneficial impact on their quality of life.
In conclusion, we suggest that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, with a role for B cells/plasma cells and a pattern of autoantibodies emerging after infection and persisting over time. Key symptoms may result from the consequent functional disturbance in blood flow autoregulation causing tissue hypoxia on exertion and associated autonomic and metabolic responses to maintain energy homeostasis.
Finally, there is growing concern for patients with “long COVID.” Research is needed to determine whether the symptoms, which may resemble those of ME/CFS, are caused by subtle organ damage from the viral infection or whether subgroups of “long haulers” actually have a postinfectious immune disturbance and pathomechanism similar to those in ME/CFS.

As Their Numbers Grow, COVID-19 “Long Haulers” Stump Experts
Rita Rubin, MA
JAMA. 2020;324(14):1381-1383. doi:10.1001/jama.2020.17709
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For 32-year-old Hanna Lockman of Louisville, Kentucky, it all started March 12. She was at work when she suddenly felt a stabbing pain in her chest.
“It just got worse and worse and worse, to the point I was crying from the pain,” she recalled in a recent interview. At 3 am, the pain sent her to the emergency department. “I had developed a dry cough, maybe a mild fever. I don’t remember.”
Five months, 16 emergency department trips, and 3 short hospitalizations later, Lockman can’t remember a lot of things. She places the blame squarely on coronavirus disease 2019 (COVID-19).
“I joke, ‘Well, COVID has eaten my brain, because I can’t remember how to remember words, keep track of medication,’” she said. “My brain just feels like there’s a fog.”
Lockman considers herself to be a “long hauler,” someone who still hasn’t fully recovered from COVID-19 weeks or even months after symptoms first arose. She serves as an administrator of 2 “Long Haul COVID Fighters” Facebook groups, whose members now number more than 8000.
The longer the pandemic drags on, the more obvious it becomes that for some patients, COVID-19 is like the unwelcome houseguest who won’t pack up and leave.
“Anecdotally, there’s no question that there are a considerable number of individuals who have a postviral syndrome that really, in many respects, can incapacitate them for weeks and weeks following so-called recovery and clearing of the virus,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in July during a COVID-19 webinar organized by the International AIDS Society.
That appeared to be the case with the first severe acute respiratory syndrome (SARS), which emerged in 2002 and was also caused by a coronavirus. Some people who were hospitalized with SARS still had impaired lung function 2 years after their symptoms began, according to a prospective study of 55 patients in Hong Kong. But only 8096 people were diagnosed with SARS worldwide—a fraction of the COVID-19 cases reported each day in the US alone.
In a recent JAMA research letter, 125 of 143 Italian patients ranging in age from 19 to 84 years still experienced physician-confirmed COVID-19–related symptoms an average of 2 months after their first symptom emerged. All had been hospitalized, with their stays averaging about 2 weeks; 80% hadn’t received any form of ventilation.
Physicians at a Paris hospital recently reported that they saw an average of 30 long haulers every week between mid-May, when the COVID-19 lockdown ended in France, and late July. The patients’ average age was around 40 years, and women outnumbered men 4 to 1.
As with SARS, many COVID-19 long haulers are health care workers who had massive exposure to the virus early in the pandemic, neuroimmunologist Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), noted in a recent editorial.
Overall, approximately 10% of people who’ve had COVID-19 experience prolonged symptoms, a UK team estimated in a recently published Practice Pointer on postacute COVID-19 management. And yet, the authors wrote, primary care physicians have little evidence to guide their care.
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Fatigue: Biomedicine, Health & Behavior 
A hierarchical logistic regression predicting rapid respiratory rates from post-exertional malaise
Joseph Cotler ,Ben Z. Katz,Corine Reurts-Post,Ruud Vermeulen &Leonard A. Jason
Received 01 Sep 2020, Accepted 28 Oct 2020, Published online: 16 Nov 2020
https://doi.org/10.1080/21641846.2020.1845287


ABSTRACT
Background
Past research has found high rates of hyperventilation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but hyperventilation can be influenced by psychological factors. Clinical respiratory rates have been less frequently assessed.
Aim
This study aimed to identify the predictors of rapid respiratory rates in patients referred an outpatient clinic specializing in ME/CFS.
Methods
Adults (n = 216) referred to an outpatient clinic specializing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) participated in a two-day cardiopulmonary exercise test. As part of that evaluation, subjects had resting respiratory rates measured on two consecutive days. The current study used questionnaires to assess the relationship between tachypnea (rapid respiratory rates) and a variety of domains including post-exertional malaise (PEM), a common complaint in patients with ME/CFS, and psychiatric/somatic symptoms, using hierarchical logistic regression analysis.
Results
PEM was a significant predictor of tachypnea, while psychological/somatic assessments and sedentary behaviors were not significantly predictive of tachypnea.
