Dr. Rosamund Vallings
        
Howick Health & Medical Centre
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Abstracts from 17.11.2020

2/3/2021

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​The Impact of a Structured Exercise Programme upon Cognitive Function in Chronic Fatigue Syndrome Patients
by Paweł Zalewski 1,Sławomir Kujawski 1,*,Malwina Tudorowska 2,Karl Morten 3,Małgorzata Tafil-Klawe 4,Jacek J. Klawe 1,James Strong 3,Fernando Estévez-López 5,Modra Murovska 6,Julia L. Newton 7 andthe European Network on ME/CFS (EUROMENE)
1
Department of Hygiene, Epidemiology and Ergonomics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland, M. Sklodowskiej-Curie 9, 85-094 Bydgoszcz, Poland


Brain Sci. 2020, 10(1), 4; https://doi.org/10.3390/brainsci10010004
Received: 29 November 2019 / Accepted: 16 December 2019 / Published: 19 December 2019
(This article belongs to the Section Cognitive Neuroscience)
Abstract
Background: Cognitive function disturbance is a frequently described symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, the effects of a structured exercise programme (SEP) upon cognitive function in ME/CFS patients was examined. Methods: Out of the 53 ME/CFS patients initiating SEP 34 (64%) completed the 16 week programme. Cognitive function was assessed using a computerized battery test consisting of a Simple Reaction Time (SRT) (repeated three times) and Choice Reaction Time (CRT) measurements, a Visual Attention Test (VAT) and a Delayed Matching to Sample (DMS) assessment. Results: Statistically significant improvement was noted in the third attempt to SRT in reaction time for correct answers, p = 0.045, r = 0.24. Moreover, significant improvement was noted in VAT reaction time, number of correct answers and errors committed, p = 0.02, omega = 0.03, p = 0.007, r = 0.34 and p = 0.004, r = 0.35, respectively. Non-significant changes were noted in other cognitive tests. Conclusions: A substantial number of participants were unwilling or unable to complete the exercise programme. ME/CFS patients able to complete the SEP showed improved visual attention both in terms of reaction time and correctness of responses and processing speed of simple visual stimuli.
Keywords: mental function; brain fog; cognitive impairment

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Randomized Controlled Trial        Free Radic Res  . 2019 Aug;53(8):901-909.
 doi: 10.1080/10715762.2019.1645955. Epub 2019 Aug 7.
Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction
Passakorn Sawaddiruk 1 2 3, Nattayaporn Apaijai 1 2, Sahattaya Paiboonworachat 3, Tawika Kaewchur 4, Nuntana Kasitanon 5, Thidarat Jaiwongkam 1 2, Sasiwan Kerdphoo 1 2, Nipon Chattipakorn 1 2 6, Siriporn C Chattipakorn 1 2 7     PMID: 31387429 DOI: 10.1080/10715762.2019.1645955
Abstract
Although coenzyme Q10 (CoQ10) supplementation has shown to reduce pain levels in chronic pain, the effects of CoQ10 supplementation on pain, anxiety, brain activity, mitochondrial oxidative stress, antioxidants, and inflammation in pregabalin-treated fibromyalgia (FM) patients have not clearly elucidated. We hypothesised that CoQ10 supplementation reduced pain better than pregabalin alone via reducing brain activity, mitochondrial oxidative stress, inflammation, and increasing antioxidant levels in pregabalin-treated FM patients. A double-blind randomised placebo-controlled trial was conducted. Eleven FM patients were enrolled with 2 weeks wash-out then randomly allocated to 2 treatment groups; pregabalin with CoQ10 or pregabalin with placebo for 40 d. Then, patients in CoQ10 group were switched to placebo, and patients in placebo group were switched to CoQ10 for another 40 d. Pain pressure threshold (PPT), FM questionnaire, anxiety, and pain score were examined. Peripheral blood mononuclear cells (PBMCs) were isolated to investigate mitochondrial oxidative stress and inflammation at day 0, 40, and 80. The level of antioxidants and brain positron emission tomography (PET) scan were also determined at these time points. Pregabalin alone reduced pain and anxiety via decreasing brain activity compared with their baseline. However, it did not affect mitochondrial oxidative stress and inflammation. Supplementation with CoQ10 effectively reduced greater pain, anxiety and brain activity, mitochondrial oxidative stress, and inflammation. CoQ10 also increased a reduced glutathione levels and superoxide dismutase (SOD) levels in FM patients. These findings provide new evidence that CoQ10 supplementation provides further benefit for relieving pain sensation in pregabalin-treated FM patients, possibly via improving mitochondrial function, reducing inflammation, and decreasing brain activity.
Keywords: Brain activity; coenzyme Q10; fibromyalgia; oxidative stress; pain; pregabalin.

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Cardiac Dimensions and Function are Not Altered among Females with the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Per Ole Iversen*,Thomas Gero von Lueder,Kristin Reimers Kardel 1 andKatarina Lien
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
Department of Hematology, Oslo University Hospital, 0424 Oslo, Norway
Author to whom correspondence should be addressed.
Healthcare 2020, 8(4), 406; https://doi.org/10.3390/healthcare8040406
Received: 24 September 2020 / Revised: 13 October 2020 / Accepted: 15 October 2020 / Published: 16 October 2020
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition associated with several negative health outcomes. A hallmark of ME/CFS is decreased exercise capacity and often profound exercise intolerance. The causes of ME/CSF and its related symptoms are unknown, but there are indications of a dysregulated metabolism with impaired glycolytic vs oxidative energy balance. In line with this, we recently demonstrated abnormal lactate accumulation among ME/CFS patients compared with healthy controls after exercise testing. Here we examined if cardiac dimensions and function were altered in ME/CFS, as this could lead to increased lactate production. Methods: We studied 16 female ME/CFS patients and 10 healthy controls with supine transthoracic echocardiography, and we assessed cardiac dimensions and function by conventional echocardiographic and Doppler analysis as well as novel tissue Doppler and strain variables. Results: A detailed analyses of key variables of cardiac dimensions and cardiac function revealed no significant differences between the two study groups. Conclusion: In this cohort of well-described ME/CFS patients, we found no significant differences in echocardiographic variables characterizing cardiac dimensions and function compared with healthy controls.  
Keywords: cardiac function; echocardiography; myalgic encephalomyelitis/chronic fatigue syndrome

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Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS
  • Milica Milivojevic ,Xiaoyu Che ,Lucinda Bateman,Aaron Cheng,Benjamin A. Garcia,Mady Hornig, Manuel Huber,Nancy G. Klimas,Bohyun Lee,Hyoungjoo Lee,Susan Levine,Jose G. Montoya,
  • Daniel L. Peterson,Anthony L. Komaroff,W. Ian Lipkin 
  • Published: July 21, 2020   https://doi.org/10.1371/journal.pone.0236148
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774–0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806–0.846) and ME/CFS without sr-IBS (AUC = 0.754–0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.
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Substrate utilisation of cultured skeletal muscle cells in patients with CFS
Cara Tomas, Joanna L. Elson, Julia L. Newton & Mark Walker 
Scientific Reports volume 10, Article number: 18232 (2020) Cite this article
Abstract
Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower levels of ATP and have AMP-activated protein kinase dysfunction. This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis. Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle. The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients. The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease. The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.

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Persistent Symptoms in Patients After Acute COVID-19 - July 9, 2020
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. 2020;324(6):603-605. doi:10.1001/jama.2020.12603
In Italy, a large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods
In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included.
Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5
In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results
From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. The mean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. The characteristics of the study population are summarized in the Table.
Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. The Figure shows that a high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion
This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6
Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed.
Section Editor: Jody W. Zylke, MD, Deputy Editor.

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Open Access  Published: 24 September 2020
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings & Warren Tate 
Journal of Translational Medicine volume 18, Article number:  


Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.
Methods
To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.
Results
A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.
Conclusions
The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
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Front. Neurol., 28 August 2020 | https://doi.org/10.3389/fneur.2020.00828
Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée1,2*, Anastasios Michos2, Brandon Drum1,2, Mikael Fahlgren2,3, Robert Szulkin1 and Bo C. Bertilson1,2,3
  • 1Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
  • 2ME-center, Bragée Clinics, Stockholm, Sweden
  • 3Academic Primary Health Care Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
The pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is unknown. In this study, we test the hypothesis that hypermobility, signs of intracranial hypertension (IH), and craniocervical obstructions may be overrepresented in patients with ME/CFS and thereby explain many of the symptoms. Our study is a retrospective, cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS as defined by the Canada Consensus Criteria. The first 272 patients with ME/CFS were invited to participate, and 229 who provided prompt informed consent were included. Hypermobility was assessed using the Beighton Score. IH was assessed indirectly by the quotient of the optic nerve sheet diameter (ONSD)/eyeball transverse diameter on both sides as measured on magnetic resonance imaging (MRI) of the brain. We also included assessment of cerebellar tonsil position in relation to the McRae line, indicating foramen magnum. Craniocervical obstructions were assessed on MRI of the cervical spine. Allodynia was assessed by quantitative sensory testing (QST) for pain in the 18 areas indicative of fibromyalgia syndrome (FMS). A total of 190 women, mean age 45 years, and 39 males, mean age 44 years, were included. Hypermobility was identified in 115 (50%) participants. MRI of the brain was performed on 205 participants of whom 112 (55%) had an increased ONSD and 171 (83%) had signs of possible IH, including 65 (32%) who had values indicating more severe states of IH. Cerebellar tonsils protruding under the McRae line into the foramen magnum were identified in 115 (56%) of the participants. MRI of the cervical spine was performed on 125 participants of whom 100 (80%) had craniocervical obstructions. Pain at harmless pressure, allodynia, was found in 96% of the participants, and FMS was present in 173 participants or 76%. Compared to a general population, we found a large overrepresentation of hypermobility, signs of IH, and craniocervical obstructions. Our hypothesis was strengthened for future studies on the possible relation between ME/CFS symptoms and hypermobility, IH, and craniocervical obstructions in a portion of patients with ME/CFS. If our findings are confirmed, new diagnostic and therapeutic approaches to this widespread neurological syndrome should be considered.
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Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
C (Linda) MC van Campen, Peter C. Rowe 2 and Frans C Visser
Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Author to whom correspondence should be addressed.
Healthcare 2020, 8(4), 394; https://doi.org/10.3390/healthcare8040394
Received: 7 September 2020 / Revised: 6 October 2020 / Accepted: 9 October 2020 / Published: 11 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a large study with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, we showed that 86% had symptoms of orthostatic intolerance in daily life and that 90% had an abnormal reduction in cerebral blood flow (CBF) during a standard tilt test. A standard head-up tilt test might not be tolerated by the most severely affected bed-ridden ME/CFS patients. Sitting upright is a milder orthostatic stress. The present study examined whether a sitting test, measuring cerebral blood flow by extracranial Doppler, would be sufficient to provoke abnormal reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: 100 severe ME/CFS patients were studied, (88 females) and were compared with 15 healthy controls (HC) (13 females). CBF was measured first while seated for at least one hour, followed by a CBF measurement in the supine position. Fibromyalgia was present in 37 patients. Demographic data as well as supine heart rate and blood pressures were not different between ME/CFS patients and HC. Heart rate and blood pressure did not change significantly between supine and sitting both in patients and HC. Supine CBF was not different between patients and HC. In contrast, absolute CBF during sitting was lower in patients compared to HC: 474 (96) mL/min in patients and 627 (89) mL/min in HC; p < 0.0001. As a result, percent CBF reduction while seated was −24.5 (9.4)% in severe ME/CFS patients and −0.4 (1.2)% in HC (p < 0.0001). In the ten patients who had no orthostatic intolerance complaints in daily life, the CBF reduction was −2.7 (2.1)%, which was not significantly different from HC (p = 0.58). The remaining 90 patients with orthostatic intolerance complaints had a −26.9 (6.2)% CBF reduction. No difference in CBF parameters was found in patients with and without fibromyalgia. Patients with a previous diagnosis of postural orthostatic tachycardia syndrome (POTS) had a significantly larger CBF reduction compared with those without POTS: 28.8 (7.2)% vs. 22.3 (9.7)% (p = 0.0008). Conclusions: A sitting test in severe ME/CFS patients was sufficient to provoke a clinically and statistically significant mean CBF decline of 24.5%. Patients with a previous diagnosis of POTS had a larger CBF reduction while seated, compared to patients without POTS. The magnitude of these CBF reductions is similar to the results in less severely affected ME/CFS patients during head-up tilt, suggesting that a sitting test is adequate for the diagnosis of orthostatic intolerance in severely affected patients.
Keywords: orthostatic intolerance; cerebral blood flow; sitting; myalgic encephalomyelitis; chronic fatigue syndrome; severe disease; ME/CFS
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Letters  Covid-19: “Just stay at home”
Long covid: doctors must assess and investigate patients properly
BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4583 (Published 02 December 2020)Cite this as: BMJ 2020;371:m4583
Amali U Lokugamage, consultant obstetrician and gynaecologist and honorary associate professor12,  Mary-Ann Bowen, general practitioner3,  Jennifer Blair, consultant anaesthetist4
a.lokugamage@ucl.ac.uk
Jensen’s article provides a poignant patient perspective and reflects well the experiences of many patients that were very sick at the peak of the first wave of covid-19 but were denied proper medical assessment and told to “stay at home.”1 Of course it is important to “show you care” and empathise with the patient. But, as part of an online group of over 500 doctors (ever growing in number) affected by long covid, we are disappointed that the learning points don’t include “doctors should assess and investigate patients properly.” Before the covid-19 pandemic, symptoms such as low oxygen levels, tachycardia, and shortness of breath would warrant examination and investigation, especially when persistent and in previously fit and healthy patients.
It saddens us to hear such low expectations from general practice and secondary care. This is a new disease, and we are surprised about the lack of professional curiosity to explain new and sometimes seemingly odd symptoms. Numerous BMJ publications support the need for further assessment.234 Pathological consequences such as myocarditis5 or a thromboembolic episode6 may explain symptoms, and these have been noted to occur months after onset in long covid support groups. The medical profession needs to evolve rapid transformative pathways to deal with the long term sequelae of covid-19 that include full investigation of patients. This is becoming urgent, as new covid cases are increasing again and we are already starting to see a new wave of patients with long covid.
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​
Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology
  • Evguenia Nepotchatykh, et al
Scientific Reports volume 10, Article number: 19620 (2020)  
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient's symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS. Our study aimed to investigate circulating microRNA expression in severely ill ME/CFS patients before and after an innovative stress challenge that stimulates PEM. Our findings highlight the differential expression of eleven microRNAs associated with a physiological response to PEM. The present study uncovers specific microRNA expression signatures associated with ME/CFS in response to PEM induction and reports microRNA expression patterns associated to specific symptom severities. The identification of distinctive microRNA expression signatures for ME/CFS through a provocation challenge is essential for the elucidation of the ME/CFS pathophysiology, and lead to accurate diagnoses, prevention measures, and effective treatment options.
Accurate and objective determination of myalgic encephalomyelitis/chronic fatigue syndrome disease severity with a wearable sensor
  • Turner Palombo, Andrea Campos, Suzanne D. Vernon & Shad Roundy 
Journal of Translational Medicine volume 18, Article number: 423 (2020)  
Abstract
Background
Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.
Methods
A commercially available inertial measurement unit (IMU), the Shimmer, was selected for this research. A Kalman filter was used to convert IMU data collected by the Shimmer to angle estimates. Angle estimate accuracy was confirmed by comparison to a motion capture system. Leg angle estimates were then converted to personalized daily UpTime scores using a critical angle of 39º from vertical to differentiate between upright (feet on the floor) and not upright. A 6-day, case–control study with 15 subjects (five healthy controls, five moderate-level ME/CFS, and five severe-level ME/CFS) was conducted to determine the utility of UpTime for assessing disease severity.
Results
UpTime was found to be a significant measure of ME/CFS disease severity. Severely ill ME/CFS patients spend less than 20% of each day with feet on the floor. Moderately ill ME/CFS patients spend between 20–30% of each day with feet on the floor. Healthy controls have greater than 30% UpTime. IMU-measured UpTime was more precise than self-reported hours of upright activity which were over-estimated by patients.
Conclusions
UpTime is an accurate and objective measure of upright activity, a measure that can be used to assess disease severity in ME/CFS patients. Due to its ability to accurately monitor upright activity, UpTime can also be used as a reliable endpoint for evaluating ME/CFS treatment efficacy. Future studies with larger samples and extended data collection periods are required to fully confirm the use of UpTime as a measure of disease severity in ME/CFS. With the added perspective of large-scale studies, this sensor-based platform could provide a recovery path for individuals struggling with ME/CFS.
Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population
  • Toshimori Kitami, et al
Scientific Reports volume 10, Article number: 19933 (2020)  
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
Diverse Functional Autoantibodies in Patients with COVID-19
Eric Y. Wang,1,* Tianyang Mao,1,* Jon Klein,1,* Yile Dai,1,* John D. Huck,1 Feimei Liu,1 Neil S. Zheng,1 Ting Zhou,1 Benjamin Israelow,1 Patrick Wong,1 Carolina Lucas,1 Julio Silva,1 Ji Eun Oh,1 Eric Song,1 Emily S. Perotti,1 Suzanne Fischer,1 Melissa Campbell,5 John B. Fournier,5 Anne L. Wyllie,3 Chantal B. F. Vogels,3 Isabel M. Ott,3 Chaney C. Kalinich,3 Mary E. Petrone,3 Anne E. Watkins,3 Yale IMPACT Team,¶ Charles Dela Cruz,4 Shelli F. Farhadian,5 Wade L. Schulz,6,7 Nathan D. Grubaugh,3 Albert I. Ko,3,5 Akiko Iwasaki,1,3,8,# and Aaron M. Ring1,2,#
Author information Copyright and License information Disclaimer
Version 2. medRxiv. Preprint. 2020 Dec 12.
doi: 10.1101/2020.12.10.20247205  PMCID: PMC7743105  PMID: 33330894
Abstract
COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.
Review


Am J Cardiovasc Drugs  . 2018 Jun;18(3):195-204.   doi: 10.1007/s40256-017-0252-1.
Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome: A Systematic Review
Megan E Gee 1, Alicia K Watkins 2, Jamie N Brown 3, Emily J A Young 4
Affiliations expand PMID: 29330767  DOI: 10.1007/s40256-017-0252-1
Abstract
Introduction: Postural orthostatic tachycardia syndrome (POTS) impacts millions of patients, but there is currently no gold standard treatment for this condition. Ivabradine is a novel heart rate (HR) lowering agent that acts on the sinoatrial node cells by selectively inhibiting the If-current.
Objective: The objective of this systematic review is to evaluate the evidence for the efficacy and safety of ivabradine for the treatment of POTS.
Methods: MEDLINE (from 1956 to August 2017) and EMBASE (from 1957 to August 2017) were queried with the following search term: "postural orthostatic tachycardia syndrome" OR "postural tachycardia syndrome" OR "chronic orthostatic intolerance" AND "ivabradine." Articles in English with clinical outcomes of human patient(s) treated with ivabradine for POTS were included.
Results: The initial search identified 73 articles. After screening, 13 articles were included. Two prospective open-label trials, three retrospective cohort studies, and eight case reports evaluated the safety and efficacy of ivabradine in a total of 132 patients with postural tachycardia. Overall, ivabradine lowered HR and provided symptomatic relief of POTS without blood pressure lowering. Dizziness, nausea, headache, and fatigue were the most common side effects and often did not lead to discontinuation of treatment.
Conclusion: Based on this small sample, ivabradine appears to be a reasonable option for patients with POTS who have failed or are unable to tolerate other treatment options, however, but a randomized controlled trial in this population is needed.
Cureus. 2020 Apr; 12(4): e7868.
Published online 2020 Apr 28. doi: 10.7759/cureus.7868
PMCID: PMC7255540
Ivabradine in Postural Orthostatic Tachycardia Syndrome: A Review of the Literature
Faryal Tahir,1 Taha Bin Arif,1 Zainab Majid,1 Jawad Ahmed,1 and Muhammad Khalid2,3
Abstract
Introduction and background
The first informal mention of postural orthostatic tachycardia syndrome (POTS) was by Da Costa, in 1871, who referred to it as “soldier’s heart” or “irritable heart” [1]. However, Schondorf and Low, in 1993, first described POTS in the adult population as an increase in the heart rate (HR) in a symptomatic patient by more than 30 beats per min (bpm) when the patient moves from supine to upright position [2]. In 2015, Heart Rhythm Society defined POTS on the basis of three points: (1) a clinical syndrome characterized by symptoms of lightheadedness, blurring of vision, palpitations, intolerance to exercise, and fatigue; (2) an increase of ≥30 bpm (≥40 bpm in those aged 12-19 years) in the HR when the person stands up from a recumbent position; and (3) absence of orthostatic hypotension [3]. Orthostatic hypotension is characterized by a more than 20 mmHg drop in systolic blood pressure (BP) on standing [3]. The incidence of POTS varies globally from 0.2% to 1% in the developed countries with an increased prevalence among females, Caucasian race, and individuals from 13 to 50 years of age [4,5,6-8]. The affected individuals account for 3,000,000 cases alone in the United States of America (USA) [9]. A recent 2019 study has shown that the incidence of POTS has increased fourfold since 2000 [8].
POTS is an autonomic disorder characterized by symptoms such as palpitations, dyspnea, chest discomfort, lightheadedness, nausea, blurred vision, chronic fatigue, sleeping abnormalities, migraines, hypermobile joints, abdominal pain, irritable bowel, and bladder symptoms as well affecting various systems [9,10]. Only 30% of individuals have reported fainting along with the symptoms of POTS [9]. Usually, there is a two-year (median) delay in the diagnosis of disease from the onset of symptoms [7]. The pathophysiology of POTS is not completely understood due to a variety of symptoms showing that the disease is multifactorial [4,9,10]. Chronic fatigue syndrome, inappropriate sinus tachycardia, and vasovagal syncope are few conditions associated with POTS [4].
There is no approved uniform management strategy for POTS and hence, no drug has been approved by the US Food and Drug Administration (FDA) for it [4]. Non-pharmacological therapies include lifestyle modifications such as increased hydration and salt intake, and use of support stockings [11]. Pharmacological therapies include beta-blockers (first line), alpha-agonists (first or second line), mineralocorticoids (second line), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs), and rarely used drugs include pyridostigmine, desmopressin, and erythropoietin [4,11]. However, there has been evidence of beneficial outcomes with the use of ivabradine in POTS patients, as seen in prospective and retrospective studies [12-16].
Ivabradine is an FDA-approved drug for stable symptomatic heart failure (HF) and patients with an ejection fraction (EF) of ≤35% [17,18]. European Society of Cardiology recommends ivabradine as second-line therapy for patients whose angina has been poorly controlled by other medications, namely calcium-channel blockers (CCBs), beta-blockers, or nitrates (short-acting) [19].
Ivabradine increases the diastolic time and reduces the HR by inhibiting channels responsible for maintaining cardiac pacemaker current, If (funny current). The selective blocking of these trans-membrane ion channels that conduct the inward depolarizing sodium (Na) and potassium (K) current slows down the HR without affecting systemic vascular resistance and cardiac inotropy [18,20,21]. Ivabradine has been+ associated with many severe side effects such as bradycardia, heart block, sinus arrest, QT prolongation, torsades de pointes, and fetal toxicity. Other less severe side effects include, but are not limited to, vertigo, diplopia, rash, and hypotension [17,18].
Ivabradine is not an FDA-approved drug for POTS but due to its ability to reduce HR, it has shown improvement in POTS patients in many studies [12-16]. This review aims to provide a comprehensive and up-to-date picture of all the studies and case reports that utilized ivabradine for the treatment of POTS along with a precise overview of epidemiology, pathophysiology, and types of POTS.


Persistent Symptoms in Patients After Acute COVID-19
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. 2020;324(6):603-605. doi:10.1001/jama.2020.12603 July 9, 2020
What Is It Like to Have COVID-19?
In Italy, a large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods
In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included.
Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5
In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results
From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. The mean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. The characteristics of the study population are summarized in the Table.
Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. The Figure shows that a high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion
This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6
Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed.
Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans
Author links open overlay panelKiranThapaliyaabSonyaMarshall-GradisnikaDonStainesaLeightonBarndena
https://doi.org/10.1016/j.nicl.2020.102366Get rights and content
Neurolmage Clinical   Vol 28 2020cc
Highlights
We showed increased T1w/T2w in ME/CFS in contrast to other neurodegenerative diseases.
Higher T1w/T2w occurred in basal ganglia and white matter tracts.
Increased T1w/T2w indicates increased myelin and/or iron levels.
T1w/T2w regressions vs clinical measures were abnormal in cingulate cortex and white matter foci.
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls. We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level. Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.
A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease
Sean Holden, Rebekah Maksoud, Natalie Eaton-Fitch, Hélène Cabanas, Donald Staines & Sonya Marshall-Gradisnik 
Published: 29 July 2020
Journal of Translational Medicine volume 18, Article number: 290 (2020) Cite this article
The Correction to this article has been published in Journal of Translational Medicine 2020 18:407
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls.
Methods
Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.
Results
Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes.
Conclusion
Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.
Front. Public Health, 21 August 2020 | https://doi.org/10.3389/fpubh.2020.00420
The Economic Impacts of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Australian Cohort
Shara Close1, Sonya Marshall-Gradisnik2*, Joshua Byrnes3, Peter Smith2, Son Nghiem3 and Don Staines2
1Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
2National Centre for Neuroimmunology and Emerging Diseases, Griffith University.
Centre for Applied Health Economics, Griffith University, Nathan, QLD, Australia


Objectives: This study aims to estimate direct and indirect health economic costs associated with government and out-of-pocket (OOP) expenditure based on health care service utilization and lost income of participants and carers, as reported by Australian Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patient survey participants.
Design: A cost of illness study was conducted to estimate Australian cost data for individuals with a ME/CFS diagnosis as determined by the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the 1994 CDC Criteria (Fukuda).
Setting and participants: Survey participants identified from a research registry database provided self-report of expenditure associated with ME/CFS related healthcare across a 1-month timeframe between 2017 and 2019.
Main outcome measures: ME/CFS related direct annual government health care costs, OOP health expenditure costs, indirect costs associated with lost income and health care service use patterns.
Results: The mean annual cost of health care related expenditure and associated income loss among survey participants meeting diagnostic criteria for ME/CFS was estimated at $14.5 billion. For direct OOP and Government health care expenditure, high average costs were related to medical practitioner attendance, diagnostics, natural medicines, and device expenditure, with an average attendance of 10.6 referred attendances per annum and 12.1 GP visits per annum related specifically to managing ME/CFS.
Conclusions: The economic impacts of ME/CFS in Australia are significant. Improved understanding of the illness pathology, diagnosis, and management, may reduce costs, improve patient prognosis and decrease the burden of ME/CFS in Australia.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Organic Disease or Psychosomatic Illness? A Re-Examination of the Royal Free Epidemic of 1955 
Rosemary Underhill 1,* and Rosemarie Baillod 2
Medicina 2021, 57, 12. https://dx.doi.org/10.3390/ medicina57010012 Received: 20 November 2020 Accepted: 22 December 2020 Published: 26 December 2020 
Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
 Correspondence: petro8888@aol.com 
Abstract: 
Background and Objectives: Controversy exists over whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an organic disease or a psychosomatic illness. ME/CFS usually occurs as sporadic cases, but epidemics (outbreaks) have occurred worldwide. Myalgic encephalomyelitis was named to describe an outbreak affecting the lymphatic, muscular, and nervous systems that closed the Royal Free hospital for three months in 1955. Fifteen years later, two psychiatrists concluded that epidemic hysteria was the likely cause. ME/CFS research studies show multiple pathophysiological differences between patients and controls and a possible etiological role for infectious organisms, but the belief that ME/CFS is psychosomatic is widespread and has been specifically supported by the epidemic hysteria hypothesis for the Royal Free outbreak. Our objective was to obtain accounts from ex-Royal Free hospital staff who personally experienced the 1955 outbreak and evaluate evidence for it being an infectious illness versus epidemic hysteria. 
Materials and Methods: Statements in the newsletters of two organizations for staff who had worked at the Royal Free hospital invited anyone who had experienced the 1955 Royal Free outbreak to contact the authors. Accounts of the outbreak from telephone interviews and letters were evaluated against the “epidemic hysteria hypothesis” paper and original medical staff reports. 
Results: Twentyseven ex-Royal Free hospital staff, including six who had developed ME, provided descriptions typical of an infectious illness affecting the lymphatic, muscular, and nervous systems, and were not consistent with epidemic hysteria. 
Conclusions: The 1955 Royal Free hospital epidemic of myalgic encephalomyelitis was an organic infectious disease, not psychogenic epidemic hysteria. 
Keywords: Chronic fatigue syndrome; epidemic hysteria; mass hysteria; myalgic encephalomyelitis; psychosomatic illness; Royal Free epidemic
Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact 
medRxiv preprint doi: https://doi.org/10.1101/2020.12.24.20248802; this version posted December 27, 2020


Hannah E. Davis1 *, Gina S. Assaf1 *, Lisa McCorkell1 *, Hannah Wei1 *, Ryan J. Low1,2*, Yochai Re’em1,3*, Signe Redfield1 , Jared P. Austin4 , Athena Akrami1, 


 Patient-Led Research for COVID-19, 2 Sainsbury Wellcome Centre, University College London, London, UK, 3 NewYork-Presbyterian Hospital / Weill Cornell Medicine, NYC, USA, 4 Oregon Health and Science University, Portland, OR, USA + Corresponding author, email: athena.akrami@ucl.ac.uk 
Abstract Objective. To characterize the symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health. Design. International web-based survey of suspected and confirmed COVID-19 cases with illness lasting over 28 days and onset prior to June 2020. 
Setting. Survey distribution via online COVID-19 support groups and social media 
Participants. 3,762 respondents from 56 countries completed the survey. 1166 (33.7%) were 40-49 years old, 937 (27.1%) were 50-59 years old, and 905 (26.1%) were 30-39 years old. 2961 (78.9%) were women, 718 (19.1%) were men, and 63 (1.7%) were nonbinary. 8.4% reported being hospitalized. 27% reported receiving a laboratory-confirmed diagnosis of COVID-19. 96% reported symptoms beyond 90 days.
 Results. Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%). These three symptoms were also the three most commonly reported overall. In those who recovered in less than 90 days, the average number of symptoms peaked at week 2 (11.4, 9.4 to 13.6), and in those who did not recover in 90 days, the average number of symptoms peaked at month 2 (17.2, 16.5 to 17.8). Respondents with symptoms over 6 months experienced an average of 13.8 (12.7 to 14.9) symptoms in month 7. 85.9% (84.8% to 87.0%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 45.2% (42.9% to 47.2%) reported requiring a reduced work schedule compared to pre-illness and 22.3% (20.5% to 24.3%) were not working at the time of survey due to their health conditions. 
Conclusions. Patients with Long COVID report prolonged multisystem involvement and significant disability. Most had not returned to previous levels of work by 6 months. Many patients are not recovered by 7 months, and continue to experience significant symptom burden.
Neurology
Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine—a meta-analysis 
  1. Suhairul Sazali, http://orcid.org/0000-0002-7353-2839
  2. Salziyan Badrin, http://orcid.org/0000-0002-6372-1476
  3. Mohd Noor Norhayati, Nur Suhaila Idris


Abstract
Objective To determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine.
Design Systematic review and meta-analysis.
Data sources Cochrane Central Register of Controlled Trials, CENTRAL, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Psychological Information Database (PsycINFO) from inception till December 2019.
Study selection All randomised control trials comparing CoQ10 with placebo or used as an adjunct treatment included in this meta-analysis. Cross-over designs and controlled clinical trials were excluded.
Data synthesis Heterogeneity at face value by comparing populations, settings, interventions and outcomes were measured and statistical heterogeneity was assessed by means of the I2 statistic. The treatment effect for dichotomous outcomes were using risk ratios and risk difference, and for continuous outcomes, mean differences (MDs) or standardised mean difference; both with 95% CIs were used. Subgroup analyses were carried out for dosage of CoQ10 and if CoQ10 combined with another supplementation. Sensitivity analysis was used to investigate the impact risk of bias for sequence generation and allocation concealment of included studies.
Results Six studies with a total of 371 participants were included in the meta-analysis. There is no statistically significant reduction in severity of migraine headache with CoQ10 supplementation. CoQ10 supplementation reduced the duration of headache attacks compared with the control group (MD: −0.19; 95% CI: −0.27 to −0.11; random effects; I2 statistic=0%; p<0.00001). CoQ10 usage reduced the frequency of migraine headache compared with the control group (MD: −1.52; 95% CI: −2.40 to −0.65; random effects; I2 statistic=0%; p<0.001).
Conclusion CoQ10 appears to have beneficial effects in reducing duration and frequency of migraine attack.
PROSPERO registration number CRD42019126127.
Imaging  Jan 5, 2021:Brain Responses to Noxious Stimuli in Patients With Chronic Pain
A Systematic Review and Meta-analysis
Anna Xu, BS1; Bart Larsen, PhD1; Alina Henn, MS2; et alErica B. Baller, MD, MS1,3,4; J. Cobb Scott, PhD1,5; Vaishnavi Sharma, BA1; Azeez Adebimpe, PhD1; Allan I. Basbaum, PhD6; Gregory Corder, PhD1; Robert H. Dworkin, PhD7; Robert R. Edwards, MD8; Clifford J. Woolf, MB, BCh, PhD9,10; Simon B. Eickhoff, MD11,12; Claudia R. Eickhoff, MD12,13; Theodore D. Satterthwaite, MD, MA1
JAMA Netw Open. 2021;4(1):e2032236. doi:10.1001/jamanetworkopen.2020.32236
Key Points: Question  Do the brains of patients with chronic pain respond differently to noxious stimuli?
Findings  This systematic review and meta-analysis of 37 experiments from 29 unique articles including 944 participants found that patients with chronic pain were not associated with significant differential responses to noxious stimuli that induce pain compared with healthy controls.
Meaning  Chronic pain does not appear to be associated with consistent marked alterations in the brain’s response to noxious stimuli.


