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Abstracts from 1 April 2021

14/6/2021

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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
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Abstracts from 1 June 2021

1/6/2021

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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     E[email protected]
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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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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settings
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.
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