Conclusions
These findings suggest that respiratory rate may be useful as an objective clinical metric of PEM, and potentially ME/CFS.
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A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic Working Group of the European Network on ME/CFS (EUROMENE)
by Derek F. H. Pheby  Diana Araja Uldis Berkis Elenka Brenna John Cullinan Jean-Dominique de Korwin  Lara Gitto  Dyfrig A. Hughes  Rachael M. Hunter  Dominic Trepel and Xia Wang-Steverding
Author to whom correspondence should be addressed.
Medicina 2021, 57(1), 7; https://doi.org/10.3390/medicina57010007
Received: 24 November 2020 / Revised: 11 December 2020 / Accepted: 21 December 2020 / Published: 24 December 2020
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs’ knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.
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Network and Systems MedicineVol. 3, No. 1
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Vaishnavi Narayan     Narayan Shivapurkar , and  James N. Baraniuk
Published Online:18 Nov 2020https://doi.org/10.1089/nsm.2019.0009
Abstract
Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise.
Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise.
Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia.
Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS.
Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
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Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study
Ludovic Giloteaux, Adam O’Neal, Jesús Castro-Marrero, Susan M. Levine & Maureen R. Hanson 
Journal of Translational Medicine volume 18, Article number: 387 (2020) Published: 12 October 2020
Abstract:
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.
Methods
We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.
Results
ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.
Conclusions
Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.
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Neurology: May 12, 2020; 94 (19) SPECIAL EDITORIAL
 View ORCID Profile                      Avindra Nath
First published March 30, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009455
In 1896, Sir William Osler1 said, “Humanity has but three great enemies: fever, famine, and war; of these by far the greatest, by far the most terrible, is fever.” This rings true even today.
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has stricken fear and panic among the public, health care workers, patients, politicians, and financial markets. Fear strikes the minds of the unprepared. So we must ask ourselves why have we been caught by surprise? In the recent past, there have been many major epidemics. This includes Ebola, Zika, dengue, chikungunya, acute flaccid myelitis, and H1N1 influenza, to name a few. But SARS-CoV2 is different. It struck home! And so very rapidly. It emerged in the region of Wuhan in China around December last year, and by March, every state in the United States and over a hundred countries have reported cases of the infection with deaths in all the adult age groups. The predictions are dire. The entire health care system could potentially be overwhelmed and could crumble. Signs of that are already evident in New York and Washington state. Grocery stores have empty shelves, pharmacies are running out of critical medications, and there is scarcity of personal protection equipment and ventilators.
The major clinical manifestations of the SARS-CoV2 infection are due to pulmonary complications. Although most have mild symptoms, such as fever, headache, cough, dyspnea, myalgia, and anosmia, some develop acute respiratory distress syndrome about a week into the illness, which can result in death.2 Rhabdomyolysis can be a late complication of the infection.3 The mortality rate is about 3%–4%. Terminally, patients go into coma, which is thought to be due to hypoxia or multiorgan failure. But many unanswered questions remain. Could the headache be symbolic of viral meningitis? There is a report of detection of the virus in the CSF of 1 patient (encephalitis.info/blog/coronavirus). Does anosmia suggest involvement of the olfactory bulbs? In mouse models of coronavirus encephalitis, the virus can enter the brain transneuronally through the olfactory pathways.4 Hence, this relatively innocuous symptom could be indicative of a potentially more serious complication. Can the respiratory syndrome be due to brainstem involvement? Brain imaging and pathologic evaluation of the brain are necessary to understand the full impact of the virus. The elderly and immunocompromised patients are particularly vulnerable. Many have underlying neurologic comorbidities. Hypertension and diabetes seem to stand out as the most common comorbidities in patients with more severe manifestations of the infection. An interesting hypothesis has emerged around the use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension and diabetes to explain this phenomenon. ACE2 is the receptor for SARS-CoV2.5 The use of ACE inhibitors leads to increased expression of ACE2, making the cells more vulnerable to infection with the virus. Clinical studies are underway to test this hypothesis. ACE2 can be found on endothelial cells in the brain and can be induced in neurons, raising the possibility that strokes associated with SARS-CoV2 might be directly related to the infection, and encephalitis could be a potential complication.