Abstract: Importance  Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies.
Objective  To identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses.
Data Sources  All fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS.
Study Selection  Experiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P < .001 or cluster-corrected P < .05). Two independent reviewers evaluated titles and abstracts returned by the search. In total, 3682 abstracts were screened, and 1129 full-text articles were evaluated.
Data Extraction and Synthesis  Thirty-seven experiments from 29 articles met inclusion criteria for meta-analysis. Coordinates reporting significant activation differences between patients with chronic pain and healthy controls were extracted. These data were meta-analyzed using activation likelihood estimation. Data were analyzed from December 2019 to February 2020.
Main Outcomes and Measures  A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to noxious stimuli between patients and healthy controls were spatially convergent. Follow-up analyses examined the directionality of any differences. Finally, an exploratory (nonpreregistered) region-of-interest analysis examined differences within the pain network.
Results  The 37 experiments from 29 unique articles included a total of 511 patients and 433 controls (944 participants). Whole-brain meta-analyses did not reveal significant differences between patients and controls in brain responses to noxious stimuli at the preregistered statistical threshold. However, exploratory analyses restricted to the pain network revealed aberrant activity in patients.
Conclusions and Relevance  In this systematic review and meta-analysis, preregistered, whole-brain analyses did not reveal aberrant fMRI activity in patients with chronic pain. Exploratory analyses suggested that subtle, spatially diffuse differences may exist within the pain network. Future work on chronic pain biomarkers may benefit from focus on this core set of pain-responsive areas.
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12/13/2020

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Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods
Front. Neurol., 10 January 2019 | https://doi.org/10.3389/fneur.2018.01033
Michael B. VanElzakker*, Sydney A. Brumfield and Paula S. Lara Mejia
  • Division of Neurotherapeutics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying. The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement. The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable. We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies. We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.
_________________________________________________________________________________

NeuroImage: Clinical      Volume 28, 2020, 102366
Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans
KiranThapaliyaabSonyaMarshall-GradisnikaDonStainesaLeightonBarndena
https://doi.org/10.1016/j.nicl.2020.102366Get rights and content
Highlights
We showed increased T1w/T2w in ME/CFS in contrast to other neurodegenerative diseases.
Higher T1w/T2w occurred in basal ganglia and white matter tracts.
Increased T1w/T2w indicates increased myelin and/or iron levels.
T1w/T2w regressions vs clinical measures were abnormal in cingulate cortex and white matter foci.
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls. We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level. Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.
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Hum Mol Genet. 2020 Aug 3;ddaa169. doi: 10.1093/hmg/ddaa169. Online ahead of print.
Genetic Risk Factors of ME/CFS: A Critical Review
Joshua J Dibble 1, Simon J McGrath 2, Chris P Ponting 1
PMID: 32744306      DOI: 10.1093/hmg/ddaa169
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes. Despite a prevalence of approximately 0.2-0.4% and its high public health burden, and evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases. Here we critically review existing evidence that genetic factors alter ME/CFS risk before concluding that most ME/CFS candidate gene associations are not replicated by the larger CFS cohort within UK Biobank. Multiple genome-wide association studies of this cohort also have not yielded consistently significant associations. Ahead of upcoming larger genome-wide association studies we discuss how these could generate new lines of enquiry into the DNA variants, genes and cell-types that are causally involved in ME/CFS disease.
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption
by Markus Tölle 1,Helma Freitag 2,Michaela Antelmann 2,Jelka Hartwig 2,Mirjam Schuchardt 1,Markus van der Giet 1,Kai-Uwe Eckardt 1,Patricia Grabowski 2,† andCarmen Scheibenbogen1
Department of Nephrology and Medical Intensive Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, 12203 Berlin, Germany
Institute of Medical Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), 13353 Berlin, Germany
J. Clin. Med. 2020, 9(8), 2443; https://doi.org/10.3390/jcm9082443
Received: 13 July 2020 / Accepted: 28 July 2020 / Published: 30 July 2020
(This article belongs to the Special Issue Apheresis in Neurological Disorders)
Abstract
(1) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disease. There is evidence for an autoimmune mechanism for ME/CFS with an infection-triggered onset and dysfunction of ß2-adrenoreceptor antibodies (ß2AR-AB). In a first proof-of-concept study, we could show that IA was effective to reduce ß2AR-AB and led to improvement of various symptoms. (2) Five of the ME/CFS patients who had clinical improvement following treatment with a five-day IA were retreated in the current study about two years later with a modified IA protocol. The severity of symptoms was assessed by disease specific scores during a follow-up period of 12 months. The antibodies were determined by ELISA. (3) The modified IA treatment protocol resulted in a remarkable similar clinical response. The treatment was well tolerated and 80–90% decline of total IgG and ß2AR-AB was achieved. Four patients showed a rapid improvement in several clinical symptoms during IA therapy, lasting for six to 12 months. One patient had no improvement. (4) We could provide further evidence that IA has clinical efficacy in patients with ME/CFS. Data from our pilot trial warrant further controlled studies in ME/CFS.
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Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
by Eiren Sweetman 1,Alex Noble 1,Christina Edgar 1,Angus Mackay 1,Amber Helliwell 1,Rosamund Vallings 2,Margaret Ryan 3 andWarren Tate 1,*
Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand
Howick Health and Medical Centre, Auckland 2014, New Zealand
Department of Anatomy, University of Otago, Dunedin 9016, New Zealand
Author to whom correspondence should be addressed.
Diagnostics 2019, 9(3), 73; https://doi.org/10.3390/diagnostics9030073
Received: 30 May 2019 / Revised: 22 June 2019 / Accepted: 3 July 2019 / Published: 10 July 2019
(This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2–3 years that promise new leads towards an effective clinical diagnostic test that may have a general application. Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing. View Full-Text

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Journal of translational medicine:
A SWATH-MS analysis of ME/CFS peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction: Sweetman,Vallings,Tate et al Aug 2020
Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.

Methods: To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.

Results: A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.

Conclusions: The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.
https://www.researchsquare.com/article/rs-52172/v1
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Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS
  • Milica Milivojevic ,Xiaoyu Che ,Lucinda Bateman,Aaron Cheng,Benjamin A. Garcia,Mady Hornig, Manuel Huber,Nancy G. Klimas,Bohyun Lee,Hyoungjoo Lee,Susan Levine,Jose G. Montoya,
  • Daniel L. Peterson,Anthony L. Komaroff,W. Ian Lipkin 
  • Published: July 21, 2020  Plos One
  • https://doi.org/10.1371/journal.pone.0236148
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774–0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806–0.846) and ME/CFS without sr-IBS (AUC = 0.754–0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.

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Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review
Zack Y. Shan, Leighton R. Barnden, Richard A. Kwiatek, Sandeep Bhuta, Daniel F. Hermens & Jim Lagopoulos 
Journal of Translational Medicine volume 18, Article number: 335 (2020)  
Published: 01 September 2020


Abstract
Background
Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible.
Method
To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported.
Results
63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies.
Conclusion
Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.

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Front. Neurol., 11 August 2020 | https://doi.org/10.3389/fneur.2020.00826
How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS
Luis Nacul1,2, Shennae O'Boyle1*, Luigi Palla3,4, Flavio E. Nacul5, Kathleen Mudie1, Caroline C. Kingdon1, Jacqueline M. Cliff6, Taane G. Clark6, Hazel M. Dockrell6 and Eliana M. Lacerda1
  • 1Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
We propose a framework for understanding and interpreting the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.
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Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients
Jihyun Lee, Suzanne D. Vernon, Patricia Jeys, Weam Ali, Andrea Campos, Derya Unutmaz, Brayden Yellman & Lucinda Bateman 
Journal of Translational Medicine volume 18, Article number: 314 (2020)  
Abstract
Background
Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.
Methods
A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years (< 4 ME/CFS) and 75 ME/CFS patients sick for more than 10 years (> 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups.
Results
At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The < 4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to > 10 ME/CFS and HCs. The < 4 ME/CFS group experienced significantly more OI symptoms compared to > 10 ME/CFS and HCs. The circulatory decompensation observed in the < 4 ME/CFS group was not related to age or medication use.
Conclusions
Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for < 4 years. This suggests inadequate ventricular filling from low venous pressure. The 10-minute NLT can be used to diagnose and treat the circulatory decompensation in this newly recognized subgroup of ME/CFS patients. The > 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.
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J Transl Med. 2020 Jul 29;18(1):290. doi: 10.1186/s12967-020-02452-3.
A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease
Sean Holden 1 2 3, Rebekah Maksoud 4 5 6, Natalie Eaton-Fitch 1 3 7, Hélène Cabanas 1 3, Donald Staines 1 3, Sonya Marshall-Gradisnik 1 3
PMID: 32727475 PMCID: PMC7392668 DOI: 10.1186/s12967-020-02452-3
Abstract
Background: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls.
Methods: Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.
Results: Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes.
Conclusion: Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.
Keywords: Chronic Fatigue Syndrome; Energy metabolism; Mitochondria; Myalgic Encephalomyelitis; Systemic Exertion Intolerance Disease.
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Elife . 2020 Jul 7;9:e59177. doi: 10.7554/eLife.59177.
A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm
Michael R Garvin 1, Christiane Alvarez 1, J Izaak Miller 1, Erica T Prates 1, Angelica M Walker 1 2, B Kirtley Amos 3, Alan E Mast 4, Amy Justice 5, Bruce Aronow 6 7, Daniel Jacobson 1 2 8
PMID: 32633718   PMCID: PMC7410499 DOI: 10.7554/eLife.59177
Abstract
Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.
Keywords: COVID-19; bradykinin; computational biology; human; human biology; hyaluronic acid; medicine; pathogenesis; renin-angiotensin system; systems biology.
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Front. Neurol., 18 September 2020 | https://doi.org/10.3389/fneur.2020.01025


Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Barbara Stussman1*, Ashley Williams2, Joseph Snow3, Angelique Gavin4, Remle Scott1, Avindra Nath4 and Brian Walitt5
1National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health (NIH), Bethesda, MD, United States
Background: Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by persistent and disabling fatigue, exercise intolerance, cognitive difficulty, and musculoskeletal/joint pain. Post–exertional malaise is a worsening of these symptoms after a physical or mental exertion and is considered a central feature of the illness. Scant observations in the available literature provide qualitative assessments of post–exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. To enhance our understanding, a series of outpatient focus groups were convened.
Methods: Nine focus groups totaling 43 patients who reported being diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome were held between November 2016 and August 2019. Focus groups queried post–exertional malaise in daily life and participants' retrospective memory of post–exertional malaise that followed an exercise provocation with a cardiopulmonary exercise test. Data analysis followed the grounded theory method to systematically code and categorize the data to find meaningful patterns. A qualitative software package was used to move text into categories during data coding.
Results: A wide range of symptoms were attributed to exertion both in daily lives and following cardiopulmonary exercise testing. While three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints), participants' descriptions were notable for their unique individual variations. Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test. Patients described post–exertional malaise as interfering with their ability to lead a “normal” life.
Conclusion: The experience of post–exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome varies greatly between individuals and leads to a diminished quality of life. myalgic encephalomyelitis/chronic fatigue syndrome patients describe post–exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options.
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Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis
by Joanna Słomko 1,*,Fernando Estévez-López 2,Sławomir Kujawski 1,Monika Zawadka-Kunikowska 1,Małgorzata Tafil-Klawe 3,Jacek J. Klawe 1,Karl J. Morten 4,Justyna Szrajda 1,Modra Murovska 5,Julia L. Newton 6 andPaweł Zalewski 1 on behalf of the European Network on ME/CFS (EUROMENE)
1
J. Clin. Med. 2020, 9(8), 2531; https://doi.org/10.3390/jcm9082531
Received: 15 July 2020 / Revised: 3 August 2020 / Accepted: 4 August 2020 / Published: 5 August 2020
(This article belongs to the Section Epidemiology & Public Health)
Abstract
In this study we set out to define the characteristics of autonomic subgroups of patients with Chronic Fatigue Syndrome (CFS). The study included 131 patients with CFS (Fukuda criteria). Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Fatigue Impact Scale, Fatigue Severity Scale, Epworth Sleepiness Scales, the self-reported Composite Autonomic Symptom Scale. Autonomic parameters were measured at rest with a Task Force Monitor (CNS Systems) and arterial stiffness using an Arteriograph (TensioMed Kft.). Principal axis factor analysis yielded four factors: fatigue, subjective and objective autonomic dysfunction and arterial stiffness. Using cluster analyses, these factors were grouped in four autonomic profiles: 34% of patients had sympathetic symptoms with dysautonomia, 5% sympathetic alone, 21% parasympathetic and 40% had issues with sympathovagal balance. Those with a sympathetic-dysautonomia phenotype were associated with more severe disease, reported greater subjective autonomic symptoms with sympathetic over-modulation and had the lowest quality of life. The highest quality of life was observed in the balance subtype where subjects were the youngest, had lower levels of fatigue and the lowest values for arterial stiffness. Future studies will aim to design autonomic profile-specific treatment interventions to determine links between autonomic phenotypes CFS and a specific treatment.
Keywords: autonomic; chronic fatigue; quality of life

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Front. Pediatr., 12 June 2020 | https://doi.org/10.3389/fped.2020.00293
Review of the Quality Control Checks Performed by Current Genome-Wide and Targeted-Genome Association Studies on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Anna D. Grabowska1, Eliana M. Lacerda2, Luís Nacul2,3 and Nuno Sepúlveda4,5*
  • 1Department of Biophysics and Human Physiology, Medical University of Warsaw, Warsaw, Poland
Introduction
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and post-exertion malaise, accompanied by other symptoms (1, 2). The direct cause of the disease remains elusive, but it may include genetic factors alongside environmental triggers, such as strong microbial infections and other stressors (3, 4).
With the aim to identify putative genetic factors that could explain the pathophysiological mechanisms of ME/CFS, four genome-wide association studies (GWAS) and two targeted-genome association studies (TGAS) were conducted in the past decade (5–10). In the four GWAS, thousands of genetic markers located across the whole genome were evaluated for their statistical association with ME/CFS (5–8). The two TGAS had the same statistical objective of the four GWAS, but alternatively investigated the association of the disease with numerous genetic markers located in candidate genes related to inflammation and immunity (9) and in genes encoding diverse adrenergic receptors (10). The findings from all these different studies suggested conflicting evidence of genetic association with ME/CFS: from absence of association (7), through mild association (10) up to moderate associations of a relatively small number of genetic markers (5, 6, 9). The most optimistic GWAS suggested more than 5,500 candidate gene-disease associations (8). This inconsistency in the reported findings prompted us to review the respective data. With this purpose, the present opinion paper first revisits the recommended quality control (QC) checks for GWAS and TGAS, and then summarizes which ones were performed by those studies on ME/CFS.

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October 26, 2020
Association of Therapies With Reduced Pain and Improved Quality of Life in Patients With FibromyalgiaA Systematic Review and Meta-analysis
Rodrigo Oliveira Mascarenhas, MSc1; Mateus Bastos Souza, BAppSc2; Murilo Xavier Oliveira, PhD2; et alAna Cristina Lacerda, PhD2; Vanessa Amaral Mendonça, PhD2; Nicholas Henschke, PhD3; Vinícius Cunha Oliveira, PhD2
JAMA Intern Med. Published online October 26, 2020. doi:10.1001/jamainternmed.2020.5651
Question  What is the association of therapies with reduced pain and improved quality of life in patients with fibromyalgia?
Findings  In this systematic review, the effectiveness of most therapies for fibromyalgia was not supported. Strong evidence supported only cognitive behavioral therapy for pain, as well as antidepressants and central nervous system depressants for pain and quality of life, but these associations were small.
Meaning  Some therapies may be associated with small reductions in pain and improvements in quality of life in people with fibromyalgia; however, current evidence is lacking for most therapies.


Abstract
Importance  Fibromyalgia is a chronic condition that results in a significant burden to individuals and society.
Objective  To investigate the effectiveness of therapies for reducing pain and improving quality of life (QOL) in people with fibromyalgia.
Data Sources  Searches were performed in the MEDLINE, Cochrane, Embase, AMED, PsycInfo, and PEDro databases without language or date restrictions on December 11, 2018, and updated on July 15, 2020.
Study Selection  All published randomized or quasi-randomized clinical trials that investigated therapies for individuals with fibromyalgia were screened for inclusion.
Data Extraction and Synthesis  Two reviewers independently extracted data and assessed risk of bias using the 0 to 10 PEDro scale. Effect sizes for specific therapies were pooled using random-effects models. The quality of evidence was assessed using the Grading of Recommendations Assessment (GRADE) approach.
Main Outcomes and Measures  Pain intensity measured by the visual analog scale, numerical rating scales, and other valid instruments and QOL measured by the Fibromyalgia Impact Questionnaire.
Results  A total of 224 trials including 29 962 participants were included. High-quality evidence was found in favor of cognitive behavioral therapy (weighted mean difference [WMD], −0.9; 95% CI, −1.4 to −0.3) for pain in the short term and was found in favor of central nervous system depressants (WMD, −1.2 [95% CI, −1.6 to −0.8]) and antidepressants (WMD, −0.5 [95% CI, −0.7 to −0.4]) for pain in the medium term. There was also high-quality evidence in favor of antidepressants (WMD, −6.8 [95% CI, −8.5 to −5.2]) for QOL in the short term and in favor of central nervous system depressants (WMD, −8.7 [95% CI, −11.3 to −6.0]) and antidepressants (WMD, −3.5 [95% CI, −4.5 to −2.5]) in the medium term. However, these associations were small and did not exceed the minimum clinically important change (2 points on an 11-point scale for pain and 14 points on a 101-point scale for QOL). Evidence for long-term outcomes of interventions was lacking.
Conclusions and Relevance  This systematic review and meta-analysis suggests that most of the currently available therapies for the management of fibromyalgia are not supported by high-quality evidence. Some therapies may reduce pain and improve QOL in the short to medium term, although the effect size of the associations might not be clinically important to patients.

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Adding medical cannabis to standard analgesic treatment for fibromyalgia: a prospective observational study
Va. Giorgi1, Sa. Bongi 
CER12788 2020 Vol.38, N°123 ,Suppl.123 - PI 0053, PF 0059
Abstract
OBJECTIVES:
To assess any clinical improvement attributable to the addition of medical cannabis treatment (MCT) to the stable (>3 months) standard analgesic treatment of fibromyalgia (FM) patients, the retention rate and any changes in the concomitant analgesic treatment over a period of six months.
METHODS:
The study involved 102 consecutive FM patients with VAS scores ≥4 despite standard analgesic treatment. Patients were prescribed two oil-diluted cannabis extracts: Bedrocan (22% THC, <1% CBD), and Bediol (6.3% THC, 8% CBD). FM severity was periodically assessed using Fibromyalgia Impact Questionnaire (FIQR), Fibromyalgia Assessment Scale (FAS), FACIT-Fatigue score, Pittsburgh Sleep Quality Index (PSQI), and Zung Depression and Anxiety Scales. During the study, patients were allowed to reduce or stop their concomitant analgesic therapy.
RESULTS:
The 6-month retention rate was 64%. A significant improvement in the PSQI and FIQR was observed in respectively 44% and 33% of patients. 50% showed a moderate improvement in the anxiety and depression scales. Multiple regression analysis showed a correlation between the body mass index (BMI) and FIQR improvement (p=0.017). Concomitant analgesic treatment was reduced or suspended in 47% of the patients. One-third experienced mild adverse events, which did not cause any significant treatment modifications.
CONCLUSIONS:
This observational study shows that adjunctive MCT offers a possible clinical advantage in FM patients, especially in those with sleep dysfunctions. The clinical improvement inversely correlated with BMI. The retention rate and changes in concomitant analgesic therapy reflect MCT efficacy of the improved quality of life of patients. Further studies are needed to confirm these data, identify MCT-responsive sub-groups of FM patients, and establish the most appropriate posology and duration of the therapy.
PMID: 32116208 [PubMed]
Received: 19/09/2019 - Accepted : 09/12/2019 - In Press: 05/02/2020 - Published: 21/02/2020
© Clinical and Experimental Rheumatology
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Pain. 2019 Apr;160(4):860-869. doi: 10.1097/j.pain.0000000000001464.
An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia
Tine van de Donk 1, Marieke Niesters 1, Mikael A Kowal 2, Erik Olofsen 1, Albert Dahan 1, Monique van Velzen 1
PMID: 30585986 PMCID: PMC6430597 DOI: 10.1097/j.pain.0000000000001464
Abstract
In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their [INCREMENT]-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, <1-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4-mg CBD, <1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30% decrease in pain scores compared to placebo (90% vs 55% of patients, P = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = -0.5, P < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (P < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions, and the role of psychotropic symptoms on pain relief.
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Environmental, Neuro-immune, and Neuro-oxidative Stress Interactions in Chronic Fatigue Syndrome
Geir Bjørklund, Maryam Dadar, Lyudmila Pivina, Monica Daniela Doşa,  Yuliya Semenova & Michael Maes 
Molecular Neurobiology volume 57, pages4598–4607(2020) 
Abstract
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS) is a complex, multisystem disease that is characterized by long-term fatigue, exhaustion, disabilities, pain, neurocognitive impairments, gastrointestinal symptoms, and post-exertional malaise, as well as lowered occupational, educational, and social functions. The clinical and biomarker diagnosis of this disorder is hampered by the lack of validated diagnostic criteria and laboratory tests with adequate figures of merit, although there are now many disease biomarkers indicating the pathophysiology of CFS. Here, we review multiple factors, such as immunological and environmental factors, which are associated with CFS and evaluate current concepts on the involvement of immune and environmental factors in the pathophysiology of CFS. The most frequently reported immune dysregulations in CFS are modifications in immunoglobulin contents, changes in B and T cell phenotypes and cytokine profiles, and decreased cytotoxicity of natural killer cells. Some of these immune aberrations display a moderate diagnostic performance to externally validate the clinical diagnosis of CFS, including the expression of activation markers and protein kinase R (PKR) activity. Associated with the immune aberrations are activated nitro-oxidative pathways, which may explain the key symptoms of CFS. This review shows that viral and bacterial infections, as well as nutritional deficiencies, may further aggravate the immune-oxidative pathophysiology of CFS. Targeted treatments with antioxidants and lipid replacement treatments may have some clinical efficacy in CFS. We conclude that complex interactions between immune and nitro-oxidative pathways, infectious agents, environmental factors, and nutritional deficiencies play a role in the pathophysiology of CFS.

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Radiology and imaging - BMJ Vol 10 Issue 8
Using structural and functional MRI as a neuroimaging technique to investigate chronic fatigue syndrome/myalgic encephalopathy: a systematic review
 Basim Almutairi1,2, Christelle Langley3, Esther Crawley4, 
  • http://orcid.org/0000-0001-6125-7326Ngoc Jade Thai1
Abstract
Objective This systematic review aims to synthesise and evaluate structural MRI (sMRI) and functional MRI (fMRI) studies in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
Methods We systematically searched Medline and Ovid and included articles from 1991 (date of Oxford diagnostic criteria for CFS/ME) to first April 2019. Studies were selected by predefined inclusion and exclusion criteria. Two reviewers independently reviewed the titles and abstracts to determine articles for inclusion, full text and quality assessment for risk of bias.
Results sMRI studies report differences in CFS/ME brain anatomy in grey and white matter volume, ventricular enlargement and hyperintensities. Three studies report no neuroanatomical differences between CFS/ME and healthy controls. Task-based fMRI investigated working memory, attention, reward and motivation, sensory information processing and emotional conflict. The most consistent finding was CFS/ME exhibited increased activations and recruited additional brain regions. Tasks with increasing load or complexity produced decreased activation in task-specific brain regions.
Conclusions There were insufficient data to define a unique neural profile or biomarker of CFS/ME. This may be due to inconsistencies in finding neuroanatomical differences in CFS/ME and the variety of different tasks employed by fMRI studies. But there are also limitations with neuroimaging. All brain region specific volumetric differences in CFS/ME were derived from voxel-based statistics that are biased towards group differences that are highly localised in space. fMRI studies demonstrated both increases and decreases in activation patterns in CFS/ME, this may be related to task demand. However, fMRI signal cannot differentiate between neural excitation and inhibition or function-specific neural processing. Many studies have small sample sizes and did not control for the heterogeneity of this clinical population. We suggest that with robust study design, subgrouping and larger sample sizes, future neuroimaging studies could potentially lead to a breakthrough in our understanding of the disease.
http://creativecommons.org/licenses/by-nc/4.0/

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Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
by C (Linda) MC van Campen 1,*,Peter C. Rowe 2 andFrans C Visser 1
Healthcare 2020, 8(4), 394; https://doi.org/10.3390/healthcare8040394
Received: 7 September 2020 / Revised: 6 October 2020 / Accepted: 9 October 2020 / Published: 11 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a large study with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, we showed that 86% had symptoms of orthostatic intolerance in daily life and that 90% had an abnormal reduction in cerebral blood flow (CBF) during a standard tilt test. A standard head-up tilt test might not be tolerated by the most severely affected bed-ridden ME/CFS patients. Sitting upright is a milder orthostatic stress. The present study examined whether a sitting test, measuring cerebral blood flow by extracranial Doppler, would be sufficient to provoke abnormal reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: 100 severe ME/CFS patients were studied, (88 females) and were compared with 15 healthy controls (HC) (13 females). CBF was measured first while seated for at least one hour, followed by a CBF measurement in the supine position. Fibromyalgia was present in 37 patients. Demographic data as well as supine heart rate and blood pressures were not different between ME/CFS patients and HC. Heart rate and blood pressure did not change significantly between supine and sitting both in patients and HC. Supine CBF was not different between patients and HC. In contrast, absolute CBF during sitting was lower in patients compared to HC: 474 (96) mL/min in patients and 627 (89) mL/min in HC; p < 0.0001. As a result, percent CBF reduction while seated was −24.5 (9.4)% in severe ME/CFS patients and −0.4 (1.2)% in HC (p < 0.0001). In the ten patients who had no orthostatic intolerance complaints in daily life, the CBF reduction was −2.7 (2.1)%, which was not significantly different from HC (p = 0.58). The remaining 90 patients with orthostatic intolerance complaints had a −26.9 (6.2)% CBF reduction. No difference in CBF parameters was found in patients with and without fibromyalgia. Patients with a previous diagnosis of postural orthostatic tachycardia syndrome (POTS) had a significantly larger CBF reduction compared with those without POTS: 28.8 (7.2)% vs. 22.3 (9.7)% (p = 0.0008). Conclusions: A sitting test in severe ME/CFS patients was sufficient to provoke a clinically and statistically significant mean CBF decline of 24.5%. Patients with a previous diagnosis of POTS had a larger CBF reduction while seated, compared to patients without POTS. The magnitude of these CBF reductions is similar to the results in less severely affected ME/CFS patients during head-up tilt, suggesting that a sitting test is adequate for the diagnosis of orthostatic intolerance in severely affected patients. 
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Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection
  • Liam Townsend  ,Adam H. Dyer ,Karen Jones,Jean Dunne,Aoife Mooney,Fiona Gaffney,Laura O'Connor,Deirdre Leavy,Kate O'Brien,Joanne Dowds,Jamie A. Sugrue,David Hopkins,Ignacio Martin-Loeches,Niall Conlon 
  • Published: November 9, 2020  Plos One  https://doi.org/10.1371/journal.pone.0240784
Abstract
Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.
Editor: Giordano Madeddu, University of Sassari, ITALY
Received: July 22, 2020; Accepted: October 2, 2020; Published: November 9, 2020
. PLoS ONE 15(11): e0240784. https://doi.org/10.1371/journal.pone.0240784

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10/26/2020

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Epidemiological and clinical factors associated with post-exertional malaise severity in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Alaa Ghali, ï  Paul Richa, ï  Carole Lacout, ï  Aline Gury, ï  Anne-Berengere Beucher,   Chadi Homedan, ï  Christian Lavigne & ï  Geoffrey Urbanski 
Journal of Translational Medicine volume 18, Article number: 246 (2020)  
  • Published: 22 June 2020
Abstract
Background
Post-exertional malaise (PEM), the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), occurs generally after exposure to a stressor. It is characterized by the worsening of ME/CFS symptoms and results in aggravating the course of the disease and the quality of life of patients. Due to its unpredictable onset, severity, and recovery time, identifying patients with higher risk for severe PEM would allow preventing or reducing its occurrence. We thus aimed at defining possible factors that could be associated with PEM severity.
Methods
Adult patients fulfilling ME international consensus criteria who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2019 were included retrospectively. All patients were systematically hospitalized for an etiological workup and overall assessment. We reviewed their medical records for data related to the assessment: epidemiological data, fatigue features, clinical manifestations, and ME/CFS precipitants. PEM severity was appreciated by the Center for Disease Control self-reported questionnaire. The study population was classified into quartiles according to PEM severity scores. Analyses were performed with ordinal logistic regression to compare quartile groups.
Results
197 patients were included. PEM severity was found to be positively associated with age at disease onset ≥ 32 years (OR 1.8 [95% CI 1.1–3.0] (p = 0.03)), recurrent infections during the course of the disease (OR 2.1 [95% CI 1.2–3.7] (p = 0.009)), and when ME/CFS was elicited by a gastrointestinal infectious precipitant (OR 5.7 [1.7–19.3] (p = 0.006)).
Conclusion
We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients’ quality of life.

