Abstracts from 1 January 2022

 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.

____________________________________________________________________________________
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 [email protected]

• 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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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

____________________________________________________________________________________

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.
____________________________________________________________________________________

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
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.

____________________________________________________________________________________

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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.  
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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.

____________________________________________________________________________________

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.

____________________________________________________________________________________

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.
____________________________________________________________________________________

Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis
Leonard A Jason1*, et al Emails: Leonard Jason: [email protected]; 
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.

____________________________________________________________________________________

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.
____________________________________________________________________________________

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.
____________________________________________________________________________________

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

____________________________________________________________________________________

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
____________________________________________________________________________________

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.

____________________________________________________________________________________

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.