There are several human coronaviruses (HCoVs). Most cause mild respiratory symptoms and resolve. However, in recent years, new coronaviruses have jumped species and infected humans with devastating consequences. Several acute neurologic syndromes have been associated with coronaviruses (table). Severe acute respiratory syndrome coronavirus 1 has been detected in the CSF of a patient with encephalitis and acute respiratory distress syndrome.6 Middle East respiratory syndrome coronavirus can cause a severe acute disseminated encephalomyelitis and a vasculopathy.7 A postinfectious brainstem encephalitis and Guillain-Barré syndrome have also been described.8 HCoV-OC43 can also cause an acute disseminated encephalomyelitis with lesions scattered throughout the brain, cerebellum, and spinal cord.9 Immunocompromised individuals are particularly vulnerable. A fatal encephalitis can occur in immunocompromised patients with HCoV-OV43. In these patients, infection of neurons has been demonstrated at autopsy.10 A similar concern has been raised with SARS-CoV2. Many patients with autoimmune syndromes such as multiple sclerosis, myasthenia gravis, neuromyelitis optica, or sarcoidosis are on a wide variety of immunosuppressive therapies. Drugs that cause systemic immune suppression wound be of concern. It might be prudent for such patients to take extra precautions to prevent exposure to the virus and to reevaluate the dosages of the medications. However, it may not be advisable to take them off treatment because the underlying illness will surely re-emerge, causing serve manifestations in many. With restrictions on travel being imposed and all elective patient appointments being canceled, there is an urgent cry for teleneurology as a substitute for face-to-face interactions with patients. However, to make this work, we need to develop a centralized system to license physicians in the entire country and not in each state individually.
Seropositivity for coronaviruses has been reported in a variety of neurologic disorders, which include encephalitis,11 optic neuritis,12 multiple sclerosis,13 and Parkinson disease.14 Virus has also been isolated from the CSF and brain of patients with multiple sclerosis.15 Viruses implicated include HCoV-229E, HCoV-293, and HCoV-OC43. But the significance of these findings is not clear because these viruses are very prevalent and their causative role in these diseases has not been established.
In the past century, we have made tremendous progress in the prevention, diagnosis, and treatment of diseases. We can dissolve clots in the carotids, we can fix mutated genes before they can cause harm, and we can image the brain and its networks with exquisite precision, yet we have been brought down to our knees by the tiniest of organisms, about 60 nm in size. We need to retool and rethink how we train physicians in the practice of neurology and physician scientists in the academic neurology and how we prioritize drug development for neurologic diseases, and we need to enable academia and pharma to develop treatments not based on profits but rather on costs to humanity. Although we all recognize the hundreds of viruses that can cause encephalitis and result in devastation to large populations, we have no treatment for any of these organisms except for herpes encephalitis. It is time for us to recognize that we are facing a crisis in neurology.16 The time to take action is now.
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Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029
Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*

• 1Independent Researcher, Sint Martens Latem, Belgium
• 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
• 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
• 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.
Introduction
Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (1, 5, 6). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (7–10). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (12, 13).
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology (14, 15). The most common peri-onset events reported by patients are infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%) (16). “Impaired function, post-exertional malaise (an exacerbation of some or all of an individual's ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep” are considered to be core symptoms (14). The severity of the symptoms varies: “very severely affected patients experience profound weakness, almost constant pain, severe limitations to physical and mental activity, sensory hypersensitivity (light, touch, sound, smell, and certain foods), and hypersensitivity to medications” (17). We have listed a few hall mark symptoms that are often found in critically ill patients in chronic intensive care (ICU) patients and ME/CFS patients Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. These mechanisms characterize prolonged critical illness regardless of the nature of the initial severe injury or infection (3, 8–10); similarly, we propose that these mechanisms could underlie the perpetuation of illness in ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins, or other). We provide an overview of these mechanisms in ICU patients and discuss their relevance for understanding ME/CFS. We also bring findings from fibromyalgia into the discussion here because ME/CFS and fibromyalgia are often jointly considered in the literature (20, 21); fibromyalgia is similarly a syndrome that is medically unexplained, often comorbid with ME/CFS, and “shares the core symptoms of fatigue, sleep problems and cognitive difficulties” (22). Additional research projects are required to investigate the validity of this hypothesis building on the findings from critical illness and ME/CFS summarized here.
This hypothesis may be particularly relevant in light of the current COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms despite successfully defeating the virus—termed “post COVID-19 syndrome” or “long COVID-19”—that resemble ME/CFS 
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Association of Therapies With Reduced Pain and Improved Quality of Life in Patients With FibromyalgiaA Systematic Review and Meta-analysis
Rodrigo Oliveira Mascarenhas, MSc1; Mateus Bastos Souza, BAppSc2; Murilo Xavier Oliveira, PhD2; et alAna Cristina Lacerda, PhD2; Vanessa Amaral Mendonça, PhD2; Nicholas Henschke, PhD3; Vinícius Cunha Oliveira, PhD2
JAMA Intern Med. 2021;181(1):104-112. doi:10.1001/jamainternmed.2020.5651
Key Points
Question  What is the association of therapies with reduced pain and improved quality of life in patients with fibromyalgia?
Findings  In this systematic review, the effectiveness of most therapies for fibromyalgia was not supported. Strong evidence supported only cognitive behavioral therapy for pain, as well as antidepressants and central nervous system depressants for pain and quality of life, but these associations were small.