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Predicting GP visits: A multinomial logistic regression investigating GP visits amongst a cohort of UK patients living with Myalgic encephalomyelitis
  • R. Stephen Walsh, Andrew Denovan, Kenneth Drinkwater,  &, Reddington S 
  • Neil Dagnall 
BMC Family Practice volume 21, Article number: 105 (2020)  
Abstract
Background
Myalgic Encephalomyelitis (ME) is a chronic condition whose status within medicine is the subject of on-going debate. Some medical professionals regard it as a contentious illness. Others report a lack of confidence with diagnosis and management of the condition. The genesis of this paper was a complaint, made by an ME patient, about their treatment by a general practitioner. In response to the complaint, Healthwatch Trafford ran a patient experience-gathering project.
Method
Data was collected from 476 participants (411 women and 65 men), living with ME from across the UK. Multinomial logistic regression investigated the predictive utility of length of time with ME; geographic location (i.e. Manchester vs. rest of UK); trust in GP; whether the patient had received a formal diagnosis; time taken to diagnosis; and gender. The outcome variable was number of GP visits per year.
Results
All variables, with the exception of whether the patient had received a formal diagnosis, were significant predictors.
Conclusions
Relationships between ME patients and their GPs are discussed and argued to be key to the effective delivery of care to this patient cohort. Identifying potential barriers to doctor patient interactions in the context of ME is crucial.

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International Journal of Cardiology,  Hypertension.  Volume 5, June 2020, 100032
Paradigm shift to disequilibrium in the genesis of orthostatic intolerance in patients with myalgic encephalomyelitis and chronic fatigue syndrome
Author links open overlay panel KunihisaMiwaa1YukichiInoueb1
https://doi.org/10.1016/j.ijchy.2020.100032Get rights and content
Highlights    Most patients with chronic fatigue syndrome suffers from orthostatic intolerance (OI).
OI significantly restricts daily functional capacity.
Circulatory and autonomic nervous dysregulation is not the sole cause of OI.
Disequilibrium should be recognized as the important cause of OI.
Disequilibrium is more influential cause of OI than postural orthostatic tachycardia.
Abstract
Background
Orthostatic intolerance (OI) markedly impairs activities of daily living in patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. OI is surmised to be a cardiovascular symptom correlated with cerebral hypo-perfusion and exaggerated sympathetic activation. Postural instability or disequilibrium may be part of the etiology of OI.
Methods     The study comprised 72 patients with ME (18 men, 54 women; mean age, 37 ± 10 years) who underwent neurological examinations and the 10 min standing test. We quantified disequilibrium (instability upon standing with feet together and eyes shut), ability to complete the 10 min standing test, and postural orthostatic tachycardia (POT) during the test.
Results      Disequilibrium was detected in 23/72 (32%) patients and POT in 16 (22%). Nineteen (26%) patients failed to complete the 10 min standing test; disequilibrium was significantly more common in the 19- patient subgroup than in the 53-patient test-completing subgroup (89% vs. 11%, p < 0.01). However, the rate of POT was not different between the groups (21% vs. 23%, p = 1.00). Compared with the 49 (68%) patients without disequilibrium, the 23 (32%) patients with disequilibrium were significantly more likely to have failed to complete the test (74% vs. 4%, p < 0.01). The rate of POT was comparable between the groups (23% vs. 22%, p = 1.00). Among patients with disequilibrium who failed to complete the 10 min standing test and had a previous record, 6/8 had completed the test 6–24 months earlier when all six had reported no disequilibrium.
Conclusion
Disequilibrium should be recognized as an important cause of OI in patients with ME.

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Journal of Experimental Neurology Commentary 
https://www.scientificarchives.com/journal/journal-of-experimental-neurology Skeletal 
Muscle Weakness Often Occurs in Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) 
Yves Jammes1,2, Frédérique Retornaz2* 
1 C2VN UMR Inra Inserm, Faculty of Medicine, Aix-Marseille University, France 2 Department of Internal Medicine, European Hospital, Marseille, France fr 
Received date: April 16, 2020, Accepted date: May 14, 2020 Copyright: © 2020 Jammes Y, et al.
 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 
This commentary considers the occurrence of skeletal muscle weakness in patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/ CFS), already reported by Jammes et al. in the last issue of Clinical Biomechanics [1]. These authors showed that numerous patients with severe body fatigue and clinical criteria of ME/CFS had reduced values of maximal handgrip strength in proportion of their lowered maximal performance at work measured on a cycloergometer. Here, we discuss these data in terms of pathophysiological mechanisms of muscle failure. Remember that ME/CFS is a multisystem disease characterized by an intense fatigue worsened by physical/ mental activity [2-4], often associated with postexertional malaise (PEM) [3,5]. Several body systems including the muscular and nervous systems are affected in ME/CFS. The symptoms combine fatigue, loss of memory and/or concentration, headaches, unrefreshing sleep, unexplained muscle or joint pain, sore throat and sometimes enlarged lymph nodes in neck or armpits [6]. ME/CFS pathogenesis appears to have a number of factors; different stressors (such as physical exertion, Highlights • Altered muscle function often occurs in ME/CFS patients. • Reduced handgrip strength is proportional to lowered physical performance • Muscle fatigue could result from altered muscle excitability at work • Reduced central motor command is also documented in relation of encephalomyelitis • Subgroups of ME/CFS patients without muscle weakness are documented Abstract This commentary complements data reported in Clinical Biomechanics [1] reporting reduced maximal handgrip strength in numerous patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) in proportion to their lowered maximal physical performances. The causes of muscle weakness in these patients are open to discussion. Literature data reveal a reduction of central command to skeletal muscles in some ME/CFS patients, related to encephalomyelitis. Altered muscle membrane excitability, that is “peripheral fatigue”, is also described in relation with an imbalance of the oxidant / anti-oxidant status. On the other hand, subgroups of chronically fatigued patients with clinical criteria of ME/CFS do not suffer from any muscle weakness. Thus, clinical data do not sufficiently clarify homogeneous ME/CFS pathology.

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Persistent Symptoms in Patients After Acute COVID-19 In Italy,
2020 American Medical Association  JAMA Published online July 9, 2020
 A large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19. 
Methods | In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included. Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5 In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation). 
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results | From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. Themean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. A high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%). 
Discussion  This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6 Clinicians and researchers have focused on the acute phase of COVID-19, but continuedmonitoring after discharge for longlasting effects is needed. 
Angelo Carfì, MD Roberto Bernabei, MD Francesco Landi, MD, PhD 
Corresponding Author: Angelo Carfì, MD, Centro Medicina dell’Invecchiamento, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, 00168 Rome, Italy (angelo.carfi@ policlinicogemelli.it). 
Accepted for Publication: June 23, 2020. Published Online: July 9, 2020. doi:10.1001/jama.2020.12603

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J Med Virol. 2020 Mar 4.   doi: 10.1002/jmv.25744. Online ahead of print.
Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome
Evelina Shikova 1 2, Valentina Reshkova 3, Аntoniya Kumanova 1, Sevdalina Raleva 1, Dora Alexandrova 2, Natasa Capo 4 5, Modra Murovska 6, European Network on ME/CFS (EUROMENE)
  • PMID: 32129496    
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) are suspected as etiological agents for ME/CFS. This study aims to estimate prevalence and type (active/latent) of EBV, CMV, and HHV-6 infections in Bulgarian ME/CFS patients. In the study were included 58 patients with ME/CFS and 50 healthy controls. Virus-specific antibodies were detected by enzyme-linked immunosorbent assay and viral genomic sequences in peripheral blood mononuclear cell (PBMCs) and plasma samples by nested polymerase chain reaction (PCR). We did not observe any significant differences in virus-specific immunoglobulin G and immunoglobulin M positivity rates between patients with ME/CFS and control group. In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples. EBV DNA was detected in 4%, and CMV and HHV-6 DNA were not found in plasma samples of controls. The frequency of viral genome detection in PBMCs of patients and controls was 74% vs 78% for CMV, 81% vs 84% for EBV, and 82.8% vs 82% for HHV-6. The difference in frequency of EBV active infection in ME/CFS and control group was statistically significant (P = .0027). No ME/CFS and control individuals with active CMV and HHV-6 infection were observed. In conclusion, this study using both serological and PCR-based techniques for distinguishing between active and latent infection showed high rate of active EBV infection among patients with ME/CFS indicating that at least in a subset of cases, EBV is important factor for the development of disease.
Keywords: CMV; EBV; ELISA; HHV-6 infection; PCR; active infection; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.

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· Hypothesis · March 2020 · 
“Neither dying, nor recovering”: 
Learning from Intensive Care Units to Solve Chronic Fatigue Syndrome (ME/CFS) 
Dominic Stanculescu* Independent, Belgium
 Introduction 
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology and without reliable treatments. Some researchers consider ME/CFS to be a maladaptive response to stressors (physical, infectious, or emotional) [1]. Similarly, the failure of a subset of intensive care unit (ICU) patients to begin recovery is also increasingly considered the result of maladaptive responses to the stress of severe injury or infection [2;3;4]. Irrespective of the initial critical illness, these “chronic” ICU patients experience severe ME/CFSlike symptoms that include profound muscular weakness, cognitive impairment, pain, and vulnerability to infection [5]. Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) "vicious cycles" between cytokines, oxidative and nitrosative stress (O&NS), and low thyroid hormone function.

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Adv Rheumatol 2020 Jun 29;60(1):34. doi: 10.1186/s42358-020-00135-7.
Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow up
Suman Tanwar 1 2, Bhawna Mattoo 1, Uma Kumar 3, Renu Bhatia 4
PMID: 32600394
 Abstract
Objectives: Fibromyalgia Syndrome (FMS), is a chronic pain disorder with poorly understood pathophysiology. In recent years, repetitive transcranial magnetic stimulation (rTMS) has been recommended for pain relief in various chronic pain disorders. The objective of the present research was to study the effect of low frequency rTMS over the right dorsolateral prefrontal cortex (DLPFC) on pain status in FMS.
Methods: Ninety diagnosed cases of FMS were randomized into Sham-rTMS and Real-rTMS groups. Real rTMS (1 Hz/1200 pulses/8 trains/90% resting motor threshold) was delivered over the right DLPFC for 5 consecutive days/week for 4 weeks. Pain was assessed by subjective and objective methods along with oxidative stress markers. Patients were followed up for 6 months (post-rTMS;15 days, 3 months and 6 months).
Results: In Real-rTMS group, average pain ratings and associated symptoms showed significant improvement post rTMS. The beneficial effects of rTMS lasted up to 6 months in the follow-up phase. In Sham-rTMS group, no significant change in pain ratings was observed.
Conclusion: Right DLPFC rTMS can significantly reduce pain and associated symptoms of FMS probably through targeting spinal pain circuits and top-down pain modulation .
Trial registration: Ref No: CTRI/2013/12/004228.
Keywords: Chronic pain; Dorsolateral prefrontal cortex; Neuromodulation; Nociceptive flexion reflex; Non-invasive therapy; Oxidative stress.

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May 26, 2020; 94 (21) ARTICLE - Neurology
Effect of yoga as add-on therapy in migraine (CONTAIN)
A randomized clinical trial
 View ORCID ProfileAnand Kumar, Rohit Bhatia, Gautam Sharma, Dhanlika Dhanlika, Sreenivas Vishnubhatla, Rajesh Kumar Singh, Deepa Dash, Manjari Tripathi, M.V. Padma Srivastava
First published May 6, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009473
Abstract
Objective To evaluate the effectiveness of yoga as an adjuvant to conventional medical management on clinical outcomes in patients with migraine.
Methods CONTAIN was a prospective, randomized, open-label superiority trial with blinded endpoint assessment carried out at a single tertiary care academic hospital in New Delhi, India. Patients enrolled were aged 18–50 years with a diagnosis of episodic migraine and were randomized into medical and yoga groups (1:1). Randomization was computer-generated with a variable block size and concealed. A predesigned yoga intervention was given for 3 months. Outcomes were recorded by a blinded assessor. The primary endpoint was a decrease in headache frequency, headache intensity, and Headache Impact Test (HIT)–6 score. Secondary outcomes included change in Migraine Disability Assessment (MIDAS) score, pill count, and proportion of headache free patients.
Results Between April 2017 and August 2018, 160 patients with episodic migraine were randomly assigned to medical and yoga groups. A total of 114 patients completed the trial. Baseline measures were comparable except for a higher mean headache frequency in the yoga group. Compared to medical therapy, the yoga group showed a significant mean delta value reduction in headache frequency (delta difference 3.53 [95% confidence interval 2.52–4.54]; p < 0.0001), headache intensity (1.31 [0.60–2.01]; p = 0.0004), HIT score (8.0 [4.78–11.22]; p < 0.0001), MIDAS score (7.85 [4.98–10.97]; p < 0.0001), and pill count (2.28 [1.06–3.51]; p < 0.0003).
Conclusion Yoga as an add-on therapy in migraine is superior to medical therapy alone. It may be useful to integrate a cost-effective and safe intervention like yoga into the management of migraine.
Clinicaltrials.gov identifier CTRI/2017/03/008041.

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NICE advises against using graded exercise therapy for patients recovering from covid-19
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2912 (Published 21 July 2020)Cite this as: BMJ 2020;370:m2912
  1. Ingrid Torjesen
Graded exercise therapy may not be appropriate for treating post-viral fatigue in patients recovering from covid-19, the National Institute for Health and Care Excellence (NICE) has advised doctors.
In a statement NICE said that it was aware of concerns related to the impact of graded exercise therapy (GET) for managing post-viral fatigue in patients recovering from covid-19. It noted that its current advice on managing chronic fatigue may not be appropriate for this group of patients and acknowledged that it could also be out of date for other groups.1
“NICE’s guideline on ME/CFS [chronic fatigue syndrome] (CG53) was published in 2007,2 many years before the current pandemic, and it should not be assumed that the recommendations apply to people with fatigue following covid-19,” the statement said.
It emphasised that the recommendations on GET in this guideline applied only to patients with a diagnosis of chronic fatigue syndrome as part of specialist care, where it should be part of an individualised, person centred programme of care, where GET is recommended only for people with mild to moderate symptoms.
NICE added, “As the guideline is currently being updated, it is possible that these recommendations may change. The evidence for and against graded exercise therapy is one of the important issues the guideline committee is considering.”
NICE plans to consult on its updated guidance in November 2020. In the interim it advises doctors to use recent guidance from NHS England on the aftercare needs of inpatients recovering from covid-19, which includes advice on managing fatigue.3 That guidance says that “it is important to ensure a gradual return to activities and exercise and to teach pacing methods.”
Much of the support for GET comes from a study published in the Lancet in 2011, which concluded that patients with chronic fatigue syndrome benefited more from cognitive behavioural therapy and GET than from pacing therapy.4 Many patients reported that GET made them feel worse and that pacing was more effective,5 and the study’s methodology was heavily criticised.6 A review conducted by the Health Research Authority concluded that the study was properly conducted,7 but the review focused on the research process, not the conclusions.
Post-exertional malaise
The large number of patients experiencing post-viral fatigue after covid-19 has now shone a spotlight on the controversial technique again.
Among this number is Paul Garner, professor of infectious disease at the Liverpool School of Tropical Medicine and director of the Centre for Evidence Synthesis in Global Health. Early in his recovery Garner realised that he was experiencing post-exertional malaise, as every time he did any exercise that increased his heart rate, such as cycling or yoga, he found himself back in bed.89
Garner, who is coordinating editor of the Cochrane Infectious Diseases Group and one of the founders of the Cochrane Collaboration, said that he was “furious” when he read the 2007 NICE advice and the conclusions of the Cochrane review, which also support exercise therapy and mention uncertainty about the side effects of adaptive pacing.10
“Obviously, I know that if I increase my exercise I will be thrown back to bed,” he said. “What I struggle with as a highly driven medic is stopping myself overdoing it. That’s what I need help with—I don’t need help to increase my exercise.”
Garner researched and started using pacing, finding the approach helpful. However, he emphasised that the technique was complex and that there was very little information in the medical literature. “GPs need some really practical guidance on how they rehabilitate these patients. People are having to search out techniques or generate them themselves,” he said.
He added that, while some charities and health authorities had put out guidance, it was “difficult to negotiate” and that a centralised approach coordinated by NICE or the Royal College of General Practitioners, involving medical professionals and patients, was needed quickly.

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Proc Natl Acad Sci U S A . 2020 Jun 9;117(23):13044-13055.
 doi: 10.1073/pnas.2000625117. Epub 2020 May 20.
Epstein-Barr virus co-opts TFIIH component XPB to specifically activate essential viral lytic promoters
Dinesh Verma 1, Trenton Mel Church 1, Sankar Swaminathan 2 3
  • PMID: 32434920   PMCID: PMC7293708 (available on 2020-11-20) DOI: 10.1073/pnas.2000625117
Abstract
Epstein-Barr virus (EBV) is associated with epithelial and lymphoid malignancies, establishes latent infection in memory B cells, and intermittently produces infectious virions through lytic replication. Released virions play a key role in latent reservoir maintenance and transmission. Lytic EBV transcription differs from cellular transcription in requiring a virus-encoded preinitiation complex that binds to TATT motifs unique to EBV late lytic promoters. Expression of 15 late lytic genes that are important for virion production and infectivity is particularly dependent on the EBV SM protein, a nuclear protein expressed early during lytic reactivation that binds to viral RNAs and enhances RNA stability. We recently discovered that spironolactone blocks EBV virion production by inhibiting EBV SM function. Since spironolactone causes degradation of xeroderma pigmentosum group B-complementing protein (XPB), a component of human transcription factor TFIIH, in both B lymphocytes and epithelial cells, we hypothesized that SM utilizes XPB to specifically activate transcription of SM target promoters. While EBV SM has been thought to act posttranscriptionally, we provide evidence that SM also facilitates EBV gene transcription. We demonstrate that SM binds and recruits XPB to EBV promoters during lytic replication. Depletion of XPB protein, by spironolactone treatment or by siRNA transfection, inhibits SM-dependent late lytic gene transcription but not transcription of other EBV genes or cellular genes. These data indicate that SM acts as a transcriptional activator that has co-opted XPB to specifically target 15 EBV promoters that have uniquely evolved to require XPB for activity, providing an additional mechanism to differentially regulate EBV gene expression.
Keywords: Epstein–Barr virus; XPB; herpesvirus; transcription.

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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3609-14. doi: 10.1073/pnas.1523686113. Epub 2016 Mar 14.
Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function
Dinesh Verma 1, Jacob Thompson 1, Sankar Swaminathan 2
  • PMID: 26976570   PMCID: PMC4822607   DOI: 10.1073/pnas.1523686113
Abstract
Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses.
Keywords: Epstein–Barr virus; antiviral; herpesvirus; posttranscriptional regulation; spironolactone.

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Persistent Symptoms in Patients After Acute COVID-19
Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et alfor the Gemelli Against COVID-19 Post-Acute Care Study Group
JAMA. Published online July 9, 2020. doi:10.1001/jama.2020.12603
In Italy, a large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).1 Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.
Methods
In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included.
Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.5
In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).
This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.
Results
From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. The mean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. The characteristics of the study population are summarized in the Table.
Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. The Figure shows that a high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Discussion
This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.6
Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed.
Section Editor: Jody W. Zylke, MD, Deputy Editor.

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Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
by C (Linda) M.C. van Campen 1,*,Peter C. Rowe 2 andFrans C. Visser 1
Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Healthcare 2020, 8(2), 169; https://doi.org/10.3390/healthcare8020169
Received: 5 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected) 
Abstract
Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m2 and BMI was 24.0(5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS. View Full-Text
Keywords: orthostatic intolerance; cerebral blood flow; 20 degree tilt table testing; myalgic encephalomyelitis; chronic fatigue syndrome; postural orthostatic tachycardia syndrome; stroke volume index; cardiac index

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Health Care Responsibility and Compassion-Visiting the Housebound Patient Severely Affected by ME/CFS
by Caroline Kingdon *,Dionysius Giotas,Luis Nacul andEliana Lacerda
Department of Clinical Research, London School of Hygiene & Tropical Medicine, Faculty of Infectious and Tropical Diseases, London WC1E 7HT, UK
Healthcare 2020, 8(3), 197; https://doi.org/10.3390/healthcare8030197
Received: 9 June 2020 / Revised: 1 July 2020 / Accepted: 2 July 2020 / Published: 4 July 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Many people with severe Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) commonly receive no care from healthcare professionals, while some have become distanced from all statutory medical services. Paradoxically, it is often the most seriously ill and needy who are the most neglected by those responsible for their healthcare. Reasons for this include tensions around the complexity of making an accurate diagnosis in the absence of a biomarker, the bitter debate about the effectiveness of the few available treatments, and the very real stigma associated with the diagnosis. Illness severity often precludes attendance at healthcare facilities, and if an individual is well enough to be able to attend an appointment, the presentation will not be typical; by definition, patients who are severely affected are home-bound and often confined to bed. We argue that a holistic model, such as ‘‘Compassion in Practice’’, can help with planning appointments and caring for people severely affected by ME/CFS. We show how this can be used to frame meaningful interactions between the healthcare practitioners (HCPs) and the homebound patient.
Keywords: ME/CFS; severe ME/CFS; validation; engagement; health encounters; housebound; bedbound

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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
by C (Linda) M. C. van Campen 1,*,Peter C. Rowe 2
Healthcare 2020, 8(3), 192; https://doi.org/10.3390/healthcare8030192
Received: 28 April 2020 / Revised: 17 June 2020 / Accepted: 25 June 2020 / Published: 30 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected) 
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. View Full-Text
Keywords: chronic fatigue syndrome; cardiopulmonary exercise testing; oxygen consumption; VO2 peak; ventilatory threshold; VO2 VT; myalgic encephalitis; workload; ME/CFS severity grade

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Risk factors for suicide in chronic fatigue syndrome
Madeline L. Johnson,Joseph Cotler,Julia M. Terman &Leonard A. Jason
Published online: 12 Jun 2020 – Journal of Death Studies
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) includes symptoms such as post-exertional malaise, unrefreshing sleep, and cognitive impairments. Several studies suggest these patients have an increased risk of suicidal ideation and early mortality, although few have published in this area. This study explores risk factors for suicide among 64 individuals with ME/CFS using archival data, 17 of which died from suicide. Results indicated an increased risk of suicide for those for those utilizing the label CFS, for those with limited overall functioning, and for those without comorbid illnesses. Findings suggest that stigma and functional impairments limit access to care and social supports.

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Pain. 2020 Jul 10.   doi: 10.1097/j.pain.0000000000001996. Online ahead of print.
A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia
Miranda Al van Tilburg 1 2 3, Marc Parisien 4, Richard G Boles 5, Gillian L Drury 4, Julian Smith-Voudouris 4, Vivek Verma 4, Samar Khoury 4, Anne-Julie Chabot-Doré 4, Andrea G Nackley 6 7, Shad B Smith 6, William E Whitehead 8, Denniz A Zolnoun 9, Gary D Slade 10 11 12, Inna Tchivileva 10, William Maixner 6, Luda Diatchenko 4
  • PMID: 32658146


Abstract
Alterations in cellular energy metabolism have been implicated in chronic pain suggesting a role for mitochondrial DNA (mtDNA). Previous studies reported associations of a limited number of mtDNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPC) was examined. mtDNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with five CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism (SNP) m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (OR=4.6, P=4.3x10). This relationship was even stronger in women (OR=5.1, P=2.8x10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR=4.3, P=2.6x10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.

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Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts
Brain, Behaviour and Immunity  Volume 7, August 2020, 10010
AnnieBynkeabPerJulincdCarl-GerhardGottfrieseHaraldHeideckefCarmenScheibenbogengJonasBergquistab
https://doi.org/10.1016/j.bbih.2020.100107Get rights and content
Highlights


Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear aetiology and no clear diagnostic biomarker available.
This study support the existance of a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.
Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.
This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.
We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n ​= ​24), only plasma from the second cohort (n ​= ​24) together with plasma samples (n ​= ​24) and CSF (n ​= ​6) from healthy controls.
All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.
Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

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Front. Public Health, 21 August 2020 | https://doi.org/10.3389/fpubh.2020.00420
The Economic Impacts of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Australian Cohort
Shara Close1, Sonya Marshall-Gradisnik2*, Joshua Byrnes3, Peter Smith2, Son Nghiem3 and Don Staines2
  • 1Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
  • 2National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia
  • 3Centre for Applied Health Economics, Griffith University, Nathan, QLD, Australia
Objectives: This study aims to estimate direct and indirect health economic costs associated with government and out-of-pocket (OOP) expenditure based on health care service utilization and lost income of participants and carers, as reported by Australian Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patient survey participants.
Design: A cost of illness study was conducted to estimate Australian cost data for individuals with a ME/CFS diagnosis as determined by the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the 1994 CDC Criteria (Fukuda).
Setting and participants: Survey participants identified from a research registry database provided self-report of expenditure associated with ME/CFS related healthcare across a 1-month timeframe between 2017 and 2019.
Main outcome measures: ME/CFS related direct annual government health care costs, OOP health expenditure costs, indirect costs associated with lost income and health care service use patterns.
Results: The mean annual cost of health care related expenditure and associated income loss among survey participants meeting diagnostic criteria for ME/CFS was estimated at $14.5 billion. For direct OOP and Government health care expenditure, high average costs were related to medical practitioner attendance, diagnostics, natural medicines, and device expenditure, with an average attendance of 10.6 referred attendances per annum and 12.1 GP visits per annum related specifically to managing ME/CFS.
Conclusions: The economic impacts of ME/CFS in Australia are significant. Improved understanding of the illness pathology, diagnosis, and management, may reduce costs, improve patient prognosis and decrease the burden of ME/CFS in Australia.
Clin neurophysiological Prac. 2020; 5: 50–58.
Published online 2020 Feb 8. doi: 10.1016/j.cnp.2020.01.003  PMCID: PMC7044650 PMID: 32140630

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Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography
C. (Linda) M.C. van Campen,a,⁎ Freek W.A. Verheugt,b Peter C. Rowe,c and Frans C. Vissera
Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005).
Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.
Transl Med. 2020 Aug 15;18(1):314.    doi: 10.1186/s12967-020-02481-y.

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Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients
Jihyun Lee 1, Suzanne D Vernon 2, Patricia Jeys 1, Weam Ali 1, Andrea Campos 1, Derya Unutmaz 3, Brayden Yellman 1, Lucinda Bateman 1
  • PMID: 32799889 PMCID: PMC7429890 DOI: 10.1186/s12967-020-02481-y
Abstract
Background: Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.
Methods: A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years (< 4 ME/CFS) and 75 ME/CFS patients sick for more than 10 years (> 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups.
Results: At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The < 4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to > 10 ME/CFS and HCs. The < 4 ME/CFS group experienced significantly more OI symptoms compared to > 10 ME/CFS and HCs. The circulatory decompensation observed in the < 4 ME/CFS group was not related to age or medication use.
Conclusions: Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for < 4 years. This suggests inadequate ventricular filling from low venous pressure. The 10-minute NLT can be used to diagnose and treat the circulatory decompensation in this newly recognized subgroup of ME/CFS patients. The > 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.
Keywords: 10-minute NASA lean test; Circulatory decompensation; ME/CFS; Orthostatic intolerance; Point-of-care.

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Long covid”: the Dutch response
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3202 (Published 14 August 2020)Cite this as: BMJ 2020;370:m3202
  1. Jako Burgers, general practitioner
  2. j.burgers@nhg.org
Persisting symptoms after covid-191 is also recognised as a serious problem in the Netherlands, with many GPs treating these patients. People who have been seriously ill with covid-19 and are still having lung problems can register and share their experiences on the website of the Lung Fund (coronalongplein.nl). We estimate that the number of patients in the Netherlands with “long covid-19” is 10 000 to 20 000.
We have undertaken a series of actions to tackle this problem.
Firstly, we have developed rapid guidance to support clinicians in primary and secondary care in decision making about diagnosis and treatment. Because of a lack of evidence, most recommendations are based on expert opinion.
Secondly, the Dutch government has decided to reimburse physiotherapy, exercise therapy, ergotherapy, and dietetics in primary care to a maximum of six months. The results of individual treatment will be monitored and evaluated systematically.
Thirdly, research has started on follow-up of patients with covid-19 funded by the Netherlands Organisation for Health Research and Development. One of the research aims is to identify predictors of chronicity.
We hope that more evidence will soon become available on the large group of patients with covid-19 that have not been admitted to hospital. This will help to develop evidence based guidelines and to contribute to effective management of patients with persistent symptoms.

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Covid-19 and chronic fatigue
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2922 (Published 30 July 2020)Cite this as: BMJ 2020;370:m2922
  1. Article Frances M K Williams, professor of genomic epidemiology and honorary consultant rheumatologist1,  
  2. Nina Muirhead, dermatology surgeon2,  
  3. Carmine Pariante, professor of biological psychiatry3
  4. frances.williams@kcl.ac.uk
Salisbury’s article on patients with prolonged symptoms of covid-19 should be distributed to all healthcare practitioners.1 Chronic fatigue is an important and distressing symptom in rheumatic2 and other diseases3 as well as in the complex multisystem disease myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).4 It is poorly covered in many medical school curriculums. 

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DR Clin Trans Res. 2020 Jul;5(3):224-232. doi: 10.1177/2380084419872135. Epub 2019 Aug 28.
Brain Responses in CFS and TMD to Autonomic Challenges: An Exploratory fMRI Study
Q C Vuong 1, J R Allison 2, A Finkelmeyer 1, J Newton 3 4, J Durham 2 5 6       PMID: 31461628
 Abstract
Introduction: Dysfunction of the autonomic nervous system (ANS) is seen in chronic fatigue syndrome (CFS) and temporomandibular disorders (TMDs). Both conditions have poorly understood pathophysiology. Several brain structures that play a role in pain and fatigue, such as the insular cortex and basal ganglia, are also implicated in autonomic function.
Objectives: ANS dysfunction may point to common neurophysiologic mechanisms underlying the predominant symptoms for CFS and TMD. No studies to date have investigated the combination of both conditions. Thus, our aim was to test whether patients with CFS with or without TMD show differences in brain responses to autonomic challenges.
Methods: In this exploratory functional imaging study, patients with CFS who screened positive for TMD (n = 26), patients who screened negative for TMD (n = 16), and age-matched control participants (n = 10) performed the Valsalva maneuver while in a 3-T magnetic resonance imaging scanner. This maneuver is known to activate the ANS.
Results: For all 3 groups, whole-brain F test showed increased brain activation during the maneuver in the superior and inferior frontal gyri, the left and right putamen and thalamus, and the insular cortex. Furthermore, group contrasts with small-volume correction showed that patients with CFS who screened positive for TMD showed greater activity in the left insular cortex as compared with patients who screened negative and in the left caudate nucleus as compared with controls.
Conclusion: Our results suggest that increased activity in the cortical and subcortical regions observed during autonomic challenges may be modulated by fatigue and pain. ANS dysfunction may be a contributing factor to these findings, and further work is required to tease apart the complex relationship among CFS, TMD, and autonomic functions.
Knowledge transfer statement: Brain activity related to activation of the autonomic nervous system in patients with chronic fatigue syndrome who screened positive for painful temporomandibular disorder was greater than in patients who screened negative; activity was seen in brain regions associated with autonomic functions and pain. These findings suggest that autonomic dysfunction may play a role in the pathophysiology of both conditions, explain some of the apparent comorbidity between them, and offer avenues to help with treatment.

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Living with covid-19
Fiona Godlee, The BMJ  Aug 2020
“Death is not the only adverse outcome of covid-19,” writes Nisreen Alwan, an epidemiologist who is experiencing a range of prolonged, fluctuating, and debilitating symptoms several months after her initial mild illness.1 Like a growing number of people around the world, she has what is being called post-acute or long covid.
While most people recover quickly and completely from the virus, stories of persistent and troubling symptoms have now moved from anecdote to the evidence of crowd sourced cohorts. Reports suggest that one in three people have not fully recovered several weeks after initial illness. A smaller but still substantial proportion have symptoms and difficulties that persist for months. These are not people who have been seriously ill in hospital, whose difficult journey to recovery is better understood.2 These are often physically fit, younger people who report persistent exercise intolerance, breathlessness and cough,3 anxiety, palpitations, and poor concentration. Paul Garner describes boom and bust—the illusion of recovery only to fall back into mental and physical exhaustion.4 These false dawns add to the burden for “long haulers,” he says, which for him includes intense fatigue, mood swings, muscle and joint pains, headaches, and brain fog.
One of the most distressing aspects of living with long covid, says Garner, is the dismissive attitude of some doctors. This may change as more doctors find themselves affected. So how should doctors respond to their patients struggling with this complex and worrying multisystem disorder? Trish Greenhalgh and colleagues recommend taking a whole person, pragmatic approach with symptom management that avoids overinvestigation.5 With so much uncertainty about the cause and course of long covid, a doctor’s key role is to be a witness, they say, “‘honouring the story’ of the patient whose protracted recovery is unexpected, alarming, and does not make sense.”
The challenge for those in charge of our public health response to covid-19 is to make sense of this emergent information. Policies and messaging must now reflect the risks to younger people of developing prolonged illness and multiple organ damage, especially in light of other new information about the risks of airborne transmission.67 For this, we need to be able to quantify the risks through proper population surveillance and to mitigate them with effective systems of rapid testing, tracing, isolation, and support.8 In the UK, at least, such crucial traditional public health approaches still seem a long way off.9
Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest

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Brain, Behaviour and Immunity Vol:7 Aug 2020 100107
Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts
Author links open overlay panel  AnnieBynkeabPerJulincdCarl-GerhardGottfrieseHaraldHeideckefCarmenScheibenbogengJonasBergquistab
https://doi.org/10.1016/j.bbih.2020.100107Get rights and content
Highlights
Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear aetiology and no clear diagnostic biomarker available.
This study support the existance of a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.
Abstract
Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.
This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.
We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n ​= ​24), only plasma from the second cohort (n ​= ​24) together with plasma samples (n ​= ​24) and CSF (n ​= ​6) from healthy controls.
All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.
Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

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Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Eun-Jin Lim & Chang-Gue Son 
Journal of Translational Medicine volume 18, Article number: 289 (2020)  
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown causes. From the perspectives on the etiology and pathophysiology, ME/CFS has been labeled differently, which influenced changes in case definitions and terminologies. This review sought to feature aspects of the history, developments, and differential symptoms in the case definitions.
Methods
A search was conducted through PubMed published to February 2020 using the following search keywords: case definition AND chronic fatigue syndrome [MeSH Terms]. All reference lists of the included studies were checked. Of the included studies, the number of citations and the visibility in the literatures of the definitions were considered for comparisons of the criteria.
Results
Since the first 'ME' case definition was developed in 1986, 25 case definitions/diagnostic criteria were created based on three conceptual factors (etiology, pathophysiology, and exclusionary disorders). These factors can be categorized into four categories (ME, ME/CFS, CFS, and SEID) and broadly characterized according to primary disorder (ME-viral, CFS-unknown, ME/CFS-inflammatory, SEID-multisystemic), compulsory symptoms (ME and ME/CFS-neuroinflammatory, CFS and SEID-fatigue and/or malaise), and required conditions (ME-infective agent, ME/CFS, CFS, SEID-symptoms associated with fatigue, e.g., duration of illness). ME and ME/CFS widely cover all symptom categories, while CFS mainly covers neurologic and neurocognitive symptoms. Fatigue, cognitive impairment, PEM, sleep disorder, and orthostatic intolerance were the overlapping symptoms of the 4 categories, which were included as SEID criteria.
Conclusions
This study comprehensively described the journey of the development of case definitions and compared the symptom criteria. This review provides broader insights and explanations to understand the complexity of ME/CFS for clinicians and researchers.
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Front Neurosci : 2020 Jun 26;14:688.  doi: 10.3389/fnins.2020.00688. eCollection 2020.
Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
C Linda M C van Campen 1, Peter C Rowe 2, Freek W A Verheugt 3, Frans C Visser 1
PMID: 32670016 PMCID: PMC7332734 DOI: 10.3389/fnins.2020.00688
Abstract
Introduction: Orthostatic intolerance (OI) is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction has been demonstrated during head-up tilt testing (HUT) in those with ME/CFS: worse scores on cognitive tests occur with increasing tilt angles and increasing complexity of the cognitive challenge. The aim of our study was to determine whether cognitive impairment persists after completion of HUT.
Methods and results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome.
Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.


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Empty mast cell syndrome: fallacy or fact?
Journal of Clinical Pathology   vol 73 Issue 5 
http://orcid.org/0000-0001-9102-278X Omar E Mohamed1,Richard L Baretto1, Ian Walker2, 
Cathryn Melchior1, Jane Heslegrave1, Ruth Mckenzie2, Chidanand Hullur2, Anjali Ekbote1, 
Mamidipudi Thirumala Krishna1,3
Abstract
Post-anaphylaxis mast cell anergy (PAMA), commonly referred to as ‘empty mast cell (MC) syndrome’, is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4–6 weeks postanaphylaxis to avoid false-negative results.
This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified.
View Full Text
http://dx.doi.org/10.1136/jclinpath-2019-206157

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Paediatric patients with myalgic encephalomyelitis/chronic fatigue syndrome value understanding and help to move on with their lives
Katherine Rowe
First published:18 December 2019  ACTA Paediatrica
 
https://doi.org/10.1111/apa.15054
Abstract
Aim
The aim of this study was to document qualitative questionnaire feedback regarding management from a cohort observational study of young people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods
Between 1991 and 2009, 784 paediatric patients, age 6‐18 years, were diagnosed with ME/CFS following referral to a specialised clinic at the Royal Children's Hospital, Melbourne. Over a 14‐year period, feedback was requested on up to seven occasions.
Management included the following: symptom management and a self‐management lifestyle plan that included social, educational, physical and a pleasurable activity outside of home. They adjusted it by severity of illness, stage of education, family circumstances and life interests.
Results
Questionnaires were returned from 626 (80%) with 44% providing feedback more than once. They reported that their management plan allowed them to regain control over their lives. They cited early diagnosis, empathetic, informed physicians, self‐management strategies and educational liaison as helping them to function and remain socially engaged. Ongoing support, particularly assistance to navigate the education system, was essential for general well‐being and ability to cope.
Conclusion
Young people valued regaining the control over their lives that was lost through illness, support to maintain social contacts and assistance to achieve educational and/or life goals.
Key Notes
  • A cohort observational study of 784 young people with myalgic encephalomyelitis/chronic fatigue syndrome provided feedback across a 14‐year period regarding helpful strategies and ways to improve management.
  • Early diagnosis, empathetic informed physicians, assistance with symptom control, self‐management strategies, educational liaison and advocacy enabled them to regain control, remain socially engaged and function optimally.
  • Doctors and teachers awareness of helpful strategies could significantly reduce distress with this illness.
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2020 Apr 10;15(4):e0231136. doi: 10.1371/journal.pone.0231136. eCollection 2020.PLoS one
The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function.
Tomas C1, Elson JL1,2, Strassheim V3, Newton JL1,3, Walker M1.
Abstract
Myalgic encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) has been associated with abnormalities in mitochondrial function. In this study we have analysed previous bioenergetics data in peripheral blood mononuclear cells (PBMCs) using new techniques in order to further elucidate differences between ME/CFS and healthy control cohorts. We stratified our ME/CFS cohort into two individual cohorts representing moderately and severely affected patients in order to determine if disease severity is associated with bioenergetic function in PBMCs. Both ME/CFS cohorts showed reduced mitochondrial function when compared to a healthy control cohort. This shows that disease severity does not correlate with mitochondrial function and even those with a moderate form of the disease show evidence of mitochondrial dysfunction. Equations devised by another research group have enabled us to calculate ATP-linked respiration rates and glycolytic parameters. Parameters of glycolytic function were calculated by taking into account respiratory acidification. This revealed severely affected ME/CFS patients to have higher rates of respiratory acidification and showed the importance of accounting for respiratory acidification when calculating parameters of glycolytic function. Analysis of previously published glycolysis data, after taking into account respiratory acidification, showed severely affected patients have reduced glycolysis compared to moderately affected patients and healthy controls. Rates of ATP-linked respiration were also calculated and shown to be lower in both ME/CFS cohorts. This study shows that severely affected patients have mitochondrial and glycolytic impairments, which sets them apart from moderately affected patients who only have mitochondrial impairment. This may explain why these patients present with a more severe phenotype.
10.1371/journal.pone.0231136

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Journal of Cellular and Molecular medicine
 Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender‐specific changes in the microRNA expression profiling in ME/CFS
Amanpreet K. Cheema,Leonor Sarria,Mina Bekheit,Fanny Collado, Eloy Almenar‐Pérez, Eva Martín‐Martínez, Jose Alegre, Jesus Castro‐Marrero, Mary A. Fletcher, Nancy G. Klimas 
First published:14 April 2020
 
https://doi.org/10.1111/jcmm.15260
Funding information:
This study was supported by NIH awards 1R15NS087604‐01A1, 1R21AI124187‐01 and Presidential Faculty Research and Development Grant from Nova Southeastern University (all awarded to LN). We are grateful to all the participants who took part in the studies. The study used PBMC samples collected under CDMRP award W81XWH‐09‐2‐0071 (PI: NK), NIH awards 5R01NS090200‐02 (PI: MAF) and 5R01AR057853‐04 (PI: NK), UCV‐2019‐270‐001 (PI: EO) and Catalonia Association for Fibromyalgia, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Environmental Sensitivities/Multiple Chemical Sensitivity (ACAF, www.fibromialgia.cat). The sponsors had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by either by the Department of Defense or National Institute of Health.
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Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
  • Eloy Almenar-Pérez, Leonor Sarría, Lubov Nathanson & Elisa Oltra 
Scientific Reports volume 10, Article number: 2064 (2020)
2099 Accesses 79 Altmetric   Published: 07 February 2020


Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystemic disease of unknown etiology, affecting thousands of individuals worldwide. Its diagnosis still relies on ruling out medical problems leading to unexplained fatigue due to a complete lack of disease-specific biomarkers. Our group and others have explored the potential value of microRNA profiles (miRNomes) as diagnostic tools for this disease. However, heterogeneity of participants, low numbers, the variety of samples assayed, and other pre-analytical variables, have hampered the identification of  disease-associated miRNomes. In this study, our team has evaluated, for the first time, ME/CFS miRNomes in peripheral blood mononuclear cells (PBMCs) and extracellular vesicles (EVs) from severely ill patients recruited at the monographic UK ME biobank to assess, using standard operating procedures (SOPs), blood fractions with optimal diagnostic power for a rapid translation of a miR-based diagnostic method into the clinic. Our results show that routine creatine kinase (CK) blood values, plasma EVs physical characteristics (including counts, size and zeta-potential), and a limited number of differentially expressed PBMC and EV miRNAs appear significantly associated with severe ME/CFS (p < 0.05). Gene enrichment analysis points to epigenetic and neuroimmune dysregulated pathways, in agreement with previous reports. Population validation by a cost-effective approach limited to these few potentially discriminating variables is granted.

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Clinical Neurpophysiology Practice    Research paper  Vol 5 2020
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography
C. (Linda) M.C.van CampenaFreek W.A.VerheugtbPeter C.RowecFrans C.Vissera
https://doi.org/10.1016/j.cnp.2020.01.003Get rights and content
Highlights
Doppler imaging to measure cerebral blood flow is feasible during tilt testing.
Cerebral blood flow in ME/CFS patients is reduced during tilt testing.
90% of ME/CFS patients show abnormal cerebral blood flow reduction on tilt testing.
Cerebral blood flow reduction correlates with symptoms of orthostatic intolerance.
Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005).
Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.

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An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients
by Daniel Missailidis 1,Sarah J. Annesley 1,Claire Y. Allan 1,Oana Sanislav 1,Brett A. Lidbury 2,
Department of Physiology, Anatomy, and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
National Centre for Epidemiology and Population Health, Research School of Population Health, Australian National University, Canberra, ACT 2601, Australia
Int. J. Mol. Sci. 2020, 21(3), 1074; https://doi.org/10.3390/ijms21031074
Received: 4 December 2019 / Revised: 2 February 2020 / Accepted: 4 February 2020 / Published: 6 February 2020
Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures) 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated 
Keywords: myalgic encephalomyelitis; chronic fa

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In-vivo imaging of neuroinflammation in veterans with Gulf War illness
Brain,Behaviour and Immunity   4.2.2020
ZeynabAlshelha1Daniel S.Albrechta1CourtneyBerganaOluwaseunAkejubDaniel ClauwcLisaConboydRobert R.EdwardseMinhaeKimaYvonne C.LeefEkaterinaProtsenkoaVitalyNapadowaeKimberlySullivangMarco L.Loggiaa
a
Received 17 October 2019, Revised 27 January 2020, Accepted 30 January 2020, Available online 4 February 2020.
https://doi.org/10.1016/j.bbi.2020.01.020Get rights and content
Highlights
Gulf war illness (GWI) is a chronic condition characterised by musculoskeletal pain, cognitive problems and fatigue.
Levels of translocator protein (TSPO), a marker of neuroinflammation, are increased in the brain of veterans with GWI.
These results support a role for neuroinflammation in GWI.
Abstract
Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes.
Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13).
Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines.
Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.

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020 Apr 1:102527. doi: 10.1016/j.autrev.2020.102527. [Epub ahead of print]
A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors.
Wirth K1, Scheibenbogen C2.
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.
Copyright © 2020. Published by Elsevier B.V.
PMID:32247028   DOI:10.1016/j.autrev.2020.102527

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Inj J  Mol Sci 2020 Feb 8;21(3). pii: E1142. doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Missailidis D1, Sanislav O1, Allan CY1, Annesley SJ1, Fisher PR1.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
KEYWORDS:
ME/CFS; Seahorse respirometry; TORC1; biomarker; chronic fatigue syndrome; complex V; diagnosis; mitochondria; myalgic encephalomyelitis

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Brain Imaging Behav 2020 Apr;14(2):562-572. doi: 10.1007/s11682-018-0029-4.
Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.
Mueller C1, Lin JC1, Sheriff S2, Maudsley AA2, Younger JW3.
Author information
Abstract
Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.
KEYWORDS:
Anterior cingulate; Brain temperature; Chronic fatigue syndrome; Magnetic resonance spectroscopy; Metabolites; Neuroinflammation
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J Translational Med 2020 Apr 19;18(1):173. doi: 10.1186/s12967-020-02341-9.
Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome.
Jammes Y1,2, Adjriou N1, Kipson N1, Criado C1, Charpin C2, Rebaudet S2, Stavris C2, Guieu R1, Fenouillet E1,3, Retornaz F4.
Abstract
BACKGROUND:
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.
METHODS:
Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.
RESULTS:
Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.
CONCLUSIONS:
Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS. Trial registration Ethics Committee "Ouest II" of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.

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Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies
Front. Med., 31 March 2020 | https://doi.org/10.3389/fmed.2020.00108
Isabell Nilsson1, Jeremy Palmer2, Eirini Apostolou1, Carl-Gerhard Gottfries3, Muhammad Rizwan1, Charlotte Dahle1 and Anders Rosén1*
  • 1Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
  • 2The Medical School, The University Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • 3The Gottfries Clinic AB, Mölndal, Sweden
Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function. We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors. In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes.

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Risk Factors for Bites and Diseases Associated With Black-legged Ticks
A Meta-Analysis
Ilya R. Fischhoff; Felicia Keesing; Richard S. Ostfeld
Am J Epidemiol. 2019;188(9):1742-1750. 
Abstract
The emergence and spread of Lyme disease and other infections associated with black-legged ticks is causing a public health crisis. No human vaccines are currently available, and both diagnosis and treatment are sometimes ineffectual, leading to advocacy for self-directed preventative measures. These recommendations are widely communicated to the public, but there is limited evidence for their efficacy. We undertook a systematic review and mixed-effects meta-regression analysis of factors purported to increase or decrease risk of black-legged tick bites and tick-borne disease. Published articles used in the study spanned the years 1984–2018. Variables associated with increased probability of tick-borne disease, with odds ratios significantly greater than 1, included deer abundance, high density of nymph-stage black-legged ticks, landscapes with interspersed herbaceous and forested habitat, low human population density, gardens, cat ownership, and race. Contrary to recommendations, use of landscape-related tick control measures, such as clearing brush, trimming branches, and having a dry barrier between lawn and woods, tended to increase risk. Pet ownership increased bite risk. Bite risk was highest for children aged 5 years or less, with a secondary peak in persons aged 50–70 years. Although some widely disseminated recommendations are supported by the research analyzed, others require further evaluation. Additional research is also needed to understand the mechanisms underlying significant relationships.
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International Journal for Molecular Sciences 2020 Feb 8;21(3):1142.
 doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Daniel Missailidis 1, Oana Sanislav 1, Claire Y Allan 1, Sarah J Annesley 1, Paul R Fisher 1
  • PMID: 32046336  PMCID: PMC7037777  DOI: 10.3390/ijms21031142
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
Keywords: ME/CFS; Seahorse respirometry; TORC1; biomarker; chronic fatigue syndrome; complex V; diagnosis; mitochondria; myalgic encephalomyelitis.
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Front Immunol. 2020; 11: 578.
Published online 2020 Apr 9. doi: 10.3389/fimmu.2020.00578
PMCID: PMC7161310   PMID: 32328064
Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset
Sophie Steiner,1 Sonya C. Becker,1† Jelka Hartwig,1 Franziska Sotzny,1 Sebastian Lorenz,1 Sandra Bauer,1 Madlen Löbel,2 Anna B. Stittrich,3,4 Patricia Grabowski,1 and Carmen Scheibenbogen1,3,*
Author information Article notes Copyright and License information Disclaimer
Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p = 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.
Keywords: single nucleotide polymorphism (SNP), tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interferon regulatory factor 5 (IRF5), tumor necrosis factor (TNF), myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), autoimmunity

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A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques
Rebekah Maksoud ,Stanley du Preez,Natalie Eaton-Fitch,Kiran Thapaliya,Leighton Barnden,
Hélène Cabanas,Donald Staines,Sonya Marshall-Gradisnik
  • Published: April 30, 2020
  • https://doi.org/10.1371/journal.pone.0232475
Abstract
Background
Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction. The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.
Methods
A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.
Results
A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.
Conclusions
The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.

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Front. Med., 29 April 2020 | https://doi.org/10.3389/fmed.2020.00162
Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study
Ingrid G. Rekeland1, Alexander Fosså2, Asgeir Lande3, Irini Ktoridou-Valen1, Kari Sørland1, Mari Holsen4, Karl J. Tronstad5, Kristin Risa1, Kine Alme1, Marte K. Viken3,6, Benedicte A. Lie3,6, Olav Dahl5, Olav Mella1,5 and Øystein Fluge1,5*
  • 1Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
  • 2Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
  • 3Department of Medical Genetics, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway
  • 4Clinical Research Unit, Haukeland University Hospital, Bergen, Norway
  • 5Department of Biomedicine, University of Bergen, Bergen, Norway
  • 6Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway
Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.
Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.
Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.
Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.

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Brain Behav Immun. 2018 Oct;73:520-532. doi: 10.1016/j.bbi.2018.06.017. Epub 2018 Jun 20.
Sustained Stimulation of β 2- And β 3-adrenergic Receptors Leads to Persistent Functional Pain and Neuroinflammation
Xin Zhang 1, Jane E Hartung 2, Andrey V Bortsov 3, Seungtae Kim 4, Sandra C O'Buckley 3, Julia Kozlowski 3, Andrea G Nackley 5
  • PMID: 29935309    PMCID: PMC6129429   DOI: 10.1016/j.bbi.2018.06.017
Abstract
Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral β2- and β3-adrenergic receptors (β2- and β3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Here, we first sought to investigate the role of β2- and β3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The β2AR antagonist ICI118551 and β3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1β, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral β2- and β3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.
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ESC Heart Fail   . 2020 Jun;7(3):1064-1071. doi: 10.1002/ehf2.12633. Epub 2020 Mar 10.
Peripheral Endothelial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Nadja Scherbakov 1 2 3 4, Marvin Szklarski 5, Jelka Hartwig 5, Franziska Sotzny 5, Sebastian Lorenz 5, Antje Meyer 1 3 4, Patricia Grabowski 5, Wolfram Doehner 1 2 3 4, Carmen Scheibenbogen 1 5
  • PMID: 32154656 PMCID: PMC7261521 DOI: 10.1002/ehf2.12633
Abstract
Aims: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disease. Evidence for disturbed vascular regulation comes from various studies showing cerebral hypoperfusion and orthostatic intolerance. The peripheral endothelial dysfunction (ED) has not been sufficiently investigated in patients with ME/CFS. The aim of the present study was to examine peripheral endothelial function in patients with ME/CFS.
Methods and results: Thirty-five patients [median age 40 (range 18-70) years, mean body mass index 23.8 ± 4.2 kg/m2 , 31% male] with ME/CFS were studied for peripheral endothelial function assessed by peripheral arterial tonometry (EndoPAT2000). Clinical diagnosis of ME/CFS was based on Canadian Criteria. Nine of these patients with elevated antibodies against β2-adrenergic receptor underwent immunoadsorption, and endothelial function was measured at baseline and 3, 6, and 12 months follow-up. ED was defined by reactive hyperaemia index ≤1.81. Twenty healthy subjects of similar age and body mass index were used as a control group. Peripheral ED was found in 18 of 35 patients (51%) with ME/CFS and in 4 healthy subjects (20%, P < 0.05). Patients with ED, in contrast to patients with normal endothelial function, reported more severe disease according to Bell score (31 ± 12 vs. 40 ± 16, P = 0.04), as well as more severe fatigue-related symptoms (8.62 ± 0.87 vs. 7.75 ± 1.40, P = 0.04) including a higher demand for breaks [9.0 (interquartile range 7.0-10.0) vs. 7.5 (interquartile range 6.0-9.25), P = 0.04]. Peripheral ED showed correlations with more severe immune-associated symptoms (r = -0.41, P = 0.026), such as sore throat (r = -0.38, P = 0.038) and painful lymph nodes (r = -0.37, P = 0.042), as well as more severe disease according to Bell score (r = 0.41, P = 0.008) and symptom score (r = -0.59, P = 0.005). There were no differences between the patient group with ED and the patient group with normal endothelial function regarding demographic, metabolic, and laboratory parameters. Further, there was no difference in soluble vascular cell adhesion molecule and soluble intercellular adhesion molecule levels. At baseline, peripheral ED was observed in six patients who underwent immunoadsorption. After 12 months, endothelial function had improved in five of these six patients (reactive hyperaemia index 1.58 ± 0.15 vs. 2.02 ± 0.46, P = 0.06).
Conclusions: Peripheral ED is frequent in patients with ME/CFS and associated with disease severity and severity of immune symptoms. As ED is a risk factor for cardiovascular disease, it is important to elucidate if peripheral ED is associated with increased cardiovascular morbidity and mortality in ME/CFS.
Keywords: Cardiovascular risk factor; Chronic fatigue syndrome; Immune score; Peripheral endothelial dysfunction; Reactive hyperaemia index.
© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Philipp Schreiner,* Thomas Harrer,† Carmen Scheibenbogen,‡ Stephanie Lamer,§ Andreas Schlosser,§ Robert K. Naviaux,{ and Bhupesh K. Prusty*,
ImmunoHorizons 2020, 4 (4) 201-215
ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, Received for publication January 21, 2020. Accepted for publication April 5, 2020

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A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID)
  • Teilah Kathryn Huth, Natalie Eaton-Fitch, Donald Staines & Sonya Marshall-Gradisnik 
Journal of Translational Medicine volume 18, Article number: 198 (2020) Cite this article
Abstract
Background
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID) is a complex illness that has an unknown aetiology. It has been proposed that metabolomics may contribute to the illness pathogenesis of CFS/ME/SEID. In metabolomics, the systematic identification of measurable changes in small molecule metabolite products have been identified in cases of both monogenic and heterogenic diseases. Therefore, the aim of this systematic review was to evaluate if there is any evidence of metabolomics contributing to the pathogenesis of CFS/ME/SEID.
Methods
PubMed, Scopus, EBSCOHost (Medline) and EMBASE were searched using medical subject headings terms for Chronic Fatigue Syndrome, metabolomics and metabolome to source papers published from 1994 to 2020. Inclusion and exclusion criteria were used to identify studies reporting on metabolites measured in blood and urine samples from CFS/ME/SEID patients compared with healthy controls. The Joanna Briggs Institute Checklist was used to complete a quality assessment for all the studies included in this review.
Results
11 observational case control studies met the inclusion criteria for this review. The primary outcome of metabolite measurement in blood samples of CFS/ME/SEID patients was reported in ten studies. The secondary outcome of urine metabolites was measured in three of the included studies. No studies were excluded from this review based on a low-quality assessment score, however there was inconsistency in the scientific research design of the included studies. Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent.
Conclusion
The findings of this systematic review reports that a lack of consistency with scientific research design provides little evidence for metabolomics to be clearly defined as a contributing factor to the pathogenesis of CFS/ME/SEID. Further research using the same CFS/ME/SEID diagnostic criteria, metabolite analysis method and control of the confounding factors that influence metabolite levels are required.
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2020 Apr 7;8(2):E88.       doi: 10.3390/healthcare8020088.
The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report From the European Network on ME/CFS (EUROMENE)
Derek F H Pheby 1, Diana Araja 2, Uldis Berkis 3, Elenka Brenna 4, John Cullinan 5, Jean-Dominique de Korwin 6 7, Lara Gitto 8, Dyfrig A Hughes 9, Rachael M Hunter 10, Dominic Trepel 11 12, Xia Wang-Steverding 13
  • PMID: 32272608
  • DOI: 10.3390/healthcare8020088
Abstract
We have developed a Europe-wide approach to investigating the economic impact of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), facilitating acquisition of information on the economic burden of ME/CFS, and international comparisons of economic costs between countries. The economic burden of ME/CFS in Europe appears large, with productivity losses most significant, giving scope for substantial savings through effective prevention and treatment. However, economic studies of ME/CFS, including cost-of-illness analyses and economic evaluations of interventions, are problematic due to different, arbitrary case definitions, and unwillingness of doctors to diagnose it. We therefore lack accurate incidence and prevalence data, with no obvious way to estimate costs incurred by undiagnosed patients. Other problems include, as for other conditions, difficulties estimating direct and indirect costs incurred by healthcare systems, patients and families, and heterogeneous healthcare systems and patterns of economic development across countries. We have made recommendations, including use of the Fukuda (CDC-1994) case definition and Canadian Consensus Criteria (CCC), a pan-European common symptom checklist, and implementation of prevalence-based cost-of-illness studies in different countries using an agreed data list. We recommend using purchasing power parities (PPP) to facilitate international comparisons, and EuroQol-5D as a generic measure of health status and multi-attribute utility instrument to inform future economic evaluations in ME/CFS.
Keywords: ME/CFS; cost-of-illness studies; economic evaluation; economic impact; healthcare systems.