Meaning  Some therapies may be associated with small reductions in pain and improvements in quality of life in people with fibromyalgia; however, current evidence is lacking for most therapies.
Abstract
Importance  Fibromyalgia is a chronic condition that results in a significant burden to individuals and society.
Objective  To investigate the effectiveness of therapies for reducing pain and improving quality of life (QOL) in people with fibromyalgia.
Data Sources  Searches were performed in the MEDLINE, Cochrane, Embase, AMED, PsycInfo, and PEDro databases without language or date restrictions on December 11, 2018, and updated on July 15, 2020.
Study Selection  All published randomized or quasi-randomized clinical trials that investigated therapies for individuals with fibromyalgia were screened for inclusion.
Data Extraction and Synthesis  Two reviewers independently extracted data and assessed risk of bias using the 0 to 10 PEDro scale. Effect sizes for specific therapies were pooled using random-effects models. The quality of evidence was assessed using the Grading of Recommendations Assessment (GRADE) approach.
Main Outcomes and Measures  Pain intensity measured by the visual analog scale, numerical rating scales, and other valid instruments and QOL measured by the Fibromyalgia Impact Questionnaire.
Results  A total of 224 trials including 29 962 participants were included. High-quality evidence was found in favor of cognitive behavioral therapy (weighted mean difference [WMD], −0.9; 95% CI, −1.4 to −0.3) for pain in the short term and was found in favor of central nervous system depressants (WMD, −1.2 [95% CI, −1.6 to −0.8]) and antidepressants (WMD, −0.5 [95% CI, −0.7 to −0.4]) for pain in the medium term. There was also high-quality evidence in favor of antidepressants (WMD, −6.8 [95% CI, −8.5 to −5.2]) for QOL in the short term and in favor of central nervous system depressants (WMD, −8.7 [95% CI, −11.3 to −6.0]) and antidepressants (WMD, −3.5 [95% CI, −4.5 to −2.5]) in the medium term. However, these associations were small and did not exceed the minimum clinically important change (2 points on an 11-point scale for pain and 14 points on a 101-point scale for QOL). Evidence for long-term outcomes of interventions was lacking.
Conclusions and Relevance  This systematic review and meta-analysis suggests that most of the currently available therapies for the management of fibromyalgia are not supported by high-quality evidence. Some therapies may reduce pain and improve QOL in the short to medium term, although the effect size of the associations might not be clinically important to patients.

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ORIGINAL RESEARCH ARTICLE
Front. Med., 27 January 2021 | https://doi.org/10.3389/fmed.2020.602894
Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
C (Linda) M. C. van Campen1*, Peter C. Rowe2, Freek W. A. Verheugt3 and Frans C. Visser1

• 1Stichting CardioZorg, Hoofddorp, Netherlands
• 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
• 3Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, Netherlands

Introduction: Muscle pain, fatigue, and concentration problems are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These symptoms are commonly increased as part of the phenomenon of postexertional malaise (PEM). An increase in the severity of these symptoms is described following physical or mental exercise in ME/CFS patients. Another important symptom of ME/CFS is orthostatic intolerance, which can be detected by head-up tilt testing (HUT). The effect of HUT on PEM has not been studied extensively. For this purpose, we assessed numeric rating scales (NRS) for pain, fatigue, and concentration pre- and post-HUT. As pain is a core symptom in fibromyalgia (FM), we subgrouped ME/CFS patients by the presence or absence of FM.
Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT.
Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Major Impact on Lives of Both Patients and Family Members
by 
Esme Brittain1,Nina Muirhead,Andrew Y. Finlay 1 and Jui Vyas
Medicina 2021, 57(1), 43; https://doi.org/10.3390/medicina57010043
Received: 3 December 2020 / Revised: 23 December 2020 / Accepted: 30 December 2020 / Published: 7 January 2021
(This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)
Abstract
Background and objectives: To explore the impacts that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has on the patient and their family members using the WHOQOL-BREF (Abbreviated World Health Organisation Quality of Life questionnaire) and FROM-16 (Family Reported Outcome Measure-16) quality of life assessments. Materials and Methods: A quantitative research study using postal questionnaires was conducted. A total of 39 adult volunteers expressed an interest in participating in the study: 24 returned appropriately completed questionnaires. Patients with ME/CFS completed the WHOQOL-BREF and up to four of their family members completed the FROM-16 questionnaire. Results: ME/CFS negatively affects the quality of life of the patient (median scores WHOQOL-BREF: Physical health = 19, Psychological = 44, Social relationships = 37.5, Environment = 56, n = 24) and their family members’ quality of life (FROM-16: Emotional = 9.5, Personal and social = 11.5, Overall = 20.5, n = 42). There was a significant correlation between the patient’s reported quality of life scores and their family members’ mean FROM-16 total scores. Conclusions: This study identifies the major impact that having an adult family member with ME/CFS has on the lives of partners and of other family members. Quality of life of ME/CFS patients was reduced most by physical health compared to the other domains. Quality of life of family members was particularly impacted by worry, family activities, frustration and sadness. This highlights the importance of measuring the impact on the lives of family members using tools such as the FROM-16 in the ME/CFS clinical encounter and ensuring appropriate support is widely available to family members.