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2020 Mar 5.
 Trans Biomed Eng:   doi: 10.1109/TBME.2020.2978801. Online ahead of print.
Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach
Divesh Deepak Pednekar, Md Rafiul Amin, Hamid Fekri Azgomi, Kirstin Aschbacher, Leslie J Crofford, Rose T Faghih
  • PMID: 32149617     DOI: 10.1109/TBME.2020.2978801
Abstract
Objective: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies. The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.
Methods: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).
Results: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model. Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients. During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.
Conclusion: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects. As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events. Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.
Significance: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.

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Eng Med Biol Soc. 2019 Jul;2019:6896-6901.    doi: 10.1109/EMBC.2019.8857427.
A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients With Chronic Fatigue
Divesh Deepak Pednekar, Md Rafiul Amin, Hamid Fekri Azgomi, Kirstin Aschbacher, Leslie J Crofford, Rose T Faghih
  • PMID: 31947425     
Abstract
Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates. The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously. Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.

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ORIGINAL RESEARCH ARTICLE
Front. Neurosci., 26 June 2020 | https://doi.org/10.3389/fnins.2020.00688
Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
(Linda) M. C. van Campen1*, Peter C. Rowe2, Freek W. A. Verheugt3 and Frans C. Visser1
  • 1Stichting CardioZorg, Hoofddorp, Netherlands
  • 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
  • 3Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
Introduction: Orthostatic intolerance (OI) is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction has been demonstrated during head-up tilt testing (HUT) in those with ME/CFS: worse scores on cognitive tests occur with increasing tilt angles and increasing complexity of the cognitive challenge. The aim of our study was to determine whether cognitive impairment persists after completion of HUT.
Methods and Results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome.
Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.

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    •    Published: 05 June 2020
Health-related quality of life in Norwegian adolescents living with chronic fatigue syndrome
Wenche Ann Similä, Vidar Halsteinli, Ingrid B. Helland, Christer Suvatne, Hanna Elmi & Torstein Baade Rø 
Health and Quality of Life Outcomes volume 18, Article number: 170 (2020)  
Abstract
Purpose
The primary aim was to measure health related quality of life (HRQoL) in a Norwegian cohort of adolescents with Chronic Fatigue Syndrome (CFS/ME). A secondary aim was to identify factors before diagnosis, at time of diagnosis and after diagnosis that were associated with HRQoL.
Methods
In this cross-sectional population-based study, HRQoL was measured by Pediatric Quality of Life Inventory™ Generic Core scale version 4.0 (PedsQL4.0) in 63 adolescents with CFS/ME. In addition, fatigue was measured by PedsQL Multidimensional Fatigue scale (PedsQL-MFS), depressive symptoms were measured by the Short Mood and Feelings Questionnaire (SMFQ), and disruption in school activities was measured by The De Paul Pediatric Health Questionnaire (DPHQ-N). Data were also collected from medical records and patient interviews.
Results
Age at diagnosis was 15 (2) years (mean (SD)), and four out of five participants were female. Time from diagnosis to reply was 39 (22) months. Adolescents with CFS/ME reported PedsQL4.0 score 50 (17), and boys reported a better score than girls (64 vs 47, 95% Confidence Interval (CI) for difference (− 27; − 6)). There were positive associations between overall HRQoL and support from a schoolteacher, school attendance or participation in leisure activities. There were negative associations between overall HRQoL and delayed school progression, having been to rehabilitation stay and depressive symptoms.
Conclusion
HRQoL in adolescents diagnosed with CFS/ME was low. The associations between reported HRQoL, healthcare previously provided, support from a schoolteacher, school attendance and participation in leisure activity may provide information of value when developing refined strategies for healthcare among adolescents with CFS/ME. Possible causal relationships must however be explored in future studies.
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Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology
by Fernando Estévez-López 1,*,Kathleen Mudie 2,‡,Xia Wang-Steverding 3,‡,Inger Johanne Bakken 4,Andrejs Ivanovs 5,Jesús Castro-Marrero 6,Luis Nacul 2,Jose Alegre 6,Paweł Zalewski 7,Joanna Słomko 7,Elin Bolle Strand 8,9,Derek Pheby 10,Evelina Shikova 11,Lorenzo Lorusso 12,Enrica Capelli 13,Slobodan Sekulic 14,Carmen Scheibenbogen 15,Nuno Sepúlveda 2,16,Modra Murovska 17,† andEliana Lacerda 2,†,§ on behalf of The European Network on ME/CFS (EUROMENE)
Abstract
This review aimed at determining the prevalence and incidence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe. We conducted a primary search in Scopus, PubMed and Web of Science for publications between 1994 and 15 June 2019 (PROSPERO: CRD42017078688). Additionally, we performed a backward-(reference lists) and forward-(citations) search of the works included in this review. Grey literature was addressed by contacting all members of the European Network on ME/CFS (EUROMENE). Independent reviewers searched, screened and selected studies, extracted data and evaluated the methodological and reporting quality. For prevalence, two studies in adults and one study in adolescents were included. Prevalence ranged from 0.1% to 2.2%. Two studies also included incidence estimates. In conclusion, studies on the prevalence and incidence of ME/CFS in Europe were scarce. Our findings point to the pressing need for well-designed and statistically powered epidemiological studies. To overcome the shortcomings of the current state-of-the-art, EUROMENE recommends that future research is better conducted in the community, reviewing the clinical history of potential cases, obtaining additional objective information (when needed) and using adequate ME/CFS case definitions; namely, the Centers for Disease Control & Prevention−1994, Canadian Consensus Criteria, or Institute of Medicine criteria.
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Metabolites. 2020 Jan 14;10(1). pii: E34. doi: 10.3390/metabo10010034.
Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids.
Germain A1, Barupal DK2, Levine SM2, Hanson MR2.
Abstract
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.
KEYWORDS:
ME/CFS; acyl cholines; dipeptides; lipids; metabolomics; steroids
PMID:31947545
 
DOI:10.3390/metabo10010034

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    •    Original Paper  Published: 23 January 2020
The Prevalence of Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in a Community-Based Sample
  • Leonard A. Jason, Ben Z. Katz, Madison Sunnquist, Chelsea Torres, Joseph Cotler & Shaun Bhatia 
Child & Youth Care Forum (2020)C
Abstract
Background
Most pediatric prevalence studies of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been based upon data from tertiary care centers, a process known for systematic biases such as excluding youth of lower socioeconomic status and those less likely to have access to health care. In addition, most pediatric ME/CFS epidemiologic studies have not included a thorough medical and psychiatric examination. The purpose of this study was to determine the prevalence of pediatric ME/CFS from an ethnically and sociodemographically diverse community-based random sample.
Method
A sample of 10,119 youth aged 5–17 from 5622 households in the Chicagoland area were screened. Following evaluations, a team of physicians made final diagnoses. Youth were given a diagnosis of ME/CFS if they met criteria for three selected case definitions. A probabilistic, multi-stage formula was used for final prevalence calculations.
Results
The prevalence of pediatric ME/CFS was 0.75%, with a higher percentage being African American and Latinx than Caucasian. Of the youth diagnosed with ME/CFS, less than 5% had been previously diagnosed with the illness.
Conclusions
Many youth with the illness have not been previously diagnosed with ME/CFS. These findings point to the need for better ways to identify and diagnose youth with this illness.

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Open Access:  Published: 22 January 2020
Health-related quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndrome: an Australian cross-sectional study
N. Eaton-Fitch, S. C. Johnston, P. Zalewski, D. Staines & S. Marshall-Gradisnik 
Quality of Life Research (2020) 
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS.
Methods
Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL.
Results
Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties.
Conclusion
This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.

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Int J Mol Sci. 2020 Feb 8;21(3). pii: E1142. doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Missailidis D, Sanislav O, Allan CY, Annesley SJ, Fisher PR.


Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1).


These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity.


This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
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Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography
Clinical Neurophysiology Practice 8.2.20
C. (Linda) M.C.van CampenaFreek W.A.VerheugtbPeter C.RowecFrans C.Vissera
https://doi.org/10.1016/j.cnp.2020.01.003Get rights and content
Extracranial Doppler technique to measure cerebral blood flow is feasible during head-up tilt testing.
Cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients is reduced during head-up tilt testing compared to healthy volunteers.
Using a lower limit of normal of the cerebral blood flow reduction during head-up tilt testing of 13%, 90 percent of ME/CFS patients showed an abnormal cerebral blood flow reduction.
Reduction in cerebral blood flow is correlated with symptoms of orthostatic intolerance.
Abstract: The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods: 429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results: End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P<.0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P<.0005).
Conclusions: During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance: This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.
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Post-exertional malaise is associated with greater symptom burden and psychological distress in patients diagnosed with Chronic Fatigue Syndrome
Journal of Psychosomatic Research   Volume 129, February 2020, 109893


MarcellaMayaSara F.MilradbDolores M.PerdomoaSara J.CzajacMary AnnFletcherdDevika R.JutagireDaniel L.HallfNancyKlimasdMichael H.Antonia
https://doi.org/10.1016/j.jpsychores.2019.109893Get rights and content
Patients high in PEM endorse greater symptom burden than those low in PEM.
Patients high in PEM endorse greater psychological adversity than those low in PEM.
Results suggest the Fukuda case definition does not define a heterogeneous group.
PEM may identify patients who would most benefit from psychological intervention.
Abstract
Objective
Post-exertional malaise (PEM) is often considered a cardinal symptom of Chronic Fatigue Syndrome (CFS). There is no gold standard diagnostic method for CFS, however, and the Centers for Disease Control (CDC) Fukuda case definition does not require PEM. Research has identified differences in symptom burden between patients according to PEM, but whether it is associated with psychological distress has not been investigated.
Methods The CDC CFS Inventory, Fatigue Symptom Inventory, Profile of Mood States, Center for Epidemiologic Studies Depression Scale, Perceived Stress Scale, and subscales of the Sickness Impact Profile were administered to 261 patients diagnosed with the Fukuda criteria. PEM status (loPEM/hiPEM) was determined via self-reported post-exertional fatigue severity. Analyses of covariance (ANCOVA), controlling for age and gender, assessed cross-sectional group differences, and cross-sectional linear regressions using the continuous PEM severity predictor paralleled these analyses.
Results     hiPEM patients reported greater symptom intensity, frequency, and interference than loPEM counterparts (p's < .001). hiPEM patients also reported greater social disruption, depressive symptoms, and mood disturbance (p's ≤ .011). Groups did not differ in recent negative life experiences, perceived stress, or demographic variables. The results of regression analyses mirrored those of ANCOVAs.
Conclusion    This study replicates the association between PEM and symptom burden and additionally associates PEM with psychological distress; psychological distress could, however, be a consequence of symptom burden. Differences between hiPEM and loPEM CFS patients highlight the heterogeneity of diagnoses resulting from the Fukuda criteria. It is also possible that PEM identifies particularly distressed patients for whom psychological intervention would be most beneficial. 
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Maximal handgrip strength can predict maximal physical performance in patients with chronic fatigue.
Jammes Y1, Stavris C2, Charpin C2, Rebaudet S2, Lagrange G2, Retornaz F3.
Clin Biomech (Bristol, Avon). 2020 Jan 9;73:162-165. doi: 10.1016/j.clinbiomech.2020.01.003
Abstract
BACKGROUND:
Maximal handgrip strength is used to predict exercise performance in healthy older subjects and in patients with chronic obstructive pulmonary disease, breast cancer or cirrhosis. Our objective was to evaluate the ability of maximal handgrip strength to predict maximal exercise performance in patients with chronic fatigue.
METHODS:
Sixty-six patients with myalgic encephalomyelitis/chronic fatigue syndrome and 32 patients with chronic fatigue but no diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome were included. The maximal physical performance was measured on a cycle ergometer to measure the peak oxygen uptake and the maximal work rate. We searched for linear regressions between maximal handgrip strength and maximal performances.
FINDINGS:
No significant differences in slopes and ordinates of regression lines were noted between patients with or without a diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome, allowing to pool the data. Maximal handgrip strength was significantly and positively correlated with peak oxygen uptake and maximal work rate in all patients with chronic fatigue.
INTERPRETATION:
We conclude that handgrip strength can predict maximal exercise performance in patients with chronic fatigue.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Olli Polo,Pia Pesonen &Essi Tuominen
Pages 207-217 | Received 13 Sep 2019, Accepted 11 Nov 2019, Published online: 19 Nov 2019
  • https://doi.org/10.1080/21641846.2019.1692770
 ABSTRACT
Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.
Methods: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.
Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.
Conclusions: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.
KEYWORDS: Chronic fatigue syndrome, myalgic encephalomyelitis, naltrexone, therapy, pharmacology
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BMJ Case Reports
Vol 13 Issue 1.
Case report
Low-dose naltrexone as a treatment for chronic fatigue syndrome
 
  • http://orcid.org/0000-0002-7972-1841Monica Jane Bolton1, 
  • Bryan Paul Chapman2 and 
  • Harm Van Marwijk3
Abstract
Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn’s disease, fibromyalgia and Gulf War Illness. Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances. This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg. Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available.
http://creativecommons.org/licenses/by-nc/4.0/
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Int J Mol Sci   2020 Feb 6;21(3). pii: E1074. doi: 10.3390/ijms21031074.
An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients.
Missailidis D1, Annesley SJ1, Allan CY1, Sanislav O1, Lidbury BA2, Lewis DP, Fisher PR1.
Author information
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or "PEM"), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and "proton leak" as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to "normal" in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.
KEYWORDS:
Complex V; TORC1; chronic fatigue syndrome; mitochondria; myalgic encephalomyelitis; seahorse respirometry
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February 2020, 100028
Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation           Brain, Behaviour and Immunity – Vol 2
Martin A.JonsjöabcJennyÅströmcdMichael Jonese BiankaKarshikoffd KarinLodindf LindaHolmströmcg LarsAgréusfRikard K.WickselldJohnAxelssonad MatsLekanderad Gunnar L.Olssonb MikeKemaniac AnnaAndreassonaeh
https://doi.org/10.1016/j.bbih.2019.100028Get rights and content
Highlights
Investigation of the level of subjective sickness behavior, assessed with a validated questionnaire, in patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and in patients with chronic pain compared to clinical, non-clinical and experimental groups.
The level of sickness behavior is similarly high in ME/CFS and chronic pain, and equal to the level in experimentally induced inflammation via injection of bacterial endotoxin.
Higher levels of sickness behavior showed significant associations with lower levels of self-rated health and functioning.
Abstract
Background:
Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning.
Methods
Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n ​= ​38) and patients with chronic pain (n ​= ​190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n ​= ​29), primary care patients (n ​= ​163), individuals from the general population (n ​= ​155) and healthy subjects (n ​= ​48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population.
Results
LPS-injected individuals (M ​= ​16.3), patients with ME/CFS (M ​= ​16.1), chronic pain (M ​= ​16.1) and primary care patients (M ​= ​10.7) reported significantly higher SicknessQ scores than individuals from the general population (M ​= ​5.4) and healthy subjects (M ​= ​3.6) all p’s ​< ​0.001). In turn, LPS-injected individuals, patients with ME/CFS and chronic pain reported significantly higher SicknessQ scores than primary care patients (p’s ​< ​0.01). Higher levels of sickness behavior were associated with poorer self-rated health and health-related functioning (p’s ​< ​0.01), but less so in patients with ME/CFS and chronic pain than in individuals from the general population.
Conclusions
Patients with ME/CFS and chronic pain report similar high levels of sickness behavior; higher than primary care patients, and comparable to levels in experimental inflammation. Further study of sickness behavior in ME/CFS and chronic pain populations is warranted as immune-to-brain interactions and sickness behavior may be of importance for functioning as well as in core pathophysiological processes in subsets of patients.
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Front. Immunol., 21 November 2019 | https://doi.org/10.3389/fimmu.2019.02684
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections
Nuno Sepúlveda1,2*, Jorge Carneiro3, Eliana Lacerda4 and Luis Nacul4
  • 1Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause. Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their capacity to suppress the immune responses against both self and microbial antigens. Here, we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1), and Epstein–Barr virus (EBV), as often reported as triggers of ME/CFS. Using simulations of the cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue. We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential. According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease, when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.
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Oxidative medicine and cellular longevity
Volume 2019 |Article ID 1684198 | 10 pages | https://doi.org/10.1155/2019/1684198
Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study
Letizia Venturini,1 Sara Bacchi,2 Enrica Capelli,2 Lorenzo Lorusso,3 Giovanni Ricevuti,1 and Chiara Cusa1
Academic Editor: Maria Luca
Abstract
The present study discusses about the effects of a combination of probiotics able to stimulate the immune system of patients affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To this purpose, patients diagnosed according to Fukuda’s criteria and treated with probiotics were analyzed by means of clinical and laboratory evaluations, before and after probiotic administrations. Probiotics were selected considering the possible pathogenic mechanisms of ME/CFS syndrome, which has been associated with an impaired immune response, dysregulation of Th1/Th2 ratio, and high oxidative stress with exhaustion of antioxidant reserve due to severe mitochondrial dysfunction. Immune and oxidative dysfunction could be related with the gastrointestinal (GI) chronic low-grade inflammation in the lamina propria and intestinal mucosal surface associated with dysbiosis, leaky gut, bacterial translocation, and immune and oxidative dysfunction. Literature data demonstrate that bacterial species are able to modulate the functions of the immune and oxidative systems and that the administration of some probiotics can improve mucosal barrier function, modulating the release of proinflammatory cytokines, in CFS/ME patients. This study represents a preliminary investigation to verifying the safety and efficacy of a certain combination of probiotics in CFS/ME patients. The results suggest that probiotics can modify the well-being status as well as inflammatory and oxidative indexes in CFS/ME patients. No adverse effects were observed except for one patient, which displayed a flare-up of symptoms, although all inflammatory parameters (i.e., cytokines, fecal calprotectin, ESR, and immunoglobulins) were reduced after probiotic intake. The reactivation of fatigue symptoms in this patient,
whose clinical history reported the onset of CFS/ME following mononucleosis, could be related to an abnormal stimulation of the immune system as suggested by a recent study describing an exaggerated immune activation associated with chronic fatigue.
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Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome
Nadja Scherbakov  Marvin Szklarski  Jelka Hartwig  Sebastian Lorenz   Patricia Grabowski  Wolfram Doehner Carmen Scheibenbogen
First published:10 March 2020     https://doi.org/10.1002/ehf2.12633 ESC Heart Failure
Abstract
Aims
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disease. Evidence for disturbed vascular regulation comes from various studies showing cerebral hypoperfusion and orthostatic intolerance. The peripheral endothelial dysfunction (ED) has not been sufficiently investigated in patients with ME/CFS. The aim of the present study was to examine peripheral endothelial function in patients with ME/CFS.
Methods and results
Thirty‐five patients [median age 40 (range 18–70) years, mean body mass index 23.8 ± 4.2 kg/m2, 31% male] with ME/CFS were studied for peripheral endothelial function assessed by peripheral arterial tonometry (EndoPAT2000). Clinical diagnosis of ME/CFS was based on Canadian Criteria. Nine of these patients with elevated antibodies against β2‐adrenergic receptor underwent immunoadsorption, and endothelial function was measured at baseline and 3, 6, and 12 months follow‐up. ED was defined by reactive hyperaemia index ≤1.81. Twenty healthy subjects of similar age and body mass index were used as a control group. Peripheral ED was found in 18 of 35 patients (51%) with ME/CFS and in 4 healthy subjects (20%, P < 0.05). Patients with ED, in contrast to patients with normal endothelial function, reported more severe disease according to Bell score (31 ± 12 vs. 40 ± 16, P = 0.04), as well as more severe fatigue‐related symptoms (8.62 ± 0.87 vs. 7.75 ± 1.40, P = 0.04) including a higher demand for breaks [9.0 (interquartile range 7.0–10.0) vs. 7.5 (interquartile range 6.0–9.25), P = 0.04]. Peripheral ED showed correlations with more severe immune‐associated symptoms (r = −0.41, P = 0.026), such as sore throat (r = −0.38, P = 0.038) and painful lymph nodes (r = −0.37, P = 0.042), as well as more severe disease according to Bell score (r = 0.41, P = 0.008) and symptom score (r = −0.59, P = 0.005). There were no differences between the patient group with ED and the patient group with normal endothelial function regarding demographic, metabolic, and laboratory parameters. Further, there was no difference in soluble vascular cell adhesion molecule and soluble intercellular adhesion molecule levels. At baseline, peripheral ED was observed in six patients who underwent immunoadsorption. After 12 months, endothelial function had improved in five of these six patients (reactive hyperaemia index 1.58 ± 0.15 vs. 2.02 ± 0.46, P = 0.06).
Conclusions
Peripheral ED is frequent in patients with ME/CFS and associated with disease severity and severity of immune symptoms. As ED is a risk factor for cardiovascular disease, it is important to elucidate if peripheral ED is associated with increased cardiovascular morbidity and mortality in ME/CFS.
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Stemming the Rising Tide of Human-Biting Ticks and Tickborne Diseases, United States
Lars Eisen                          Emerging Infectious Diseases. 2020;26(4):641-647. 
 Abstract
Ticks and tickborne diseases are increasingly problematic. There have been positive developments that should result in improved strategies and better tools to suppress ticks, reduce human tick bites, and roll back tickborne diseases. However, we equally need to address the question of who is responsible for implementing the solutions. The current model of individual responsibility for tick control evolved from a scenario in the 1990s focusing strongly on exposure to blacklegged ticks and Lyme disease spirochetes in peridomestic settings of the northeastern United States. Today, the threat posed by human-biting ticks is more widespread across the eastern United States, increasingly complex (multiple tick species and >10 notable tickborne pathogens), and, across tick species, more spatially diffuse (including backyards, neighborhood green spaces, and public recreation areas). To mitigate tick-associated negative societal effects, we must consider shifting the responsibility for tick control to include both individual persons and professionally staffed tick-management programs.

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Benefits of adding stretching to a moderate-intensity aerobic exercise programme in women with fibromyalgia: a randomized controlled trial
Miguel Gómez-Hernández, Tomás Gallego-Izquierdo, Patricia Martínez-Merinero, ..
First Published December 18, 2019 Research Article Find in PubMed
https://doi.org/10.1177/0269215519893107
Abstract
Objective:    To investigate the effects of adding stretching to a moderate-intensity aerobic exercise programme in women with fibromyalgia.
Design:  Randomized controlled trial.
Subjects: Sixty-four female patients who were diagnosed with fibromyalgia syndrome based on the American College of Rheumatology criteria were recruited (mean age: 54.27 ± 6.94 years).
Interventions: The control group (n = 32) underwent supervised moderate-intensity cycling (50%–70% of the age-predicted maximum heart rate) three times per week for 12 weeks. The experimental group (n = 32) underwent the same exercise programme plus a stretching programme once per week for 12 weeks.
Main measures:The main measures of this study were sleep quality assessed by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, the impact of fibromyalgia on quality of life assessed by the Fibromyalgia Impact Questionnaire, and pain perception assessed by the visual analogue scale at baseline, after 4 weeks, and after 12 weeks.
Results: The experimental group experienced significant improvements at 4-week measure compared with control group: Pittsburgh Sleep Quality Index (P < 0.001); Epworth Sleepiness Scale (P = 0.002); Fibromyalgia Impact Questionnaire (0.93 ± 7.39, P < 0.001); and visual analogue scale (0.52 ± 0.05, P < 0.001). Also at 12-week measure, experimental group experienced significant improvements compared with control group: Pittsburgh Sleep Quality Index (P < 0.001), Epworth Sleepiness Scale (P < 0.001); Fibromyalgia Impact Questionnaire (1.15 ± 9.11, P < 0.001); and visual analogue scale (0.81 ± 0.62, P < 0.001).


Conclusion:
Adding stretching to a moderate-intensity aerobic exercise programme increased sleep quality, decreased the impact of fibromyalgia on the quality of life, and reduced pain compared with just a moderate-intensity aerobic exercise programme in our sample of women with fibromyalgia.


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Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Asgeir Lande, Øystein Fluge, Elin B. Strand, Siri T. Flåm, Daysi D. Sosa, 
Olav Mella, Torstein Egeland, Ola D. Saugstad, Benedicte A. Lie & Marte K. Viken 
Scientific Reports volume 10, Article number: 5267 (2020)  
Abstract
The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.
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HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome
Lucas S. Rodrigues, Luiz H. da Silva Nali, Cibele O. D. Leal, Ester C. Sabino, Eliana M. Lacerda, Caroline C. Kingdon, Luis Nacul & Camila M. Romano 
Autoimmunity Highlights volume 10, Article number: 12 (2019)  
Abstract
Background
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/MS) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role. It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases.
Methods
Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients through real time PCR.
Results
HERV-K was overexpressed only in moderately affected individuals but HERV-W showed no difference.
Conclusions
This is the first report about HERV-K differential expression in moderate ME/CFS. Although the relationship between HERVs and ME/CFS has yet to be proven, the observation of this phenomenon deserves further attention.
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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:  Available online 1 April 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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MCP-1 is increased in patients with CFS and FM, whilst several other immune markers are significantly lower than healthy controls
NinaGrovenabEgil AndreasForscAstrid KamillaStunesdeSolveig KlæboReitanab


Brain, Behaviour and Immunity Volume 4, April 2020, 100067
https://doi.org/10.1016/j.bbih.2020.100067Get rights and content
Highlights
MCP-1 is significantly increased in CFS and Fibromyalgia compared to controls.
CFS and Fibromyalgia share common features of inflammation
Decreased IL-1β, IL-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3, IL-10 and IL-17A are found in both CFS and Fibromyalgia.
Abstract
The role of the immune system in the pathogenesis of Fibromyalgia (FM) and Chronic fatigue syndrome (CFS) is not clear. We have previously reported increased levels of C-reactive protein (CRP) in these patient groups compared to healthy controls and wanted to further explore the levels of circulating immune markers in these populations.
The population consisted of three groups, 58 patients with FM, 49 with CFS and 54 healthy controls. All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university. Plasma levels of Interferon (IFN)-γ, Interleukin (IL)-1β, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-β1, TGF-β2, TGF-β3 and Tumour Necrosis Factor (TNF)-α were analysed by multiplex. Differences between the three groups CFS, FM and controls, were analysed by Kruskal Wallis tests.
MCP-1 was significantly increased in both patient groups compared to healthy controls. IL-1β, Il-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3, IL-10 and IL17 all were significantly lower in the patient groups than healthy controls. IFN-γ was significantly lower in the FM group. For IL-8, IL-10 and IL-1ra there were no significant difference when controlled for multiple testing.
In conclusion, in our material MCP-1 seems to be increased in patients both with CFS and with FM, while several other immune markers are significantly lower in patients than controls.

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Abstracts December 2019 - February 2020 #14

2/19/2020

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European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
  • Authors
  • Kathryn H. MelamedMário Santos Rudolf K. F. Oliveira  Mariana Faria Urbina Donna Felsenstein Alexander R. Opotowsky Aaron B. Waxman David M. Systrom
Abstract
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
  • Authors
  • Kathryn H. MelamedMário Santos Rudolf K. F. Oliveira  Mariana Faria Urbina Donna Felsenstein Alexander R. Opotowsky Aaron B. Waxman David M. Systrom
Abstract
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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Journal of Clinical Investigation
Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson 
First published December 12, 2019 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

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Epidemiology and Community Health: Research report
Influence of sleep problems and co-occurring musculoskeletal pain on long-term prognosis of chronic low back pain: the HUNT Study
Eivind Schjelderup Skarpsno, Paul Jarle Mork, Tom Ivar Lund Nilsen, 
Anne Lovise Nordstoga
Abstract
Background We investigated the influence of sleeplessness and number of insomnia symptoms on the probability of recovery from chronic low back pain (LBP), and the possible interplay between sleeplessness and co-occurring musculoskeletal pain on this association.
Methods The study comprised data on 3712 women and 2488 men in the Norwegian HUNT study who reported chronic LBP at baseline in 1995–1997. A modified Poisson regression model was used to calculate adjusted risk ratios (RRs) for the probability of recovery from chronic LBP at follow-up in 2006–2008, associated with sleep problems and co-occurring musculoskeletal pain at baseline.
Results Compared with persons without sleeplessness, persons who often/always experienced sleeplessness had a lower probability of recovery from chronic LBP (RR 0.65, 95% CI 0.57 to 0.74 in women and RR 0.81, 95% CI 0.69 to 0.95 in men). Although there was no clear evidence of statistical interaction between sleeplessness and co-occurring musculoskeletal pain, women and men who often/always experienced sleeplessness and had ≥5 additional chronic pain sites had RRs of recovery of 0.40 (95% CI 0.33 to 0.48) and 0.59 (95% CI 0.45 to 0.78), respectively, compared with persons without sleeplessness and 1–2 chronic pain sites.
Conclusion These findings suggest that preventing or reducing sleep problems among people with chronic LBP may have the potential of improving the long-term prognosis of this condition, also among those with several additional pain sites.
View Full Text
http://dx.doi.org/10.1136/jech-2019-212734
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Journal: Fatigue: Biomedicine, Health & Behavior 
Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Olli Polo,Pia Pesonen &Essi Tuominen
Received 13 Sep 2019, Accepted 11 Nov 2019, Published online: 19 Nov 2019
  • https://doi.org/10.1080/21641846.2019.1692770
ABSTRACT
Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.
Methods: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.
Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.
Conclusions: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.

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Brain Behav Immun. 2019 Nov 20. pii: S0889-1591(19)30762-7. doi: 10.1016/j.bbi.2019.11.015. 
Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.
Eguchi A1, Fukuda S2, Kuratsune H2, Nojima J3, Nakatomi Y4, Watanabe Y5, Feldstein AE
1 Department of Gastroenterology and Hepatology, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; JST, PRETO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA. Electronic address: akieguchi@clin.medic.mie-u.ac.jp.
2 Department of Health Welfare Sciences, Kansai University of Welfare Sciences, Kashiwara 582-0026, Japan; Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
3 Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
4 Nakatomi Fatigue Care Clinic, Osaka 541-0043, Japan.
5 Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; RIKEN Compass to Healthy Life Research Complex Program, Kobe 650-0047, Japan.
6 Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.
Copyright © 2019 Elsevier Inc. All rights reserved.PMID:31759091 DOI:10.1016/j.bbi.2019.11.015
Research:   REVIEW

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Understanding neuromuscular disorders in chronic fatigue syndrome
Yves Jammes, Frédérique Retornaz2
Abstract
Muscle failure has been demonstrated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurophysiological tools demonstrate the existence of both central and peripheral fatigue in these patients. Central fatigue is deduced from the reduced amplitude of myopotentials evoked by transcranial magnetic stimulation of the motor cortex as well as by the muscle response to interpolated twitches during sustained fatiguing efforts. An impaired muscle membrane conduction velocity assessed by the reduced amplitude and lengthened duration of myopotentials evoked by direct muscle stimulation is the defining feature of peripheral fatigue. Some patients with ME/CFS show an increased oxidative stress response to exercise. The formation of lipid hydroperoxides in the sarcolemma, which alters ionic fluxes, could explain the reduction of muscle membrane excitability and potassium outflow often measured in these patients. In patients with ME/CFS, the formation of heat shock proteins (HSPs) is also reduced. Because HSPs protect muscle cells against the deleterious effects of reactive oxygen species, the lack of their production could explain the augmented oxidative stress and the consecutive alterations of myopotentials which could open a way for future treatment of ME/CFS.
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Brief Cognitive Behavioral Therapy For Chronic Pain

Results From a Clinical Demonstration Project in Primary Care Behavioral Health
Beehler, Gregory P. MA, PhD*,†; Murphy, Jennifer L. PhD‡,§; King, Paul R. PhD*,∥; Dollar, Katherine M. PhD¶; Kearney, Lisa K. PhD, ABPP¶,#; Haslam, Aaron PhD**; Wade, Michael MS¶; Goldstein, Wade R. MA*
The Clinical Journal of Pain: October 2019 - Volume 35 - Issue 10 - p 809–817
doi: 10.1097/AJP.0000000000000747
 
Abstract
Objectives: 
Although cognitive behavioral therapy is an effective intervention for chronic pain, it is a lengthy treatment typically applied only in specialty care settings. The aim of this project was to collect preliminary effectiveness data for Brief Cognitive Behavioral Therapy for Chronic Pain (Brief CBT-CP), an abbreviated, modular form of treatment designed for use in primary care. 
Methods: 
A clinical demonstration project was conducted in which Brief CBT-CP was delivered to primary care patients by 22 integrated care providers practicing in the Primary Care Behavioral Health model of Veterans Health Administration primary care clinics. Brief measures were used at each appointment to collect patient-reported clinical outcomes. 
Results: 
One hundred eighteen patients provided sufficient data for analysis (male, 75%; mean age, 51.4 y). Multilevel modeling suggested that a composite measure of pain intensity and functional limitations showed statistically significant improvements by the third appointment (Cohen’s d=0.65). Pain-related self-efficacy outcomes showed a similar pattern of results but of smaller effect size (Cohen’s d=0.22). The exploratory analysis identified that Brief CBT-CP modules addressing psychoeducation and goal setting, pacing, and relaxation training were associated with the most significant gains in treatment outcomes. 
Discussion: 
These findings provide early support for the effectiveness of Brief CBT-CP when delivered by providers in every day Primary Care Behavioral Health settings. Results are discussed in relation to the need for additional research regarding the potential value of employing safe, population-based, nonpharmacological approaches to pain management in primary care. 
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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Bragee Clinics report

Signs of Intracranial Hypertension, Hypermobility and 
Craniocervical Obstructions in patients with 
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée , Anastasios Michos, Brandon Drum, Mikael Fahlgren, Robert 
Szulkin, Bo C Bertilson


Division of Family Medicine and Primary Care, 
Department of Neurobiology, Care Sciences 
and Society, Karolinska Institutet, Stockholm, Sweden
Division of Family Medicine and Primary Care,Stockholm Health Care Services, Region 
Stockholm, Huddinge, Sweden
ME center, Bragée Clinics, Stockholm, Sweden


Objective: To test the hypothesis that hypermobility and craniocervical obstructions is overrepresented in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and that a large portion of these patients may have a degree of intracranial hypertension explaining many of the symptoms of the ME/CFS syndrome. 
Methods: This is a retrospective cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS fulfilling the Canada Consensus Criteria. The first 272 consecutive patients with ME/CFS were invited, and 229 of these whom had signed the informed consent within six weeks were included. Hypermobility was assessed using the Beighton score. The position of cerebellar tonsils, the optic nerve sheath diameter and eyeball transverse diameter were measured in magnetic resonance imaging scans of the brain as measures correlated to intracranial hypertension. Findings of obstructions in the craniocervical junction and the cervical spine were assessed through MRI scans of the cervical spine. Radiological assessments were made by an experienced radiologist. 
Results: 190 women with a mean age of 45 years and 39 males with a mean age of 44 years were included. Hypermobility was found in 111 (49%) of the patients. Of the 205 patients with brain MRI scanning, increased diameter of the optic nerve sheath was found in 112 patients (55%), signs of possible intracranial hypertension expressed as the quote of the diameter of optic nerve/eyeball transverse diameter in left or right side were present in 171 patients (83%), and values seen with more severe states of intracranial hypertension were found in 65 of the patients (32%). Obstruction in the foramen magnum by cerebellar tonsils under the McRae line was found in 115 patients (56%). Findings of obstruction of the cervical spinal canal were found in 100 of the 125 patients (80%) with cervical scans. There was a significant overrepresentation of signs of hypermobility, intracranial hypertension and obstructions in the cranio-cervical region compared with general population. 
Conclusion: These findings, which confirms our hypothesis, may explain the widespread symptoms these patients express. If confirmed in further studies, new diagnostic and therapeutic approaches to this widespread neurological syndrome should be considered.
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From Cold Spring Harbor Laboratory
Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Ece Karhan, Courtney Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George,  View ORCID ProfilePeter N. Robinson, Suzannne D Vernon, Lucinda Bateman, Derya Unutmaz
doi: https://doi.org/10.1101/2019.12.23.887505
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNgamma;, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.
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Scientific Reports  MC6906377   2019; 9: 18817.
Published online 2019 Dec 11. doi: 10.1038/s41598-019-55473-4 PMCID: PMC6906377
PMID: 31827223
Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome
Alaa Ghali,1 Carole Lacout,1 Maria Ghali,2 Aline Gury,1 Anne-Berengere Beucher,1 Pierre Lozac’h,1 Christian Lavigne,1 and Geoffrey Urbanski  (France)
Abstract
Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate. Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55). ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.
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December 27, 2019
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia DisorderA Phase 3 Randomized Clinical Trial
Russell Rosenberg, PhD1; Patricia Murphy, PhD2,3; Gary Zammit, PhD4; et alDavid Mayleben, PhD5; Dinesh Kumar, PhD3; Shobha Dhadda, PhD3; Gleb Filippov, MD, PhD3; Antonia LoPresti, MD3; Margaret Moline, PhD3
JAMA Netw Open. 2019;2(12):e1918254. doi:10.1001/jamanetworkopen.2019.18254
Key Points
Question  Does lemborexant therapy effectively treat insomnia disorder in patients 55 years and older compared with placebo and zolpidem tartrate extended release therapy?
Findings  In this randomized double-blind clinical trial of 1006 participants 55 years and older with insomnia disorder, lemborexant therapy significantly improved both latency to persistent sleep and sleep maintenance (wake-after-sleep onset and sleep efficiency) compared objectively via polysomnography with both placebo and zolpidem tartrate extended release therapy. Efficacy was also demonstrated on patient-reported end points of sleep onset, sleep efficiency, and wake-after-sleep onset for both doses of lemborexant compared with placebo.
Meaning  Lemborexant therapy may provide an additional option for sleep onset and sleep maintenance difficulties in older patients with insomnia disorder.
Abstract
Importance  Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.
Objective  To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.
Design, Setting, and Participants  The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.
Interventions  Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.
Main Outcomes and Measures  Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.
Results  Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, −24.0 min; 95% CI, −30.0 to −18.0 min; P < .001 and for lemborexant 10 mg, −25.4 min; 95% CI, −31.4 to −19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, −6.7 min; 95% CI, −11.2 to −2.2 min; P = .004 and for lemborexant 10 mg, −8.0 min; 95% CI, −12.5 to −3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.
Conclusions and Relevance  In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.
Trial Registrations  ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39
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Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients
Cassandra Balinas, Helene Cabanas, Donald Staines Sonya Marshall-Gradisnik 
Journal of Translational Medicine volume 17, Article number: 401 (2019)  
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells. This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.
Methods
Ten ME/CFS patients (43.45 ± 12.36) and 10 HCs (43 ± 12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.
Results
Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/− subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.


Conclusion
Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.
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Original Paper   Published: 23 January 2020
The Prevalence of Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in a Community-Based Sample
  • Leonard A. Jason, Ben Z. Katz, Madison Sunnquist, Chelsea Torres, Joseph Cotler & Shaun Bhatia 
Child & Youth Care Forum (2020)Cite this article
Abstract
Background
Most pediatric prevalence studies of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been based upon data from tertiary care centers, a process known for systematic biases such as excluding youth of lower socioeconomic status and those less likely to have access to health care. In addition, most pediatric ME/CFS epidemiologic studies have not included a thorough medical and psychiatric examination. The purpose of this study was to determine the prevalence of pediatric ME/CFS from an ethnically and sociodemographically diverse community-based random sample.
Method
A sample of 10,119 youth aged 5–17 from 5622 households in the Chicagoland area were screened. Following evaluations, a team of physicians made final diagnoses. Youth were given a diagnosis of ME/CFS if they met criteria for three selected case definitions. A probabilistic, multi-stage formula was used for final prevalence calculations.
Results
The prevalence of pediatric ME/CFS was 0.75%, with a higher percentage being African American and Latinx than Caucasian. Of the youth diagnosed with ME/CFS, less than 5% had been previously diagnosed with the illness.
Conclusions
Many youth with the illness have not been previously diagnosed with ME/CFS. These findings point to the need for better ways to identify and diagnose youth with this illness.
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Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids
by Arnaud Germain 1,Dinesh K. Barupal 2,Susan M. Levine 1 andMaureen R. Hanson 1,*
1
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
2
UC Davis Genome Center—Metabolomics, University of California, Davis, CA 95616, USA
*
Author to whom correspondence should be addressed.
Metabolites 2020, 10(1), 34; https://doi.org/10.3390/metabo10010034 (registering DOI)
Received: 20 December 2019 / Revised: 9 January 2020 / Accepted: 12 January 2020 / Published: 14 January 2020
View Full-Text Download PDF 
Abstract
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients. View Full-Text
Keywords: ME/CFS; metabolomics; acyl cholines; steroids; dipeptides; lipids
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“Altered T cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)”
Principal Investigators: Liisa Selin (PhD), Anna Gil (PhD)
University of Massachusetts Medical School

Our understanding of the immunological defects present in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is severely lacking compared to other disorders, leading to a major barrier to research, diagnosis, and treatment. ME/CFS is a complex disorder affecting numerous organ systems and biological processes with studies focusing on changes in cytokines, metabolism, and identifying a potential causative infectious agent. In this pilot study, we propose to examine the role of a novel subset of immune cells, CD4+CD8+ T cells in the pathology of ME/CFS.
We recently discovered not only an increased frequency of this otherwise rare T cell in a group of ME/CFS patients we were studying, but also that they were highly activated producing unusual cytokines. We observed a difference in the activation profile of these cells in mild and severe cases of ME/CFS. In my long career of studying human T cell responses during viral infections I have never previously observed an increase in this cell type. We will examine the role they may play in the highly dysregulated immune response of ME/CFS patients. Much of the published data seems to suggest that ME/CFS may be preceded by infection, and the chronic manifestation of illness may represent an altered host response to infection, or an inability to resolve inflammation.
Based on our preliminary data, we will examine in a larger cohort, whether this unique subset of CD4+CD8+ T cells is increased in all ME/CFS donors, or does it only occur in a subgroup. We will also assess its role in mediating the disease by examining its frequency and alterations in its function in ME/CFS patients, manifesting either a mild or severe form of the disease as compared to healthy donors. Also, T cells have unique receptors (TCR) that they use to recognize foreign pathogens and eliminate them. Sometimes these TCR also inadvertently recognize self-proteins and lead to autoimmune diseases.
In our preliminary studies examining the TCR repertoire of the CD4+CD8+ population there was strong evidence they were expanded by recognizing an antigen. At this time, we do not know if this is a self or a pathogen antigen. We will therefore explore the TCR repertoire of this unique population of CD4+CD8+ T cells in order to find characteristics that will help us identify the potential antigen that is driving their expansion and activation. This would be a major step in the field potentially leading to the identification a specific infectious or autoimmune response that could be the main driver of the immunological basis of ME/CFS. Studying these unique cells (CD4+CD8+ T cells) in a larger population of ME/CFS patients has the potential to give us a biomarker (much needed for this disease) while giving us clues to the mechanisms driving the pathology of ME/CFS and thus therapy.
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Tick-Borne Encephalitis Virus, United Kingdom

Maya Holding; Stuart D. Dowall; Jolyon M. Medlock; Daniel P. Carter; Steven T. Pullan; James Lewis; Richard Vipond; Mara S. Rocchi; Matthew Baylis; Roger Hewson
Emerging Infectious Diseases. 2020;26(1):90-96. 
Abstract
During February 2018–January 2019, we conducted large-scale surveillance for the presence and prevalence of tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) in sentinel animals and ticks in the United Kingdom. Serum was collected from 1,309 deer culled across England and Scotland. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. A focus in the Thetford Forest area had the highest proportion (47.7%) of seropositive samples. Ticks collected from culled deer within seropositive regions were tested for viral RNA; 5 of 2,041 ticks tested positive by LIV/TBEV real-time reverse transcription PCR, all from within the Thetford Forest area. From 1 tick, we identified a full-length genomic sequence of TBEV. Thus, using deer as sentinels revealed a potential TBEV focus in the United Kingdom. This detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis.
Introduction
The only tickborne flavivirus in the United Kingdom documented to cause disease in vertebrates is louping ill virus (LIV), a vivirus transmitted by the deer/sheep tick, Ixodes ricinus.[1] This tick species is the most abundant and widely distributed tick species in the United Kingdom and a known vector of Lyme borreliosis. LIV is most commonly detected in sheep, cattle, and red grouse and has been reported in Scotland, Wales, and England (primarily Cumbria, Devon, and North Yorkshire).[1] Humans are incidental hosts for LIV, and infection has been reported infrequently; ≈45 clinical cases have been linked to encephalitis during the past 85 years.[1,2] However, the short window of acute infection leads to uncertainty about whether suspected cases resulted from LIV infection or some other cause, although serologic analysis to analyze recent exposure through induction of IgM-specific responses, in combination with clinical symptoms, could inform a presumptive diagnosis. Human cases are mostly linked to occupational exposure, particularly in abattoir or farm workers and occasionally in laboratory staff.[2] Although the UK Animal and Plant Health Agency holds a database of confirmed diagnoses of LIV in livestock,[3,4] the distribution and regional prevalence of LIV has not been fully defined. Records of distribution and regional prevalence are based on voluntary submissions by farmers and veterinarians from symptomatic livestock,[1] from which private submissions are not integrated. Serologic analysis has been complicated; some animals received vaccination before its withdrawal.
Tick-borne encephalitis virus (TBEV) is a closely related flavivirus that, although known to be less virulent than LIV for sheep,[5] causes a neurologic disease (tick-borne encephalitis [TBE]) after transmission to humans by infected ticks, producing clinical disease in an estimated one third of TBEV infections.[6] TBE typically has a biphasic course starting with a prodromal phase with influenza-like symptoms, followed by a symptom-free interval before neurologic disease occurs; neurologic disease ranges from mild meningitis to severe encephalitis with or without myelitis and spinal paralysis.[7] Three classic subtypes of TBEV are recognized: European (TBEV-Eu), Siberian, and Far Eastern. Two additional TBEV subtypes have recently been proposed: Baikalian subtype and the Himalayan subtype.[8] TBEV-Eu is the prevailing subtype in Western Europe where it is primarily transmitted by I. ricinus ticks and is maintained within forest and meadow biotypes in endemic foci. In the United Kingdom, TBE is considered an imported disease; opportunities for the virus to become established principally are limited because the UK climate was not thought to support the specific conditions required for enzoonotic cycles to be established for TBEV to become endemic.[9] However, changes in climate have affected the emergence, distribution, and abundance of I. ricinus in the United Kingdom;[10] thus, the risk for tickborne disease has increased.[11] A recent study provided evidence that co-infestation of tick larvae and nymphs occurs in small mammals in UK woodland.[12] The increasing range of TBEV in Western Europe was underscored recently when the Netherlands reported its first human case in 2016.[13] Moreover, retrospective serologic screening of deer serum samples and molecular analysis of questing ticks found evidence of TBEV circulation in the Netherlands as far back as 2010 and 2015.[13,14] Given the increasing possibility that TBEV could be circulating in the United Kingdom, Public Health England developed a surveillance program focusing on wild animals and ticks.
In TBEV-endemic areas in continental Europe, the prevalence of TBEV in questing ticks is low, rarely exceeding 1% even in regions where the incidence of human infections is high.[15] Therefore, instead of screening ticks directly, we used sentinel animals first to identify serologic evidence of TBEV to highlight sites for focused tick testing by specific TBEV detection using real-time reverse transcription PCR (rRT-PCR). Deer are proven as reliable sentinels for identifying areas where TBEV is present[13,15] because they have a limited home range, are available in large numbers, and are broadly dispersed within the surveillance areas. They also show long-lasting antibody responses after natural exposure to flaviviruses.[15,16]
For our study, collectors retrieved blood samples from deer culled in England and Scotland during February 2018–January 2019; when available, they also collected tick samples. We tested the blood samples for TBEV or LIV antibodies and the ticks for the presence of viral RNA by rRT-PCR.
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Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson
First published December 12, 2019 – Journal of clinical investigation 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
Graphical Abstract
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Medicine. 98(43):e17600, OCTOBER 2019
DOI: 10.1097/MD.0000000000017600
,  
PMID: 31651868
Issn Print: 0025-7974
Publication Date: October 2019
Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis
Maximillian Nelson;Jasvir Bahl;Jonathan Buckley;Rebecca Thomson;Kade Davison;


Abstract Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS. 
Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls. 
Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD±95% CI=4.14±1.38, P
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Journal of Epidemiological Research:International Peer-Reviewed and Open Access Journal for the epidemiological specialists
Home > Vol 5, No 1 (2019) > Lin
Incidence rates of brain cancer following an outbreak of Chronic Fatigue Syndrome
Cheng-Te Major Lin, Naji Younes, Paul H. Levine
Abstract
Previous studies utilizing data from the Nevada Cancer Registry suggested a transient increase in non-Hodgkin’s lymphoma (NHL) and brain cancer in northern Nevada following an outbreak of Chronic Fatigue Syndrome (CFS) in that area which was not seen in southern Nevada which had no reported CFS outbreaks.  A subsequent study from the National Cancer Institute (NCI) using data from the NCI’s Surveillance, Epidemiology and End Results (SEER) Program and Medicare documented the association between CFS and NHL on a national basis but no other cancer association was seen.  Since brain cancer has a younger age distribution than NHL, we returned to the Nevada Cancer Registry and used ten more years of data and additional analyses to determine if there was an association between CFS and brain cancer by age.  This study confirmed the increased incidence of brain cancer following the outbreak in northern Nevada but not southern Nevada with the increase limited to the under 65 age group, thus explaining why the SEER-Medicare analysis only analyzing data in the 65 and above age group did not detect this association.
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The physiological timeline of post exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
L Hodges T Nielsen D Cochrane D Baken
First published: 08 January 2020 – Translational Sports Medicine.
 https://doi.org/10.1002/tsm2.133
Abstract
With fatigue being such a dominant feature, it is important to define the timeline and its impact following exertion in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to investigate the physiological effects of repeated graded maximal exercise testing at 48 and 72 hours, along with analysing the reported time to recover from repeated graded exercise tests (PEM). ME/CFS (n = 16), age and gender matched controls (n=16) were randomly assigned to either a 48‐hour or 72‐hour protocol. Each participant completed a maximal incremental cycle exercise test on day one and again at either 48‐hours (48‐h) or 72‐hours (72‐h) later. Physiological responses were analysed at peak work rate (PWR). There were significant differences in both peak VO2 and workload (p<0.05) in the 48‐h ME/CFS group compared to the 48‐h controls in both test 1 and test 2. Significant differences in peak VO2 and workload were only demonstrated in test 2 in participants in the ME/CFS 72‐h group. There was a small but insignificant decrease in both peak VO2 and workload in the ME/CFS group at 48‐h. Interestingly those in the 72‐h ME/CFS protocol demonstrated an increase in workload (10 Watts), despite no change in VO2peak. Subjective data demonstrated the 48‐hour ME/CFS group reported significantly longer time to recover.
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RESEARCH ARTICLE (Open Access)
 Contents Vol 11(4)
A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome
Angus Mackay 1
Journal of Primary Health Care 11(4) 300-307 https://doi.org/10.1071/HC19041
Published: 29 November 2019

Journal Compilation © Royal New Zealand College of General Practitioners 2019 This is an open access article licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
Abstract
A neuro-inflammatory model is proposed to explain the onset, symptoms and perpetuation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via characteristic flare-ups (relapses). In this article, I explore the proposition that a range of triggers (intense physiological stressors such as severe viral infections, chemical toxin exposure or emotional trauma) in ME/CFS-predisposed people causes disruption in the neural circuitry of the hypothalamus (paraventricular nucleus), which induces a neuro-inflammatory reaction in the brain and central nervous system of ME/CFS patients, via over-active innate immune (glial) cells. Resulting dysfunction of the limbic system, the hypothalamus and consequently of the autonomic nervous system can then account for the diverse range of ME/CFS symptoms. Ongoing stressors feed into a compromised (inflamed) hypothalamus and if a certain (but variable) threshold is exceeded, a flare-up will ensue, inducing further ongoing neuro-inflammation in the central nervous system, thus perpetuating the disease indefinitely.


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    •    Published: 06 January 2020
Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
  • Do-Young Kim, Jin-Seok Lee, Samuel-Young Park, Soo-Jin Kim & 
  • Chang-Gue Son 
Journal of Translational Medicine volume 18, Article number: 7 (2020) Cite this article
Abstract
Background
Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.
Methods
RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.
Results
Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.
Conclusions
This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.
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J of Translational medicine 2020 Jan 6;18(1):4. doi: 10.1186/s12967-019-02184-z.
Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis.
Escorihuela RM1, Capdevila L2, Castro JR3, Zaragozà MC4, Maurel S5, Alegre J6, Castro-Marrero J7.
Abstract
BACKGROUND:
Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.
METHODS:
In this case-control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.
RESULTS:
CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.
CONCLUSIONS:
Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.
PMID: 31906988
 
PMCID:PMC6943898
 
DOI:10.1186/s12967-019-02184-z
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Psychoneuroendocrinology – vol 113.  March 2020, 104578
The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms
Martin AJonsjöabfGunnar LOlssonabRikard WicksellcKjellAlvingdLindaHolmströmaeAnnaAndreassonfg
https://doi.org/10.1016/j.psyneuen.2019.104578Get rights and content
Highlights
Associations between inflammatory markers and common symptoms in ME/CFS.
Higher levels of markers were significantly associated with higher levels of symptoms.
Biological sex moderated several associations.
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.
Methods
53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0–10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.
Results and conclusions
Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.
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  • Open Access  Published: 22 January 2020
Health-related quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndrome: an Australian cross-sectional study
N. Eaton-Fitch, S. C. Johnston, P. Zalewski, D. Staines & S. Marshall-Gradisnik 
Quality of Life Research (2020) 
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS.
Methods
Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL.
Results
Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties.
Conclusion
This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.​

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12/6/2019

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Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome
A systematic review and meta-analysis
Nelson, Maximillian J. PhDa,∗; Bahl, Jasvir S. BAppScia; Buckley, Jonathan D. PhDa; Thomson, Rebecca L. PhDa,b; Davison, Kade PhDa
Section Editor(s): NA.,
Medicine: October 2019 - Volume 98 - Issue 43 - p e17600
doi: 10.1097/MD.0000000000017600
Research Article: Systematic Review and Meta-Analysis
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.
Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.
Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD ± 95% CI = 4.14 ± 1.38, P < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = –13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = –0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (–0.34 ± 0.22, P = .002) were lower in ME/CFS patients.
Conclusions: The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.
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Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Ludovic Giloteaux, L., Goodrich, J.K., Walters, W.A., Levine, S.M., Ley, R.E., & Hanson, M.R.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918027/


Gastrointestinal disturbance is a common symptom of ME/CFS. This study examined the gut microbiota of ME/CFS patients and healthy controls.

These researchers found that ME/CFS patients have less biodiversity of gut microbiota compared with healthy controls. In addition, ME/CFS patients were more likely to have higher gut bacteria species which are reported as pro-inflammatory and less of those that are anti-inflammatory. There were also elevated levels of blood markers for microbial translocation (meaning that gut bacteria are found outside the gut) for ME/CFS patients than for healthy controls.

In summary, the results indicate imbalance or maladaptation of the gut microbiota in ME/CFS patients and an increased incidence of microbial translocation which may play a role in inflammatory symptoms of the illness.

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A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)
Authors: Corbitt, M., Eaton-Fitch, N., Staines, D., Cabanas, H., & Marshall-Gradisnik, S.
Link: https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1433-0


This literature review looked at whether there was a significant difference in cytokine levels between ME/CFS patients and healthy controls. The review examined 15 studies which met the criteria for further analysis.

Across the 15 studies, 64 cytokines were analysed. Despite moderate quality studies, results were inconclusive as to whether cytokines play a definitive role in ME/CFS other than “evidence of a concurrent inflammatory process.” 

The review also identified several limitations in these studies, including that most of the studies analyses used the Fukuda criteria, which is very broad, and means that characteristics of the patient samples are likely to differ between studies. 

The authors concluded that cytokines are unlikely to be useful as biomarkers for ME/CFS, and that more research is needed towards a diagnostic test and treatment for ME/CFS.



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Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors
Jonathan R Kerr


Journal of Clinical pathology – Vol 72, Issue 10
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity. EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit. Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.
http://dx.doi.org/10.1136/jclinpath-2019-205822

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Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Authors:    Jonas Blomberg, Muhammad Rizwan, Agnes Böhlin-Wiener, Amal Elfaitouri, Per Julin, Olof Zachrisson, Anders Rosén and Carl-Gerhard Gottfries
Institution: Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Abstract
Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.
Publication:   Blomberg et al., Frontiers in Immunology, 2019 August 14; 10:1946
Comment by ME Research UK:  Published recently in Frontiers in Immunology is a new study – funded partly by ME Research UK – from the late Prof. Jonas Blomberg in Sweden. The researchers looked for evidence of past infection with, or reactivation of, the human herpesviruses HHV-4 (also known as Epstein–Barr virus), HHV-6 and HHV-7, which have been implicated in the pathogenesis of ME/CFS. Immunoglobulin G reactivity levels to these viruses were similar in serum samples from patients and control subjects, indicating that none of these herpesviruses are more common or intense in ME/CFS patients than in the rest of the population. However, the researchers did find subtle differences in antibody reactivities to whole virus HHV-1 antigens and some recombinant HHV-4 antigens in ME/CFS samples, suggesting that the immune system of patients may interact
Physiol.Rep    2019 Jun; 7(11): e14138.Published online 2019 Jun 3. doi: 10.14814/phy2.14138
PMCID: PMC6546966    PMID: 31161646
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Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome
Katarina Lien, 1 , 2 Bjørn Johansen, 3 Marit B. Veierød, 4 Annicke S. Haslestad, 1 Siv K. Bøhn, 1 Morten N. Melsom, 5 Kristin R. Kardel, 1 and Per O. Iversen 1 , 6
Author information Article notes Copyright and License information Disclaimer
Abstract:
Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO 2) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa]) is unknown. We studied 18 female patients (18–50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18–50 years) who underwent repeated CPETs 24 h apart (CPET 1 and CPET 2) with [Laa] measured every 30th second. VO 2 at peak exercise (VO 2peak) was lower in patients than in controls on CPET 1 (P < 0.001) and decreased in patients on CPET 2 (P < 0.001). However, the difference in VO 2peak between CPETs did not differ significantly between groups. [Laa] per PO was higher in patients during both CPETs (P interaction < 0.001), but increased in patients and decreased in controls from CPET 1 to CPET 2 (P interaction < 0.001). Patients had lower VO 2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO 2 production increases relative to VO 2), but relative intensity (%VO 2peak) and [Laa] at GET did not differ significantly from controls on CPET 1. Patients had a reduction in VO 2 (P = 0.02) and PO (P = 0.01) at GET on CPET 2, but no significant differences in %VO 2peak and [Laa] at GET between CPETs. Controls had no significant differences in VO 2, PO or %VO 2peak at GET between CPETs, but [Laa] at GET was reduced on CPET 2 (P = 0.008). In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME/CFS while it lowers [Laa] in healthy subjects.
Keywords: Elevated lactate, exercise intolerance, metabolism, oxygen uptake, post‐exertional malaise

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Lyme disease: chronic illness is rare, say experts
BMJ 2019; 367 doi: https://doi.org/10.1136/bmj.l5975 (Published 10 October 2019)Cite this as: BMJ 2019;367:l5975
  •   Anna Harvey
People who have had Lyme disease rarely develop chronic problems, experts have said, warning that those who seek treatment abroad believing their symptoms are a result of the infection may be putting themselves at risk.
There are around 1000 laboratory confirmed cases of Lyme disease in England and Wales annually, with an estimated 2000 more cases successfully treated in primary care without positive blood tests, said experts at a briefing on the disease at the Science Media Centre on 9 October.
Of these patients, fewer than one in 20 experience residual symptoms.