Keywords: ME/CFS; QoL; family impact; FROM-16; WHOQOL-BREF
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Published: 04 November 2020
Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions
A. M. Helliwell, E. C. Sweetman, P. A. Stockwell, C. D. Edgar, A. Chatterjee & W. P. Tate 
Clinical Epigenetics volume 12, Article number: 167 (2020)  
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.
Results
DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.
Conclusions
Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.
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Published: 24 September 2020
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings & Warren Tate 
Journal of Translational Medicine volume 18, Article number: 365 (2020) Cite this article
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.
Methods
To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.
Results
A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.
Conclusions
The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
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2020 Nov 18;3(1):142-158. doi: 10.1089/nsm.2019.0009. eCollection 2020.
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Vaishnavi Narayan 1, Narayan Shivapurkar 1, James N Baraniuk 1
PMID: 33274349 PMCID: PMC7703497  DOI: 10.1089/nsm.2019.0009
Abstract
Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise. Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise. Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia. Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS. Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
Keywords: cerebrospinal fluid; informatics; micro-RNA (miRNA); myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); pathway analysis.
© Vaishnavi Narayan et al., 2020; Published by Mary Ann Liebert, Inc.
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2021 Feb 2;2021.01.29.21250755.
 doi: 10.1101/2021.01.29.21250755. Preprint
A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses
Phillip H Comella, Edgar Gonzalez-Kozlova, Roman Kosoy, Alexander W Charney, Irene Font Peradejordi, Shreya Chandrasekar, Scott R Tyler, Wenhui Wang, Bojan Losic, Jun Zhu, Gabriel E Hoffman, Seunghee Kim-Schulze, Jingjing Qi, Manishkumar Patel, Andrew Kasarskis, Mayte Suarez-Farinas, Zeynep H Gümüş, Carmen Argmann, Miriam Merad, Christian Becker, Noam D Beckmann, Eric E Schadt
PMID: 33564792 PMCID: PMC7872387
Abstract
The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree (Supplemental Table-1) and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.
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Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19   The Writing Committee for the COMEBAC Study Group
JAMA. Published online March 17, 2021. doi:10.1001/jama.2021.3331
COVID-19 Resource Center
Key Points
Question  What are the clinical outcomes after hospitalization for COVID-19?
Findings  Four months after hospitalization, in an uncontrolled cohort study of 478 survivors of COVID-19, at least 1 new-onset symptom was reported by telephone interview by 244 patients (51%), including fatigue in 134 of 431 (31%), cognitive symptoms in 86 of 416 (21%), and dyspnea in 78 of 478 (16%). Computed tomographic lung scan abnormalities were reported in 63% of 171 patients assessed at an ambulatory visit, mainly subtle ground-glass opacities. Fibrotic lesions were observed in 19% of these 171 patients.
Meaning  This study provides clinical status of a cohort of patients 4 months after hospitalization for COVID-19, but further research is needed to understand longer-term outcomes.
Abstract
Importance  Little is known about long-term sequelae of COVID-19.
Objective  To describe the consequences at 4 months in patients hospitalized for COVID-19.
Design, Setting, and Participants  In a prospective uncontrolled cohort study, survivors of COVID-19 who had been hospitalized in a university hospital in France between March 1 and May 29, 2020, underwent a telephone assessment 4 months after discharge, between July 15 and September 18, 2020. Patients with relevant symptoms and all patients hospitalized in an intensive care unit (ICU) were invited for further assessment at an ambulatory care visit.
Exposures  Survival of hospitalization for COVID-19.
Main Outcomes and Measures  Respiratory, cognitive, and functional symptoms were assessed by telephone with the Q3PC cognitive screening questionnaire and a checklist of symptoms. At the ambulatory care visit, patients underwent pulmonary function tests, lung computed tomographic scan, psychometric and cognitive tests (including the 36-Item Short-Form Health Survey and 20-item Multidimensional Fatigue Inventory), and, for patients who had been hospitalized in the ICU or reported ongoing symptoms, echocardiography.
Results  Among 834 eligible patients, 478 were evaluated by telephone (mean age, 61 years [SD, 16 years]; 201 men, 277 women). During the telephone interview, 244 patients (51%) declared at least 1 symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. There was further evaluation in 177 patients (37%), including 97 of 142 former ICU patients. The median 20-item Multidimensional Fatigue Inventory score (n = 130) was 4.5 (interquartile range, 3.0-5.0) for reduced motivation and 3.7 (interquartile range, 3.0-4.5) for mental fatigue (possible range, 1 [best] to 5 [worst]). The median 36-Item Short-Form Health Survey score (n = 145) was 25 (interquartile range, 25.0-75.0) for the subscale “role limited owing to physical problems” (possible range, 0 [best] to 100 [worst]). Computed tomographic lung-scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 of 171 patients (19%), involving less than 25% of parenchyma in all but 1 patient. Fibrotic lesions were observed in 19 of 49 survivors (39%) with acute respiratory distress syndrome. Among 94 former ICU patients, anxiety, depression, and posttraumatic symptoms were observed in 23%, 18%, and 7%, respectively. The left ventricular ejection fraction was less than 50% in 8 of 83 ICU patients (10%). New-onset chronic kidney disease was observed in 2 ICU patients. Serology was positive in 172 of 177 outpatients (97%).
Conclusions and Relevance  Four months after hospitalization for COVID-19, a cohort of patients frequently reported symptoms not previously present, and lung-scan abnormalities were common among those who were tested. These findings are limited by the absence of a control group and of pre-COVID assessments in this cohort. Further research is needed to understand longer-term outcomes and whether these findings reflect associations with the disease.
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Global Health   March 16, 2021
Most Patients Hospitalized With COVID-19 Have Lasting Symptoms
Bridget M. Kuehn, MSJ   JAMA. 2021;325(11):1031. doi:10.1001/jama.2021.2974
COVID-19 Resource Center
Three-quarters of patients hospitalized with coronavirus disease 2019 (COVID-19) still had at least 1 symptom 6 months after they became ill, according to recently published follow-up research.
The study included 1733 patients who were hospitalized in Wuhan, China, and discharged between January and May 2020. Fatigue and ongoing muscle weakness were reported by 63% of the patients and roughly one-quarter reported difficulty sleeping or anxiety and depression. A subset of patients still had reduced lung function and below normal results on a 6-minute walking test. Ongoing lung and mobility impairments were more prevalent among the most severely ill patients. Among 1378 patients with estimated glomerular filtration rates available during their acute illness and at follow-up, about one-third had reduced kidney function at 6 months.
Among a subgroup of 94 patients who provided plasma samples during their acute illness and 6 months later, neutralizing antibody levels had dropped by about half at the follow-up visit, raising concerns about potential reinfection, the authors warned.
“Our analysis indicates that most patients continue to live with at least some of the effects of the virus after leaving hospital, and highlights a need for post-discharge care, particularly for those who experience severe infections,” senior author Bin Cao, MD, of the National Center for Respiratory Medicine in Beijing, China, said in a statement.
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Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy,Shaun Bhatia,Mohammed Islam andLeonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
*Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.
Keywords: ME/CFS; chronic fatigue syndrome; myalgic encephalomyelitis; illness severity; homebound; bedridden

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In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
Arnaud Germain,Susan M. Levine and Maureen R. Hanson
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Proteomes 2021, 9(1), 6; https://doi.org/10.3390/proteomes9010006
Received: 1 January 2021 / Revised: 24 January 2021 / Accepted: 25 January 2021 / Published: 29 January 2021
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.
Keywords: ME/CFS; proteomics; plasma; ephrin-Eph pathway; immune metabolism; adherens junction; glucose; SOMAscan®; diagnosis

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ORIGINAL RESEARCH – Brain and Behaviour
Open‐label study with the monoamine stabilizer (‐)‐OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
Sara Haghighi Sara Forsmark Olof Zachrisson Arvid Carlsson Marie K. L. Nilsson Maria L. Carlsson Robert C. Schuit Carl‐Gerhard Gottfries
First published: 02 February 2021     https://doi.org/10.1002/brb3.2040
Abstract
Objectives
The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (‐)‐OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (‐)‐OSU6162 in ME/CFS was evaluated by means of observer‐rated scales and self‐assessment rating scales.
Materials and Methods
In the current study using an open‐label single‐arm design ME/CFS patient received treatment with (‐)‐OSU6162 during 12 weeks. The patients received the following doses of (‐)‐OSU6162: 15 mg b.i.d. during the first 4‐week period, up to 30 mg b.i.d. during the second 4‐week period and up to 45 mg b.i.d. during the third 4‐week period, with follow‐up visits after 16 and 20 weeks.
Results
Out of 33 included patients, 28 completed the 12 weeks treatment period. (‐)‐OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.
Conclusions
(‐)‐OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health‐related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo‐controlled double‐blind trials.

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UK Moves to Revise Guidelines for Treatment of Chronic Fatigue Syndrome
AJN, American Journal of Nursing: March 2021 - Volume 121 - Issue 3 - p 16
doi: 10.1097/01.NAJ.0000737248.67484.2e
Abstract
Advocates hail rejection of debunked exercise and cognitive behavior therapies.