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Effects of Smoking on Patients With Chronic Pain
A Propensity-weighted Analysis on the Collaborative Health Outcomes Information Registry
James S. Khan; Jennifer M. Hah; Sean C. Mackey
Pain. 2019;160(10):2374-2379. 
Abstract and Introduction
Abstract
Tobacco smoking is associated with adverse health effects, and its relationship to pain is complex. The longitudinal effect of smoking on patients attending a tertiary pain management center is not well established. Using the Collaborative Health Outcomes Information Registry of patients attending the Stanford Pain Management Center from 2013 to 2017, we conducted a propensity-weighted analysis to determine independent effects of smoking on patients with chronic pain. We adjusted for covariates including age, sex, body mass index, depression and anxiety history, ethnicity, alcohol use, marital status, disability, and education. We compared smokers and nonsmokers on pain intensity, physical function, sleep, and psychological and mood variables using self-reported NIH PROMIS outcomes. We also conducted a linear mixed-model analysis to determine effect of smoking over time. A total of 12,368 patients completed the CHOIR questionnaire of which 8584 patients had complete data for propensity analysis. Smokers at time of pain consultation reported significantly worse pain intensities, pain interference, pain behaviors, physical functioning, fatigue, sleep-related impairment, sleep disturbance, anger, emotional support, depression, and anxiety symptoms than nonsmokers (all P < 0.001). In mixed-model analysis, smokers tended to have worse pain interference, fatigue, sleep-related impairment, anger, emotional support, and depression over time compared with nonsmokers. Patients with chronic pain who smoke have worse pain, functional, sleep, and psychological and mood outcomes compared with nonsmokers. Smoking also has prognostic importance for poor recovery and improvement over time. Further research is needed on tailored therapies to assist people with chronic pain who smoke and to determine an optimal strategy to facilitate smoking cessation.


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Front. Immunol. | doi: 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, 4*, Katsuhiko Muraki4, 5, Donald Staines1, 2, 3, 4 and Sonya Marshall-Gradisnik1, 2, 3, 4
  • 1School of Medical Sciences, Griffith Health, Griffith University, Australia
  • 2National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Australia
  • 3Menzies Health Institute, Griffith University, Australia
  • 4National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Independent researcher, Australia
  • 5School of Pharmacy, Aichi Gakuin University, Japan
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 ion channel disorders and more specifically impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signalling 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 CFS/ME. 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 hours on sixteen age- and sex-matched healthy controls and CFS/ME patients, after modulation with pregnenolone sulfate (PregS), NTX and ononetin.
We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in Interleukin-2 (IL-2) stimulated NK cells after modulation with pregnenolone sulfate and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 hours 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 CFS/ME patients, resulting in calcium signals remodelling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for CFS/ME. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

Keywords: Transient Receptor Potential Melastatin 3 (TRPM3), Naltrexone, Calcium, Opioid Receptor, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, Natural killer cells (NK cells), Whole-cell patch clamp electrophysiology
Received: 07 Aug 2019; Accepted: 14 Oct 2019.
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Exercise therapy for chronic fatigue syndrome – Cochrane amended review of the effectiveness of graded exercise therapy
Author: Larun, L., Brurberg, K.G., Odgaard‐Jensen, J., & Price, J.R.
Link: https://www.cochrane.org/news/publication-cochrane-review-exercise-therapy-chronic-fatigue-syndrome

Cochrane is an independent, international network of researchers, clinicians, patients, carers and others interested in health, which publishes systematic reviews of research into health interventions. Cochrane is very well-respected, and its reviews are highly influential. 

The Cochrane review of exercise therapy for ME/CFS (Larun et al, 2017) has been the subject of a formal complaint about its science and methodology. This complaint led to an update of the review, which Cochrane has now published. 

The updated review concludes that there is low-moderate certainty about the evidence that exercise therapy may alleviate some symptoms of ME/CFS, and recommends further research. The review acknowledges:

  • The therapy’s long term effectiveness is uncertain due to a lack of follow-up in many studies.
  • The risk of serious side effects and the effects of exercise therapy on pain, quality of life, and depression is uncertain, due either to lack of evidence or low quality evidence.
  • Most studies are based on broader diagnostic criteria than are currently recommended for use and that “people diagnosed using other criteria may experience different effects.”
Overall, the review concludes that there is limited evidence that exercise therapy may provide short term benefit to some patients based on older, and broader diagnostic criteria for ME/CFS. In addition, Cochrane is uncertain, or very uncertain, about the long term benefits of exercise therapy and its associated risks. 

Importantly, Cochrane has committed to publish a full update of this review which will include the establishment of an independent advisory group which “will involve partners from patient-advocacy groups from different parts of the world”. Work will commence in 2020 and Emerge Australia has requested that they should be a part of this work. 

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Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls
Authors: Groven, N., Egil A.Fors, N.E, Reitanac, S.K,
Link: https://www.sciencedirect.com/science/article/pii/S0889159119302089

ME/CFS and Fibromyalgia (FM) both have clinical aspects which resemble inflammatory disorders and, in both conditions, it is thought that the immune system may play a role. C-reactive protein (CRP) is a blood marker which measures inflammation. This study used a high-sensitivity CRP (hsCRP) test, which is more sensitive than standard CRP tests, to examine CRP levels in both conditions as compared to healthy controls.

Results showed hsCRP levels were significantly higher for both the ME/CFS and FM groups compared to healthy controls and there were no differences between the two patient groups.

Overall, the higher hsCRP levels suggest inflammation is present in ME/CFS and FM patients, which may contribute to symptoms as inflammation is a well-known cause for fatigue and pain. The researchers note that inflammation could be both a target for treatment, as well as a marker to monitor the effectiveness of treatment.

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Editorial: Advances in ME/CFS Research and Clinical Care
Authors: Friedman, K.J.,   Bateman, K.,  Bested, A., & Nahle, Z.
Link: https://www.frontiersin.org/articles/10.3389/fped.2019.00370/full
This editorial provides an overview of a collection of 24 articles on ME/CFS published in the journals Frontiers in Neurology and Frontiers in Pediatrics. The collection, published between September 2018 and July 2019, sought to explore new and rejuvenated areas of ME/CFS research, as well as whether there have been improvements in clinical care. 

The editorial summarises the advances in ME/CFS research and clinical care over the last few decades, outlining the current lack of diagnostic methods and effective treatment for the illness and highlights the historical misunderstandings which patients have had to endure.

However, despite setbacks, advances are being made through the determination and compassion of those working in the field.  The collection includes: 

 
  • Three papers which evaluated potential clinical biomarkers such as hand grip strength, 2-day, cardiopulmonary exercise, and tilt table testing for diagnosing postural orthostatic tachycardia syndrome (POTS).
  • Current research into ME/CFS patient pathology including microbiome, neuroinflammation and cytokines, cardiovascular symptoms, and the establishment of biobanks to identify additional tissue abnormalities.
  • Research into how ME/CFS affects adolescents and what treatment and support benefitted them the most.
The authors note the lack of articles in the collection which focus on those who are severely unwell, despite making up 25% of the ME/CFS patient population. However, as a result of the interest in the papers in this collection, the editors have been invited to create another collection, called "ME/CFS—The Severely Affected”, which will focus exclusively on severe patients.
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NeuroImage: Clinical Volume 24, 2019, 102045


Intra brainstem connectivity is impaired in chronic fatigue syndrome
Author links open overlay panelLeighton RBarndenaZack YShanabDonald RStainesaSonyaMarshall-GradisnikaKevinFinegancTimothyIrelandcSandeepBhutac
https://doi.org/10.1016/j.nicl.2019.102045Get rights and content
Highlights
RAS connectivity was detected in HC and CFS groups both during rest and tasks
Strong connections were active for CFS from hippocampus to midbrain and medulla.
RAS connectivity was diminished in CFS in the brainstem and to the hippocampus.
RAS nuclei generate oscillatory signals which facilitate thalamocortical signal coherence.
Impaired RAS affects cortical coherence necessary for attention, memory and problem solving.
Abstract
In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

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Effect of tai chi versus aerobic exercise for fibromyalgia: comparative effectiveness randomized controlled trial
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k851 (Published 21 March 2018) Cite this as: BMJ 2018;360:k851 
Abstract
Objectives To determine the effectiveness of tai chi interventions compared with aerobic exercise, a current core standard treatment in patients with fibromyalgia, and to test whether the effectiveness of tai chi depends on its dosage or duration.
Design Prospective, randomized, 52 week, single blind comparative effectiveness trial.
Setting Urban tertiary care academic hospital in the United States between March 2012 and September 2016.
Participants 226 adults with fibromyalgia (as defined by the American College of Rheumatology 1990 and 2010 criteria) were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group.
Interventions Participants were randomly assigned to either supervised aerobic exercise (24 weeks, twice weekly) or one of four classic Yang style supervised tai chi interventions (12 or 24 weeks, once or twice weekly). Participants were followed for 52 weeks. Adherence was rigorously encouraged in person and by telephone.
Main outcome measures The primary outcome was change in the revised fibromyalgia impact questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patient’s global assessment, anxiety, depression, self efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health related quality of life.
Results FIQR scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group in FIQR scores at 24 weeks (difference between groups=5.5 points, 95% confidence interval 0.6 to 10.4, P=0.03) and several secondary outcomes (patient’s global assessment=0.9 points, 0.3 to 1.4, P=0.005; anxiety=1.2 points, 0.3 to 2.1, P=0.006; self efficacy=1.0 points, 0.5 to 1.6, P=0.0004; and coping strategies, 2.6 points, 0.8 to 4.3, P=0.005). Tai chi treatment compared with aerobic exercise administered with the same intensity and duration (24 weeks, twice weekly) had greater benefit (between group difference in FIQR scores=16.2 points, 8.7 to 23.6, P<0.001). The groups who received tai chi for 24 weeks showed greater improvements than those who received it for 12 weeks 
(difference in FIQR scores=9.6 points, 2.6 to 16.6, P=0.007). There was no significant increase in benefit for groups who received tai chi twice weekly compared with once weekly. Participants attended the tai chi training sessions more often than participants attended aerobic exercise. The effects of tai chi were consistent across all instructors. No serious adverse events related to the interventions were reported.
Conclusion Tai chi mind-body treatment results in similar or greater improvement in symptoms than aerobic exercise, the current most commonly prescribed non-drug treatment, for a variety of outcomes for patients with fibromyalgia. Longer duration of tai chi showed greater improvement. This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia.
Trial registration ClinicalTrials.gov NCT01420640.

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Clin Ther  2019 May;41(5):815-835.e6. doi: 10.1016/j.clinthera.2019.01.011. Epub 2019 Mar 6.
Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.
Jeffrey MG1, Nathanson L2, Aenlle K3, Barnes ZM4, Baig M5, Broderick G6, Klimas NG7, Fletcher MA3, Craddock TJA8.
Author information
1
Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA.
Abstract
PURPOSE:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
METHODS:
Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
FINDINGS:
The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
IMPLICATIONS:
The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies.
Copyright © 2019. Published by Elsevier Inc.
PMID:30851951 DOI:10.1016/j.clinthera.2019.01.011

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Neurosci Biobehav Rev. 2019 Dec;107:69-83. doi: 10.1016/j.neubiorev.2019.08.011. Epub 2019 Aug 26.
Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis.
Strawbridge R1, Sartor ML2, Scott F2, Cleare AJ2.
Author information
1
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Electronic address: Becci.strawbridge@kcl.ac.uk.
2
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Abstract
Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group. Results were meta-analysed from 42 studies. Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups. These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.
Copyright © 2019 Elsevier Ltd. All rights reserved.
KEYWORDS:
CFS; Chronic fatigue syndrome; Inflammation; ME/CFS; Meta-Analysis; Systematic review
PMID:31465778
 
DOI:10.1016/j.neubiorev.2019.08.011

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BMC Neurology     December 2019, 19:275 
A logistic regression analysis of risk factors in ME/CFS pathogenesis
  • Eliana M. LacerdaKeith Geraghty Caroline C. Kingdon Luigi Palla Luis Nacul
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whose exact cause remains unclear. A wide range of risk factors has been proposed that helps understanding potential disease pathogenesis. However, there is little consistency for many risk factor associations, thus we undertook an exploratory study of risk factors using data from the UK ME/CFS Biobank participants. We report on risk factor associations in ME/CFS compared with multiple sclerosis participants and healthy controls.
Methods
This was a cross-sectional study of 269 people with ME/CFS, including 214 with mild/moderate and 55 with severe symptoms, 74 people with multiple sclerosis (MS), and 134 healthy controls, who were recruited from primary and secondary health services. Data were collected from participants using a standardised written questionnaire. Data analyses consisted of univariate and multivariable regression analysis (by levels of proximity to disease onset).
Results
A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls. Being single (OR = 4.41, P <= 0.001), having lower income (OR = 3.71, P <= 0.001), and a family history of anxiety is associated with a higher risk of ME/CFS compared to healthy controls only (OR = 3.77, P < 0.001). History of frequent colds (OR = 6.31, P < 0.001) and infections before disease onset (OR = 5.12, P = 0.005), being single (OR = 3.66, P = 0.003) and having lower income (OR = 3.48, P = 0.001), are associated with a higher risk of ME/CFS than MS. Severe ME/CFS cases were associated with lower age of ME/CFS onset (OR = 0.63, P = 0.022) and a family history of neurological illness (OR = 6.1, P = 0.001).
Conclusions
Notable differences in risk profiles were found between ME/CFS and healthy controls, ME/CFS and MS, and mild-moderate and severe ME/CFS. However, we found some commensurate overlap in risk associations between all cohorts. The most notable difference between ME/CFS and MS in our study is a history of recent infection prior to disease onset. Even recognising that our results are limited by the choice of factors we selected to investigate, our findings are consistent with the increasing body of evidence that has been published about the potential role of infections in the pathogenesis of ME/CFS, including common colds/flu.
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Abstracts October 2019 #12

10/18/2019

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Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity
Brett A. Lidbury 1,*,Badia Kita 2,Alice M. Richardson 1,Donald P. Lewis 3,Edwina Privitera 3,Susan Hayward 4,David de Kretser 2,5 andMark Hedger 4
*
Diagnostics 2019, 9(3), 79; https://doi.org/10.3390/diagnostics9030079
Received: 28 May 2019 / Revised: 9 July 2019 / Accepted: 15 July 2019 / Published: 19 July 2019
(This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories. Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers. While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.  
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; activin; pathology; biomarker; cytokine; machine learning; reference intervals
Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Daniel Missailidis,Sarah J. Annesley andPaul R. Fisher *
Department of Physiology Anatomy and Microbiology, La Trobe University, VIC 3086, Australia
*
Diagnostics 2019, 9(3), 80; https://doi.org/10.3390/diagnostics9030080
Received: 18 June 2019 / Revised: 15 July 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift. Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.View Full-Text
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; ME/CFS; diagnosis; metabolism; mitochondria; inflammation; immune system; signaling; gut microbiota
Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
Article
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
Alex A. Kashi 1,Ronald W. Davis 1,2 andRobert D. Phair 3,*
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
Departments of Biochemistry and Genetics, Stanford University, Stanford, CA 94305, USA
Integrative Bioinformatics Inc., Mountain View, CA 94041, USA
Received: 24 May 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
Abstract
: 
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.
Keywords:
 tryptophan metabolism; indoleamine-2,3-dioxygenase; bistability; kynurenine pathway; substrate inhibition; myalgic encephalomyelitis; chronic fatigue syndrome; mathematical model; critical point
Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070
Article
Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases
Neil R. McGregor 1,*,Christopher W. Armstrong 2,Donald P. Lewis 3 andPaul R. Gooley 2
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville VIC 
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville VIC 3010, Australia
CFS Discovery, Donvale Medical Centre, Donvale VIC 3111, Australia
Received: 17 June 2019 / Accepted: 2 July 2019 / Published: 4 July 2019
Abstract
Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period. Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group. The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event. These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.
Human Microbiome Journal  Volume 13, August 2019, 100061
A retrospective outcome study of 42 patients with Chronic Fatigue Syndrome, 30 of whom had Irritable Bowel Syndrome. Half were treated with oral approaches, and half were treated with Faecal Microbiome Transplantation
J.N.Kenyona ShellyCoeb HooshangIzadib
Abstract
The gut microbiome comprises the community of microorganisms in the intestinal tract. Research suggests that an altered microbiome may play a role in a wide range of disorders including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods
42 participants with ME/CFS with Irritable Bowel Syndrome (IBS) were allocated into one of two groups, 21 were treated with standard oral approaches, which centred around various nutritional remedies, probiotics, prebiotics, dietary advice and lifestyle advice. The second group who had mostly failed using oral approaches, were treated with Faecal Microbiome Transplantation (FMT). Each patient received 10 Implants, each from a different screened donor, and the Implants were processed under anaerobic conditions. The transplant is delivered via a paediatric rectal catheter, which is inserted through the anus to reach the lower part of the sigmoid colon.
The results were assessed on a percentage basis before and after treatment, 0% being no improvement, 100% being maximum improvement. An exact non-parametric Mann-Whitney (one-tailed) test was used to compare medians from those on FMT compared with those receiving oral approaches only. On clinical experience over many years, the only way to judge improvement in Chronic Fatigue Syndrome as there is no test for Chronic Fatigue Syndrome, is my clinical assessment.
Results
The median for the FMT group was found to be significantly higher compared to the oral treatment group (Mann-Whitney U = 111.5, p = .003). Therefore, the FMT group improved to a greater extent (z = −2.761).
Conclusion
This study shows that FMT is a safe and a promising treatment for CFS associated with IBS. Adequately powered randomised controlled trials should be carried out to assess the effectiveness of FMT in patients with CFS and IBS.
Mitochondrial alterations in NK lymphocytes from ME/CFS patients
Isabel Barao Silvestre, Raul Y Dagda, Ruben K Dagda and Victor Darley-Usmar
J Immunol May 1, 2019, 202 (1 Supplement) 126.39;
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by profound fatigue, flu-like symptoms, trouble concentrating, and autonomic problems, all of which worsen after exertion. ME/CFS patients have impaired natural killer (NK) cell activity. NK lymphocytes are a critical first defense against viruses and cancer. ME/CFS patients have difficulties controlling viral infections and many develop non-Hodgkin’s lymphoma. Mitochondrial metabolism is crucial for immune cell function. Mitochondria dysfunction has been previously reported in ME/CFS, but it is not known whether the NK cells of these patients have altered mitochondrial metabolism that affect their activity and contribute to ME/CFS pathogenesis. More importantly, there is currently no efficient method to diagnose ME/CFS or assess efficacy of therapeutic interventions. The Bioenergetic Health Index (BHI) has been developed as promising and reliable surrogate readout of human health by measuring the bioenergetic status of immune cells. Variations in bioenergetic function in patient’s immune cells can reflect both metabolic stress and the mutable role of these cells in ME/CFS immunity and pathogenesis. In our study, we observed that the two main energy-generating mitochondrial pathways, oxidative phosphorylation and glycolysis (bioenergetics parameters), are deregulated in ME/CFS NK cells and in PBMCs. Moreover, we observed alterations in the morphology and membrane potential of the mitochondria of NK cells. These mitochondrial features can affect NK cell function and contribute to the severity of disease. To date, this is the first metabolism assessment of NK cells in ME/CFS and as potential new diagnostic tool for the disease.




    •    J-STAGE home   Biological and Pharmaceutical ...Volume 42 (2019) Issue 7
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice
Takuya Ohba, Shinichi Domoto, Miyu Tanaka, Shinsuke Nakamura, Masamitsu Shimazawa, Hideaki Hara
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients. Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS. To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA). In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group. DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS.
Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test
  • Cara Tomas, Tiffany A. Lodge, Michelle Potter, Joanna L. Elson, Julia L. Newton & Karl J. Morten 
Scientific Reportsvolume 9, Article number: 11464 (2019) |  
Abstract      The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test. We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group. Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.
Diagnostics 2019, 9(3), 91; https://doi.org/10.3390/diagnostics9030091
Review
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review
by Mateo Cortes Rivera 1,*,Claudio Mastronardi 2,Claudia T. Silva-Aldana 3,Mauricio Arcos-Burgos 4 andBrett A. Lidbury 
Facultad de Medicina, Grupo de Investigación Neuros, Universidad del Rosario, Bogotá 110211, Colombia INPAC Research Group, Fundación Universitaria Sanitas, Bogotá 110211, Colombia Center for Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110211, Colombia Group de Investigación en Psiquiatría (GIPSI), Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín 050002, Colombia The National Centre for Epidemiology and Population Health, RSPH, College of Health and Medicine, The Australian National University, Canberra ACT 2601, Australia
Received: 22 May 2019 / Accepted: 15 July 2019 / Published: 7 August 2019
Abstract 
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1. Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease. At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.
Front. Immunol., 14 August 2019 | https://doi.org/10.3389/fimmu.2019.01946
Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Jonas Blomberg1†, Muhammad Rizwan1, Agnes Böhlin-Wiener1‡, Amal Elfaitouri2, Per Julin3,4, Olof Zachrisson5, Anders Rosén6* and Carl-Gerhard Gottfries5
  • 1Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • 2Department of Infectious Disease and Tropical Medicine, Faculty of Public Health, Benghazi University, Benghazi, Libya
  • 3Neurological Rehabilitation Clinic, Stora Sköndal, Sköndal, Sweden
  • 4Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
  • 5Gottfries Clinic AB, Mölndal, Sweden
  • 6Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.
Ehlers-Danlos syndromes
BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4966 (Published 18 September 2019)Cite this as: BMJ 2019;366:l4966
  1. Neeti Ghali, consultant clinical geneticist1,  
  2. Glenda Sobey, consultant dermatologist and clinical lead2,  
  3. Nigel Burrows, consultant dermatologist3


What you need to know
  • Ehlers-Danlos syndromes (EDS) are inherited connective tissue disorders with variable severity; features include skin fragility, joint hypermobility, and rupture of blood vessels and internal organs
  • Consider the diagnosis of an EDS subtype in patients with any combination of easy bruising, poor scar formation, hyperextensible skin, joint hypermobility, joint pains without evidence of arthritis, and unexplained arterial or bowel rupture
  • Joint hypermobility alone is not enough to diagnose an EDS subtype, and not all types of EDS have pronounced hypermobility
  • Thirteen different types of EDS are currently recognised, with the molecular basis known in all except for hypermobile EDS
  • Genetic testing is recommended for EDS types with a known molecular cause to confirm the diagnosis.
Awareness of the Ehlers-Danlos syndromes (EDS) in the UK has risen over the past decade, in part due to high profile of EDS patient organisations and the EDS National Diagnostic Service commissioned in 2009. Significant advances in genetic testing have culminated in the publication of a new international classification in 2017 with 13 types identified.1 Clinicians will see an increasing number of patients, some of whom will suspect a diagnosis of EDS themselves.
This article is intended to support non-specialist clinicians to consider the diagnosis of this group of conditions in appropriate patients. It discusses the features of the different types of EDS and explains how clinicians can expect their patients to be managed in secondary care.
How this article was created
The authors are members of the International Consortium on Ehlers-Danlos Syndromes and Related Disorders and participated in literature searches used for the basis of the articles written on the new classification of EDS published in 2017. The authors have more than 10 years’ experience of EDS patient consultations and data collection in the highly specialised EDS service.
Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization
Simpson, Norah S.a; Scott-Sutherland, Jenniferb; Gautam, Shivac; Sethna, Navild; Haack, Monikab,*
PAIN: January 2018 - Volume 159 - Issue 1 - p 33–40
doi: 10.1097/j.pain.0000000000001053


Abstract
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
Pain-modulatory processes deteriorate with more chronic forms of sleep insufficiency and a couple of nights with limited recovery sleep do not resolve alterations.
Corresponding author. Address: 330 Brookline Ave, Dana 779, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel.: 617-667-5234. E-mail address: mhaack@bidmc.harvard.edu (M. Haack).
© 2018 International Association for the Study of Pain 
BMJ Open Sport Exerc Med. 2019 Jun 20;5(1):e000542. doi: 10.1136/bmjsem-2019-000542. eCollection 2019.
Novel insights of overtraining syndrome discovered from the EROS study.
Cadegiani FA1, Kater CE1.
Author information
Endocrinology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Abstract
BACKGROUND:
Excessive training and inadequate recovery could cause 'overtraining syndrome' (OTS), which is characterised by underperformance and fatigue. The pathophysiology of OTS is unclear. We aimed to describe novel mechanisms and risk factors associated with OTS, and thereby facilitate its early identification and prevention, from a comprehensive joint qualitative analysis of the findings from all the four arms of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study.
METHODS:
We compared the types and proportions of behavioural patterns of 67 evaluated parameters of OTS from 51 participants-athletes with OTS (OTS, n=14), healthy athletes (n=25) and healthy non-physically active controls (n=12). We performed overall and pairwise comparisons for statistically significant differences between the three groups (p<0.05).
RESULTS:
A total of 44 (65.7%) markers exhibited significant differences between the three groups: 32 (72.7%) showed a loss of the conditioning effect of exercise ('deconditioning'), 7 (15.9%) showed changes exclusive to OTS, 3 (6.8%) maintained the exercise-induced conditioning effects and 2 (4.5%) revealed an exacerbation of the adaptive changes to exercises.
CONCLUSION:
Our findings suggest that OTS is likely triggered by multiple factors, not restricted to excessive training, resulted from a chronic energy deprivation, leading to multiple losses in the conditioning processes typically observed in healthy athletes, as a combination of 'paradoxical deconditioning' processes, which explains the gradual and marked loss of physical conditioning found in OTS. We, therefore, suggest that the term 'paradoxical deconditioning syndrome' better represents the features of this syndrome.
KEYWORDS:
fatigue; hormones; overtraining syndrome; paradoxical deconditioning syndrome; sports endocrinology; sports performance
Hope, disappointment and perseverance: Reflections of people with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis participating in biomedical research.
Eliana Lacerda PhD, Clare McDermott PhD, Caroline C. Kingdon MSc, Jack Butterworth BA, Jacqueline M. Cliff PhD, Luis Nacul PhD 
The Clinical Understanding and Research Excellence in ME/CFS group (CureME) at the London School of Hygiene & Tropical Medicine has supported and undertaken studies in immunology, genetics, virology, clinical medicine, epidemiology and disability. It established the UK ME/CFS Biobank (UKMEB), which stores data and samples from three groups: participants with ME/CFS, Multiple Sclerosis (MS) and healthy controls. Patient and public involvement have played a central role from its inception. 
Aim To explore the views of participants with ME/CFS and MS on CureME research findings, dissemination and future biomedical research priorities. Method Five ME/CFS and MS focus groups were conducted at two UK sites. Discussions were transcribed and analysed thematically. 
Results A total of 28 UKMEB participants took part: 16 with ME/CFS and 12 with MS. Five themes emerged: (a) Seeking coherence: participants’ reactions to initial research findings; (b) Seeking acceptance: participants explore issues of stigma and validation; (c) Seeking a diagnosis: participants explore issues around diagnosis in their lives; (d) Seeking a better future: participants’ ideas on future research; and (e) Seeking to share understanding: participants’ views on dissemination. Focus groups perceived progress in ME/CFS and MS research in terms of “putting together a jigsaw” of evidence through perseverance and collaboration. Conclusion This study provides insight into the emotional, social and practical importance of research to people with MS and ME/CFS, suggesting a range of research topics for the future. Findings should inform biomedical research directions in ME/CFS and MS, adding patients’ voices to a call for a more collaborative research culture. Source: https://onlinelibrary.wiley.com/doi/full/10.1111/hex.12857
Latent Class Analysis of a Heterogeneous International Sample of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 
Kayla A. Huber, Madison Sunnquist, Leonard A. Jason 
Abstract Background: Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) routinely display differences in symptomatology, as well as illness course, onset, duration, and functional disability. Given such diversity, previous work has attempted to identify symptom-based ME/CFS subtypes. However, results have been inconsistent. 
Purpose: This study sought to elucidate potential subtypes of ME/CFS as well as explore the impact of subtype membership on health functioning. Methods: Twelve non-core (i.e., less frequently endorsed) symptoms were included in a latent class analysis of 1,210 adults with ME/CFS. Demographic and illness-related predictors of class membership were evaluated with a multinomial logistic regression. ANOVAs were then performed to determine if there were significant differences across class on the eight subscales of the ShortForm Health Survey (SF-36). Results: A six-class solution was selected, which consisted of one class that was likely to endorse all non-core symptoms, one class that was unlikely to endorse any noncore symptoms, and four classes that were likely to endorse either one or two non-core symptom domains (i.e., circulatory/neuroendocrine impairment, orthostatic intolerance, and gastro-intestinal distress). Significant functioning differences by class were present for all SF-36 subscales. 
Conclusions: These results are suggestive of subtypes of ME/CFS and, if replicated, may assist physicians in providing tailored treatment to patients and allow researchers to form more homogeneous samples. Source: HHS Public Access https://bit.ly/2kiHA1A
The IDO Metabolic Trap Hypothesis For The Etiology of ME/CFS 
Alex A. Kashi , Ronald W. Davis and Robert D. Phair 
Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics. Source: Diagnostics, https://www.mdpi.com/2075-4418/9/3/82 Open access. Full text: https://www.mdpi.com/2075-4418/9/3/82/htm
Diagnostic Sensitivity of 2-Day Cardiopulmonary Exercise Testing in ME/CFS Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 
Maximillian J. Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Daniel Clark, Richard Kwiatek & Kade Davison
 Abstract Background There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established. 
Methods 16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days. 
Results WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of − 6.3% to − 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls. 
Conclusion The decrease in WR at VT of 6.3–9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS. Source: BMC https://bit.ly/2YrHEya (open access)
From Pathophysiological Insights to Novel Therapeutic Opportunities Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: From Pathophysiological Insights to Novel Therapeutic Opportunities 
Gerwyn Morris, Basant K. Puri, Adam J. Walker. Michael Maes, Andre F.Carvalho, Ken Walder, Catherine Mazza. Michael Berk 
Abstract Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities, in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
 Source: Elsevier https://bit.ly/2lY9VuG, Paywall
The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions 
Leonard A. Jason* and Madison Sunnquist - Center for Community Research, DePaul University, Chicago, IL, United States 
One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions. 
The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed. The DSQ has demonstrated very good psychometric properties in terms of testretest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity. The DSQ allows for a clear characterization of a patient’s illness and allows scientists and clinicians to improve diagnostic reliability and validity when employing case definitions of ME and CFS. Since 1994, many researchers have used the Fukuda et al. chronic fatigue syndrome (CFS) case definition to select cases, but problems emerged in part due to this case definition not requiring core symptoms of CFS . 
In contrast, myalgic encephalomyelitis (ME) and CFS specialists have developed several adult case definitions that require essential symptoms of ME and CFS: the Canadian Consensus Criteria ME (CCC), the ME-International Consensus Criteria (ICC), and Systemic Exertion Intolerance Disease (SEID). These case definitions are a set of rules that allows investigators and clinicians to determine who has and who does not have an illness. In other words, the goals involve sensitivity (selecting those with the illness) and specificity (not selecting those without the illness). 
Criterion variance represents the largest source of diagnostic unreliability for case definitions, and it involves specifying symptoms to classify patients’ symptoms into diagnostic categories . Criterion variance can occur when there are multiple case definitions without a consensus on which symptoms need to be manifested to arrive at a diagnosis. In addition, case definition unreliability occurs when there is no consensus on scoring rules that specify how to determine whether a particular symptom is severe enough to qualify as satisfying criteria for the case definition, or when symptoms are not assessed by standardized instruments. 
These issues can result in investigators selecting samples of patients who are different on fundamental aspects of this illness. The consequences of these types of unreliability include difficulties replicating findings at different laboratories, estimating prevalence rates, identifying biomarkers, and determining effective treatments. ME and CFS case definitions have some overlapping and some different diagnostic criteria.
 In spite of the fact that there are currently alternative case definitions, it is still important to develop standardized ways to measure the symptoms just as this has occurred with other illnesses. The National Institutes of Health/Centers for Disease Control and Prevention (NIH/CDC) Common Data Elements (CDE) working group has recently recommended a set of instruments to be used by researchers, and for baseline symptoms the working group recommended using either the DePaul Symptom Questionnaire (DSQ) or a combined instrument using both the CDC’s Symptom Inventory (SI) as well as items from the DSQ (even though the SI and DSQ differ on a number of dimensions, including the time period in which symptoms are measured and anchor points for the assessment of symptoms). Because of the recommendation for the use of the DSQ, this article reviews the genesis and psychometric properties of the different versions of the DSQ. 
Source: https://bit.ly/2m0Yi6c Open access
Work Rehabilitation And Medical Retirement For Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients A Review and Appraisal of Diagnostic Strategies 
by Mark Vink and Friso Vink-Niese Received: 7 June 2019 / Revised: 11 September 2019 / Accepted: 13 September 2019 / Published: 20 September 2019 (This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS) https://bit.ly/2svVX3i 
Abstract Myalgic Encephalomyelitis/Chronic Fatigue Syndrome leads to severe functional impairment and work disability in a considerable number of patients. The majority of patients who manage to continue or return to work, work parttime instead of full time in a physically less demanding job. The prognosis in terms of returning to work is poor if patients have been on longterm sick leave for more than two to three years. Being older and more ill when falling ill are associated with a worse employment outcome. Cognitive behavioral therapy and graded exercise therapy do not restore the ability to work. Consequently, many patients will eventually be medically retired depending on the requirements of the retirement policy, the progress that has been made since they have fallen ill in combination with the severity of their impairments compared to the sort of work they do or are offered to do. However, there is one thing that occupational health physicians and other doctors can do to try and prevent chronic and severe incapacity in the absence of effective treatments. Patients who are given a period of enforced rest from the onset, have the best prognosis. Moreover, those who work or go back to work should not be forced to do more than they can to try and prevent relapses, long-term sick leave and medical retirement. 
Read the whole paper (open access) here: https://bit.ly/2mtq4sj