Proposed guidelines for management of myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS), from the United Kingdom's National Institute for Health and Care Excellence (NICE) are being hailed for their rejection of graded exercise therapy and cognitive behavior therapy (CBT) as routine treatment. Major medical organizations, advocacy groups, and patients have strongly advocated for NICE to align guidelines with scientific evidence.
The U.S. Centers for Disease Control and Prevention (CDC) in 2017 eliminated these largely useless and, in some cases, harmful therapies from its recommendations. That NICE is now following suit is good news, though many say it is long overdue. Moreover, patients are unlikely to see immediate results as new science can take years to reach clinical practice.
The illness is characterized by debilitating fatigue and difficulty with concentration and memory. An estimated 2.5 million Americans are diagnosed with ME/CFS, most of them women. Because symptoms can range widely and standard laboratory tests yield little insight as to cause, ME/CFS has been viewed as a stress-induced disorder in some women.
Graded exercise therapy and CBT became the go-to therapies for ME/CFS based on findings of a 2011 study, known as PACE, published in the Lancet. According to the study investigators, these treatments produced a sustained improvement in patients' levels of fatigue and physical function, even leading to recovery for some. Top researchers who reviewed the study, however, found major flaws. Patients also reacted negatively, saying the study's results did not reflect their experiences and reinforced inaccurate and stigmatizing beliefs about the illness as a psychological and behavioral disorder. Eventually, over 100 academics, patient groups, and others called for an independent reanalysis of the data. Despite this forceful opposition, the study remained influential with clinicians and continued to underpin treatment recommendations of major medical organizations, including the CDC and NICE.
Perceptions began to change with the 2015 release of the Institute of Medicine's landmark report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, in which the authors described ME/CFS as a “serious, chronic, complex, systemic disease” and cited newly identified biomarkers indicating immunological and neurological dysfunction. The report and continuing pressure from scientists, clinicians, and patients led the CDC to remove recommendations for graded exercise therapy and CBT as its British counterpart, NICE, now proposes to do.--Karen Roush, PhD, RN, FNP-BC,

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2021 Feb 11.   doi: 10.1089/ars.2020.8230. Online ahead of print.
Are Circulating Fibroblast Growth Factor 21 and N-Terminal Prohormone of Brain Natriuretic Peptide Promising Novel Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Joan Carles Domingo 1, Begoña Cordobilla 1, Roser Ferrer 2, Marina Giralt 2, José Alegre-Martín 3 4, Jesús Castro-Marrero 4                 PMID: 33353469
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling, and complex multisystem illness of unknown etiology. The protein fibroblast growth factor 21 (FGF21) regulates glucose homeostasis and lipid metabolism, and the protein N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is strongly associated with an elevated cardiovascular risk; however, little is known about their role in ME/CFS patients. To address this gap, we explored the association between FGF21 and NT-proBNP and oxidative stress and inflammatory markers in ME/CFS. Twenty-one ME/CFS patients and 20 matched healthy controls were included in the study. Participants filled out validated self-reported questionnaires on their current health status covering demographic and clinical characteristics. Plasma showed significantly decreased total antioxidant capacity and increased lipoperoxide levels (p = 0.009 and p = 0.021, respectively) in ME/CFS. These ME/CFS patients also had significantly increased levels of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-10, TNF-α, and C-reactive protein) (p < 0.05 for all) but not for IL-8 (p = 0.833), indicating low-grade systemic inflammation status. Circulating FGF21 and NT-proBNP levels were significantly higher (p < 0.0001 and p = 0.005, respectively) in ME/CFS patients than in healthy controls. Significantly positive correlations were found between NT-proBNP levels and IL-1β and IL-6 (p = 0.04 and p = 0.01) in ME/CFS patients but not between FGF21 and these cytokines. In contrast, no significant correlations were found for either FGF21 or NT-proBNP in controls. These findings lead to the hypothesis that elevated FGF21 and NT-proBNP levels and the association between NT-proBNP and inflammation may be promising novel diagnostic and therapeutic targets in ME/CFS.
Keywords: FGF21; NT-proBNP; chronic fatigue syndrome; cytokines; myalgic encephalomyelitis; oxidative stress.

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2021 Apr;132(4):967-974.Clin.Neurophysiology  doi: 10.1016/j.clinph.2020.11.043. Epub 2021 Jan29.
Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load
E G Klaver-Krol 1, H J Hermens 2, R C Vermeulen 3, M M Klaver 4, H Luyten 5, N R Henriquez 6, M J Zwarts 7PMID: 33639451     : 10.1016/j.clinph.2020.11.043
Abstract
Objective: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of - especially muscular -fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.
Methods: Females with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.
Results: The CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.
Conclusion: Our results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.
Significance: These findings help to detangle the underlying mechanisms of CFS.
Keywords: Chronic fatigue syndrome; Force generation; Muscle fiber conduction velocity; Muscle membrane dysfunction; Surface electromyography.
Copyright © 2021. Published by Elsevier B.V.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!
Maria Eugenia Ariza
Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA2
Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Academic Editors: Maria Teresa Sciortino and Marshall Williams
Biomolecules 2021, 11(2), 185; https://doi.org/10.3390/biom11020185
Published: 29 January 2021
(This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.
Keywords: myalgic encephalomyelitis/chronic fatigue syndrome; epstein-barr virus (EBV); human herpesvirus 6 (HHV-6); immune dysfunction; BRRF1; BLLF3; deoxyuridine triphosphate nucleotidohydrolase (dUTPase)

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Experiences of Living with Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Victoria Strassheim,Julia L. Newton3 and Tracy Collins
CRESTA Fatigue Clinic, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE4 6BE, UK
Academic Health Science Network–North East & North Cumbria, Newcastle upon Tyne NE4 5PL, UK 
Population Health Science Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
Department of Social Work, Education and Community Wellbeing, Coach Lane Campus, Northumbria University, Newcastle upon Tyne NE7 7AX, UK*
Healthcare 2021, 9(2), 168; https://doi.org/10.3390/healthcare9020168
Received: 17 December 2020 / Revised: 27 January 2021 / Accepted: 28 January 2021 / Published: 5 February 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness. Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered. This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely. Overarching themes of ‘Lived Experience’, ‘Challenges to daily life’, and ‘Management of the condition’ were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.
Keywords: ME/CFS; severe; very severe; housebound; qualitative; interview; experience

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Covid-19: Middle aged women face greater risk of debilitating long term symptoms
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n829 (Published 25 March 2021)Cite this as: BMJ 2021;372:n8
Ingrid Torjesen
Middle aged women have a higher risk of experiencing a range of debilitating ongoing symptoms, such as fatigue, breathlessness, muscle pain, anxiety, depression, and “brain fog” after hospital treatment for covid-19, suggest the findings of two unpublished studies available as preprints.
Seven in 10 patients admitted to hospital with covid-19 reported “long covid” symptoms an average of five months after discharge in the larger PHOSP-COVID study, and symptoms were more prevalent in women aged 40-60.1 White ethnicity, two or more comorbidities at admission, and receiving invasive ventilation while in hospital increased the risk, but severity of acute covid-19 disease did not seem to affect the likelihood of experiencing long covid symptoms.
Only 29% of the 1077 patients studied felt fully recovered when followed up, on average five months after discharge. Over a quarter had clinically significant symptoms of anxiety and depression, 12% had symptoms of post-traumatic stress disorder, 17% had at least mild cognitive impairment, 46% had lower physical performance than age and sex matched controls, and 20% had a new disability.
Before hospital admission 68% of patients had worked full time, but 18% of these had not returned to work and 19% had had to change their way of working because of longlasting effects.
The researchers grouped patients into four clusters according to the severity of their physical and mental symptoms post-covid: very severe (17% of patients), severe (21%), moderate with cognitive impairment (17%), and mild (46%).
Rachael Evans, National Institute for Health Research clinical scientist at the University of Leicester and a study author, said, “The symptoms are very real, but they don’t have a straightforward relationship with heart and lung damage, or certainly heart and lung damage can’t explain all the symptoms.”
Immune response
A smaller second study, from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC), found that women under 50 were five times less likely to report feeling recovered, twice as likely to report worse fatigue, seven times more likely to become more breathless, and more likely to have greater disability than men of the same age who had been admitted to hospital with covid-19.2 Disability usually affected memory, mobility, communication, vision, or hearing. More than half of the 327 patients assessed in this study did not feel fully recovered when followed up on average seven months later, and persistent symptoms were reported by 93.3%, with fatigue and breathlessness the most common.
Chris Brightling, professor of respiratory medicine at the University of Leicester and a PHOSP-COVID study researcher, speculated that sex based differences in the immune response may be responsible for the higher prevalence of long covid symptoms in women, noting that autoimmune diseases were more prevalent in women than in men at age 40-60.
“Maybe there’s a difference in the immune response acutely, such that men are more likely to have a more severe condition at the time of the infection,” he told a press conference at the Science Media Centre on 24 March. “It may be that the immune response is different in women, so you then have a continued inflammatory reaction that then leads to a higher likelihood of having long covid.”
Higher levels of C reactive protein, a marker of systemic inflammation, were seen in patients in the most severe long covid symptoms. Brightling said that a number of immune and chronic inflammatory conditions can also cause elevated C reactive protein.
About 450 000 people have been admitted to hospital with covid-19 in the UK, so a “very large” proportion of these would potentially be affected by long covid, he said, adding, “Clearly there’s an even larger number of people that have had covid in the community, and a portion of those will also have long covid.”
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