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Abstracts July 2019

7/29/2019

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Chiari malformations: principles of diagnosis and management
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1159 (Published 08 April 2019)Cite this as: BMJ 2019;365:l1159
  1. Rory J Piper, academic clinical fellow and neurosurgical trainee1,  
  2. Michael Pike, honorary consultant paediatric neurologist2,  
  3. Richard Harrington, honorary senior clinical lecturer and general practitioner3,  
  4. Shailendra A Magdum, consultant paediatric neurosurgeon1
What you need to know
  • There are different types of Chiari malformation, but they generally share the feature of the hindbrain protruding through the foramen magnum and into the spinal canal
  • Chiari 1 malformation (CM1) is more common and typically presents in childhood or early adulthood with a combination of pain (headache, neck pain, or back pain), fatigue, poor memory, and neurological symptoms. Up to a quarter of patients have no symptoms
  • Suspect Chiari 2 malformation (CM2) in infants with myelomeningocele. It may be diagnosed antenatally on ultrasound scan. Around 1 in 5 children will have associated symptoms
  • Refer patients with a confirmed or suspected diagnosis to a neurosurgeon for further investigations and management
  • The key investigation is magnetic resonance imaging of the brain and whole spine. Lumbar puncture must not be performed in these patients
  • Offer support for long term follow-up and management of symptoms. Surgery may be considered in patients with significant or progressive symptoms
Chiari malformations are a heterogeneous group of hindbrain anomalies. Six different malformations are described. Most common are Chiari 1 malformation (CM1) and Chiari 2 malformation (CM2, also termed “Arnold-Chiari malformation”) and are the focus of this review.
These are rare conditions, but symptoms may impair quality of life in both adults and children,1 causing disruption to work or education and social exclusion. The diagnosis is often delayed or missed as symptoms may be mistaken for other neurological conditions or attributed as psychogenic.2 Not enough information or explanation from healthcare professionals3 can aggravate patients’ fears on being diagnosed. Although some patients improve after surgery, others experience lifelong symptoms, progression of deficits, need for re-operation, and complications.
Non-specialists can play an important role in early diagnosis and referral, counselling, and supporting long term care for these patients. 
Front. Pediatr., 18 April 2019 | https://doi.org/10.3389/fped.2019.00131

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Advances in ME/CFS: Past, Present, and Future
Kenneth J. Friedman*  Retired, Plantation, FL, United States
The forerunner of what is today termed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was described by the U.S. Public Health Service in 1934. At the present time, we still do not know its cause and/or how to detect it by routine clinical laboratory tests. In consequence, the pathological nature of ME/CFS has been overlooked and the disease has been stigmatized by being mislabeled as psychosomatic or somatoform illness. Such misperceptions of the disease have led to insufficient research exploration of the disease and minimal to absent patient care. A 2015 Institute of Medicine report on the illness declared ME/CFS a disease affecting up to 2.5 million Americans and chastised the U.S. government for doing little to research the disease and to support its patients. Clinicians who currently treat this disease declare it to be more devastating than HIV/AIDS. A comparison of the histories of the two diseases, an examination of the current status of the two diseases, and a listing of the accomplishments that would be needed for ME/CFS to achieve the same level of treatment and care as currently experienced by patients with HIV/AIDS is provided.
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A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
R. Esfandyarpour, A. Kashi, M. Nemat-Gorgani, J. Wilhelmy, and R. W. Davis
PNAS first published April 29, 2019 https://doi.org/10.1073/pnas.1901274116
Contributed by R. W. Davis, March 26, 2019 (sent for review February 5, 2019; reviewed by Javad Gatabi and David R. Hillyard)
Significance
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease which afflicts approximately 2 million people in the United States and many more around the globe. A combination of factors might trigger ME/CFS, and there is currently no well-established blood-based biomarker to diagnose it. Taking advantage of advancements in micro/nanofabrication, direct electrical detection of cellular and molecular properties, microfluidics, and artificial intelligence techniques, we developed a nanoelectronics blood-based assay that can potentially establish a diagnostic biomarker and a drug-screening platform for ME/CFS. Given the significance of this assay, we envision it has the potential to be widely employed in research laboratories and clinics in the future as an aid to physicians as well as to our colleagues in the ME/CFS research community.
Abstract
There is not currently a well-established, if any, biological test to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The molecular aberrations observed in numerous studies of ME/CFS blood cells offer the opportunity to develop a diagnostic assay from blood samples. Here we developed a nanoelectronics assay designed as an ultrasensitive assay capable of directly measuring biomolecular interactions in real time, at low cost, and in a multiplex format. To pursue the goal of developing a reliable biomarker for ME/CFS and to demonstrate the utility of our platform for point-of-care diagnostics, we validated the array by testing patients with moderate to severe ME/CFS patients and healthy controls. The ME/CFS samples’ response to the hyperosmotic stressor observed as a unique characteristic of the impedance pattern and dramatically different from the response observed among the control samples. We believe the observed robust impedance modulation difference of the samples in response to hyperosmotic stress can potentially provide us with a unique indicator of ME/CFS. Moreover, using supervised machine learning algorithms, we developed a classifier for ME/CFS patients capable of identifying new patients, required for a robust diagnostic tool.
Mol Med 2019 Apr 23;25(1):14. doi: 10.1186/s10020-019-0083-4.

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Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients.
Cabanas H1,2,3, Muraki K4,5, Balinas C6,7,5, Eaton-Fitch N6,7,5, Staines D6,7,5, Marshall-Gradisnik S
Abstract
BACKGROUND:
Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding. The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets. We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients. We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients. Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique. In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin. Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.
METHODS:
Whole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.
RESULTS:
We confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls. The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients. In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.
CONCLUSIONS:
Impaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research. This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.
PMID:  31014226  DOI:  10.1186/s10020-019-0083-4

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Pain Res Treat 2019 Jan 16;2019:2623161. doi: 10.1155/2019/2623161. eCollection 2019.
Motor Cortex Function in Fibromyalgia: A Study by Functional Near-Infrared Spectroscopy.
Gentile E1, Ricci K1, Delussi M1, Brighina F2, de Tommaso M1.

Abstract
Previous studies indicated changes of motor cortex excitability in fibromyalgia (FM) patients and the positive results of transcranial stimulation techniques. The present study aimed to explore the metabolism of motor cortex in FM patients, in resting state and during slow and fast finger tapping, using functional Near-Infrared Spectroscopy (fNIRS), an optical method which detects in real time the metabolism changes in the cortical tissue. We studied 24 FM patients and 24 healthy subjects. We found a significant slowness of motor speed in FM patients compared to controls. During resting state and slow movement conditions, the metabolism of the motor areas was similar between groups. The oxyhemoglobin concentrations were significantly lower in patients than in control group during the fast movement task. This abnormality was independent from FM severity and duration. The activation of motor cortex areas is dysfunctional in FM patients, thus supporting the rationale for the therapeutic role of motor cortex modulation in this disabling disorder.
PMID:30792923 PMCID:PMC6354141   DOI:10.1155/2019/2623161
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Is insulin resistance the cause of fibromyalgia? A preliminary report
Miguel A. Pappolla , Laxmaiah Manchikanti,Clark R. Andersen,Nigel H. Greig,Fawad Ahmed,
Xiang Fang,Michael A. Seffinger,Andrea M. Trescot

  • Published: May 6, 2019
  • https://doi.org/10.1371/journal.pone.0216079
Abstract
Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.
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Brain Imaging and behaviour  2019  pp1-16
Resting-state functional connectivity, cognition, and fatigue in response to cognitive exertion: a novel study in adolescents with chronic fatigue syndrome
  • Authors
  • Elisha K. Josev,Charles B. Malpas,Marc L. Seal, Adam Scheinberg  Lionel Lubitz
  • Kathy Rowe,Sarah J. Knight
First Online: 17 May 2019
Abstract
Emerging evidence suggests that central nervous system dysfunction may underlie the core symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in adults, such as cognitive disturbance, fatigue and post-exertional malaise. Research into brain dysfunction in the pediatric CFS/ME context, however, is severely lacking. It is unclear whether the adolescent CFS/ME brain functions differently compared with healthy peers, particularly in situations where significant mental effort is required. This study used resting-state functional MRI in a novel repeated-measures design to evaluate intrinsic connectivity, cognitive function, and subjective fatigue, before and after a period of cognitive exertion in 48 adolescents (25 CFS/ME, 23 healthy controls). Results revealed little evidence for a differential effect of cognitive exertion in CFS/ME compared with controls. Both groups demonstrated a similar rate of reduced intrinsic functional connectivity within the default mode network (DMN), reduced sustained attentional performance, slower processing speed, and increased subjective fatigue as a result of cognitive exertion. However, CFS/ME adolescents consistently displayed higher subjective fatigue, and controls outperformed the CFS/ME group overall on cognitive measures of processing speed, sustained attention and new learning. No brain-behavior relationships were observed between DMN connectivity, cognitive function, and fatigue over time. These findings suggest that effortful cognitive tasks may elicit similar levels of energy expenditure across all individuals in the form of reduced brain functioning and associated fatigue. However, CFS/ME may confer a lower starting threshold from which to access energy reserves and cognitive resources when cognitive effort is required.
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Brain, Behavior, and Immunity
Available online 7 June 2019
Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls
NinaGrovenacEgil A.ForsbSolveig KlæboReitanac
https://doi.org/10.1016/j.bbi.2019.06.010Get rights and content
Abstract
Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are both chronic disorders that have a devastating effect on the lives of the affected patients and their families. Both conditions have overlapping clinical features that partly resemble those of inflammatory disorders. The etiology is still not understood, and it is suggested that the immune system might be a contributing factor. So far, the results are inconclusive. The purpose of this study was to compare the two conditions and investigate the level of the inflammatory marker high-sensitivity CRP (hsCRP) in CFS and FM patients compared to healthy controls.
Female participants aged 18–60 years were enrolled in this study. The group consisted of 49 CFS patients, 57 FM patients, and 54 healthy controls. hsCRP levels were significantly higher for both the CFS and the FM groups compared to healthy controls when adjusting for age, smoking, and BMI (p < .001). There was no difference between the two patient groups. The level of hsCRP was affected by BMI but not by age and smoking.
Patients with CFS and FM have higher concentrations of hsCRP compared to healthy controls. This remains significant even after adjusting for BMI. CFS and FM cannot be distinguished from each other on the basis of hsCRP in our study.
PAIN. JUN 2019
DOI: 10.1097/j.pain.0000000000001640
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PMID: 31219947 Issn Print: 0304-3959 Publication Date: 2019/06/01
Altered microbiome composition in individuals with fibromyalgia
Amir Minerbi;Emmanuel Gonzalez;Nicholas Brereton;Abraham Anjarkouchian;Ken Dewar;Mary-Ann Fitzcharles;Stéphanie Chevalier;Yoram Shir;
  • Abstract:
Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole genome sequencing. When comparing FM patients to unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine learning algorithms, the microbiomecomposition alone allowed for the classification of patients and controls (ROC AUC 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
© 2019 International Association for the Study of Pain
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Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. 
Physiological Reports, 2019 Jun; 7(11) http://bit.ly/2XQM6Ty 
Lien K1,2, Johansen B3, Veierød MB4, Haslestad AS1, Bøhn SK1, Melsom MN5, Kardel KR1, Iversen PO1,6.
Abstract
Post-exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO2 ) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa ]) is unknown. We studied 18 female patients (18-50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18-50 years) who underwent repeated CPETs 24 h apart (CPET1 and CPET2 ) with [Laa ] measured every 30th second. VO2 at peak exercise (VO2peak ) was lower in patients than in controls on CPET1 (P < 0.001) and decreased in patients on CPET2 (P < 0.001). However, the difference in VO2peak between CPETs did not differ significantly between groups. [Laa ] per PO was higher in patients during both CPETs (Pinteraction  < 0.001), but increased in patients and decreased in controls from CPET1 to CPET2 (Pinteraction  < 0.001). Patients had lower VO2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO2 production increases relative to VO2 ), but relative intensity (%VO2peak ) and [Laa ] at GET did not differ significantly from controls on CPET1 . Patients had a reduction in VO2 (P = 0.02) and PO (P = 0.01) at GET on CPET2 , but no significant differences in %VO2peak and [Laa ] at GET between CPETs. Controls had no significant differences in VO2 , PO or %VO2peak at GET between CPETs, but [Laa ] at GET was reduced on CPET2 (P = 0.008). In conclusion, previous exercise deteriorates physical performance and increases [Laa ] during exercise in patients with ME/CFS while it lowers [Laa ] in healthy subjects.
© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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The ‘Cognitive Behavioural Model’ Of Chronic Fatigue Syndrome: Critique Of A Flawed Model 
Keith Geraghty, Leonard Jason, Madison Sunnquist, David Tuller, Charlotte Blease and Charles Adeniji (The following paragraphs are taken from the study – The Editors)
 Chronic fatigue syndrome/myalgic encephalomyelitis is a debilitating illness that greatly impacts the lives of sufferers. A cognitive behavioural model attempts to explain illness onset and continuance with a hypothesis that the illness is perpetuated by patients’ irrational beliefs and avoidance behaviours. This theory underpins the promotion of cognitive behavioural therapy, a treatment that aims to change beliefs and behaviours. This article reports on a detailed review of the cognitive behavioural model. Our review finds that the model lacks high-quality evidential support, conflicts with accounts given by most patients and fails to account for accumulating biological evidence of pathological and physiological abnormalities found in patients. There is little scientific credibility in the claim that psycho-behavioural therapies are a primary treatment for this illness. The CBM of ME/CFS CBT originated in the ground-breaking work of Beck in the 1960s and 1970s, as an experimental psychological treatment for depression (Beck, 1976). Since then, the application of CBT has widened to the treatment of anxiety, phobias, obsessive compulsive disorders and more recently, ME/CFS (Wessely et al., 1989). In the United Kingdom, in the late 1980s/early 1990s, psychiatrists proposed that Beck’s CBT could be used to treat ME/CFS. A model of CFS was proposed by psychiatry that dismissed Ramsay’s ME organic infectious disease in favour of a mostly psychogenic model of CFS. The ‘cognitive behavioural model’ of CFS is Beck’s CBT modified and applied to CFS. In this sense, the CBM of ME/CFS is distinct from Beck’s CBM for depression – and must be assessed on its own merits. Proponents of the CBM write, cognitive behavioural models propose that beliefs about the unacceptability of experiencing or expressing negative thoughts and emotions can play a central role in the development and maintenance of clinical problems and can be associated with a poorer prognosis or treatment outcome. (Rimes and Chalder, 2010) Sharpe (2007, citing Wessely et al., 1989) concedes that the theory behind the use of CBT in CFS is weak: ‘… treatment is plausible, but lacks a theoretical rationale. It is possible to construct a hypothetical model by assuming that the aforementioned factors interact in self-perpetuating vicious circles’. The notion of ‘a cycle’ is repeated throughout the CBM literature. 61 Back to Table Of Contents Problematic evidence from clinical trials and practice Proponents of the CBM consistently argue that the model is validated via the success of CBT and GET in randomised controlled trials and clinical practice. It would be impossible to critique all CBT trial evidence within the confines of this article, thus we point readers to reviews of the field (Rimbaut et al., 2016) and systematic reviews (Larun et al., 2016; Price et al., 2008) that appear to show, prima facie, that CBT and GET outperform other treatments for ME/ CFS (mostly usual care) with small-tomodest effect sizes. However, this evidence is increasingly contested by reanalysis of data from clinical trials (Geraghty et al., 2017; Wilshire et al., 2018) and meta-reviews (Vink and VinkNiese, 2018). Many patients seen in CFS treatment studies appear to be drawn from psychiatric centres with high rates of psychiatric morbidity. In the study of Wessely and Powell (1989), 22 (47%) patients met the criteria for major depressive disorder. The inclusion of patients with mental health complaints that might explain their presenting fatigue is a contamination issue that persists to this day in clinical trials of CBT treatment for ME/CFS (Taylor et al., 2003). In Wessely and Powell’s work, approximately half of patients with CFS were indistinguishable from the control patients with psychiatric disorders, except for illness attribution and CFS diagnosis. Conclusion In this article, we reviewed the CBM of ME/CFS. This model is often cited in the literature as a model to guide clinical practice and treatment of this illness. We find this model to be primarily an idealised narrative model. It exists as a dogmatic model favoured by model promoters. Our review exposes stark weaknesses, inconsistencies and contradictions, both in its theoretical underpinnings and the research said to prove model validity. Our findings suggest the CBM is not fit for purpose, as it poorly reflects the accounts given by patients and it ignores the wealth of evidence showing biological, immune and neurological dysfunction in ME/CFS. Given that the CBM is cited as the basis for CBT and GET interventions, there is an urgent need for clinicians, therapists and health providers to review this treatment paradigm. Our findings help explain why so many patients reject psychotherapy. An alternative model should be formulated to better explain the biological factors that predispose, precipitate and perpetuate the illness. An explanatory model needs to closely resemble illness pathogenesis and provide logic-driven linkages between factors, including patients’ symptoms and illness behaviours. Source: http://bit.ly/2FdIGTJ Submitted by Prof. Leonard Jason
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Molecular Switch For 'Exhaustion Mode' Of Immune Cells Discovered TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection 
Francesca Alfei, Kristiyan Kanev, Maike Hofmann, Ming Wu, Hazem E. Ghoneim, Patrick Roelli, Daniel T. Utzschneider, Madlaina von Hösslin, Jolie G. Cullen, Yiping Fan, Vasyl Eisenberg, Dirk Wohlleber, Katja Steiger, Doron Merkler, Mauro Delorenzi, Percy A. Knolle, Cyrille J. Cohen, Robert Thimme, Benjamin Youngblood & Dietmar Zehn 
Nature , 17 June 2019
 Abstract Cytotoxic T-cells are essential mediators of protective immunity to viral infection and malignant tumors and are a key target for immunotherapy approaches. However, prolonged exposure to cognate antigen often attenuates the effector capacity of T-cells and limits their therapeutic potential. This process, known as T-cell exhaustion or dysfunction, is manifest through epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and up-regulate the expression of inhibitory receptors such as Programmed Cell-Death 1 (PD-1). Thus far, the underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T-cells are vaguely understood9– 12. Here we report that the development and maintenance of exhausted T-cell populations requires the thymocyte selection-associated high mobility group-box protein (Tox). Tox is induced by high antigen T-cell receptor stimulation and correlates with the presence of an “exhausted” phenotype during chronic Lymphocytic choriomeningitis virus and human hepatitis C virus infection. Removal of its DNA-binding domain reduces PD-1 expression, augments cytokine production, and results in a more polyfunctional T-cell phenotype. Such mutated T-cells initially mediate increased effector function and cause more severe immunopathology but ultimately undergo a massive decline in their quantity, notably among the subset of Tcf1+ self-renewing T cells. Altogether, we establish Tox as a critical factor for the normal progression of T-cell dysfunction, for the maintenance of exhausted T-cells during chronic infection, and we document a link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology. 
Source: https://go.nature.com/2WNJKDG.
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Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Eiren Sweetman 1,Alex Noble 1,Christina Edgar 1,Angus Mackay 1,Amber Helliwell 1,Rosamund Vallings 2,Margaret Ryan 3 andWarren Tate 1,*
Diagnostics 2019, 9(3), 73; https://doi.org/10.3390/diagnostics9030073
Received: 30 May 2019 / Revised: 22 June 2019 / Accepted: 3 July 2019 / Published: 10 July 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2–3 years that promise new leads towards an effective clinical diagnostic test that may have a general application. Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.  

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Altered microbiome composition in individuals with fibromyalgia
Minerbi, Amir1; Gonzalez, Emmanuel2,3; Brereton, Nicholas J.B.4; Anjarkouchian, Abraham5; Dewar, Ken3,6; Fitzcharles, Mary-Ann1,7; Chevalier, Stéphanie5,8,9; Shir, Yoram1
PAIN: June 18, 2019 - Volume Articles in Press - Issue - p
doi: 10.1097/j.pain.0000000000001640
  • Abstract
Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole genome sequencing. When comparing FM patients to unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine learning algorithms, the microbiomecomposition alone allowed for the classification of patients and controls (ROC AUC 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
© 2019 International Association for the Study of Pain

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Monitoring treatment harm in myalgic encephalomyelitis/chronic fatigue syndrome: A freedom-of-information study of National Health Service specialist centres in England
Graham McPhee, Adrian Baldwin, Tom Kindlon, First Published June 24, 2019 Research 
https://doi.org/10.1177/1359105319854532

Abstract
The use of graded exercise therapy and cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome has attracted considerable controversy. This controversy relates not only to the disputed evidence for treatment efficacy but also to widespread reports from patients that graded exercise therapy, in particular, has caused them harm. We surveyed the National Health Service–affiliated myalgic encephalomyelitis/chronic fatigue syndrome specialist clinics in England to assess how harms following treatment are detected and to examine how patients are warned about the potential for harms. We sent 57 clinics standardised information requests under the United Kingdom’s Freedom of Information Act. Data were received from 38 clinics. Clinics were highly inconsistent in their approaches to the issue of treatment-related harm. They placed little or no focus on the potential for treatment-related harm in their written information for patients and for staff. Furthermore, no clinic reported any cases of treatment-related harm, despite acknowledging that many patients dropped out of treatment. In light of these findings, we recommend that clinics develop standardised protocols for anticipating, recording, and remedying harms, and that these protocols allow for therapies to be discontinued immediately whenever harm is identified.
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Unemployment and work disability in individuals with chronic fatigue syndrome/myalgic encephalomyelitis: a community-based cross-sectional study from Spain
  • Jesús Castro-Marrero†Email authorView ORCID ID profile,Mónica Faro†, María Cleofé Zaragozá,Luisa Aliste,Tomás Fernández de Sevilla and
  • José Alegre
BMC Public Health201919:840
https://doi.org/10.1186/s12889-019-7225-z       Published: 28 June 2019
Abstract
Background
Few reports have examined the association between unemployment and work disability in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). This study explored the key determinants of work disability in a CFS/ME cohort.
Methods
A community-based prospective study included 1086 CFS/ME patients aged 18–65 years. Demographic and clinical characteristics and outcome measures were recorded. Multiple linear regression analysis was performed to identify key risk indicators of work disability.
Results
Four hundred and fifty patients with CFS/ME were employed (41.4%) and 636 were unemployed (58.6%). Older age at pain onset (OR: 1.44; 95% CI: 1. 12–1.84, autonomic dysfunction (OR: 2.21; 95% CI: 1.71–2.87), neurological symptom (OR: 1.66; 95% CI: 1. 30–2.13) and higher scores for fatigue (OR: 2.61; 95% CI: 2.01–3.39), pain (OR: 2.09; 95% CI: 1.47–2.97), depression (OR: 1.98; 95% CI: 1. 20–3.26), psychopathology (OR: 1.98; 95% CI: 1.51–2.61) and sleep dysfunction (OR: 1.47; 95% CI: 1. 14–1.90) were all associated with a higher risk of work disability due to illness.
Conclusions
Using an explanatory approach, our findings suggest that unemployment is consistently associated with an increased risk of work disability due to CFS/ME, although further more rigorous research is now needed to help in targeting interventions at the workplace.
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Front. Pediatr., 24 May 2019 | https://doi.org/10.3389/fped.2019.00206
Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study
Melanie Perez1, Rajeev Jaundoo2,3, Kelly Hilton1, Ana Del Alamo1,3, Kristina Gemayel1, Nancy G. Klimas1,3,4, Travis J. A. Craddock1,2,3,5* and Lubov Nathanson1,3*
Introduction: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness of unknown etiology with considerable social and economic impact. To investigate a putative genetic predisposition to ME/CFS we conducted genome-wide single-nucleotide polymorphism (SNP) analysis to identify possible variants.
Methods: 383 ME/CFS participants underwent DNA testing using the commercial company 23andMe. The deidentified genetic data was then filtered to include only non-synonymous and nonsense SNPs from exons and microRNAs, and SNPs close to splice sites. The frequencies of each SNP were calculated within our cohort and compared to frequencies from the Kaviar reference database. Functional annotation of pathway sets containing SNP genes with high frequency in ME/CFS was performed using over-representation analysis via ConsensusPathDB. Furthermore, these SNPs were also scored using the Combined Annotation Dependent Depletion (CADD) algorithm to gauge their deleteriousness.
Results: 5693 SNPs were found to have at least 10% frequency in at least one cohort (ME/CFS or reference) and at least two-fold absolute difference for ME/CFS. Functional analysis identified the majority of SNPs as related to immune system, hormone, metabolic, and extracellular matrix organization. CADD scoring identified 517 SNPs in these pathways that are among the 10% most deleteriousness substitutions to the human genome.
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Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Marshall V. Williams PhD      Brandon Cox     William P. Lafuse PhD      Maria Eugenia Ariza, PhD 
DOI: https://doi.org/10.1016/j.clinthera.2019.04.009     Clinical Therapeutics
Abstract
Neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affecting 85%–90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. Multiple reports, however, have suggested a role for Epstein-Barr virus (EBV), in particular, in ME/CFS, but its potential role, if any, in the neuroinflammatory process has not been addressed. In support of this premise, studies by our group have found that the EBV protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) induces anxiety and sickness behaviors in female mice. We also found that a small subset of patients with ME/CFS exhibited prolonged and significantly elevated neutralizing antibodies against EBV dUTPase protein in serum, which inversely correlated with ME/CFS symptoms. A larger ME/CFS case–control cohort study further confirmed that a significant percentage of patients with ME/CFS (30.91%–52.7%) were simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or human dUTPase. Altogether, these findings suggest that EBV dUTPase protein may be involved in the neuroinflammatory process observed in ME/CFS. Thus, the aim of the present study was to determine whether the EBV dUTPase protein could contribute to neuroinflammation by altering the expression of genes involved with maintaining blood–brain barrier (BBB) integrity and/or modulating synaptic plasticity.
Methods
With the use of human immortalized astrocytes, microglia, and cerebral microvascular endothelial cells, we conducted time-course (0–24 h) experiments with EBV dUTPase protein (10 μg/mL) to determine what effect(s) it may have on the expression of genes involved with BBB permeability, astrocytes and microglia cell function, tryptophan metabolism, and synaptic plasticity by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In parallel, in vivo studies were conducted in female C57Bl/6 mice. Mice were injected by the intraperitoneal route with EBV dUTPase protein (10 μg) or vehicle daily for 5 days, and the brains were collected and processed for further qRT-PCR analysis of the in vivo effect of the dUTPase on the dopamine/serotonin and γ-aminobutyric acid/glutamate pathways, which are important for brain function, using RT2 Profiler PCR Arrays.
Findings
EBV dUTPase protein altered the expression in vitro (12 of 15 genes and 32 of 1000 proteins examined) and in vivo (34 of 84 genes examined) of targets with central roles in BBB integrity/function, fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism.
Implications
The data suggest that in a subset of patients with ME/CFS, the EBV dUTPase could initiate a neuroinflammatory reaction, which contributes to the fatigue, excessive pain, and cognitive impairments observed in these patients.
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Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome
Maria PiaGiannoccaro1JudithCossins1KariSørland2ØysteinFluge2AngelaVincent1
https://doi.org/10.1016/j.clinthera.2019.04.001Get rights and content
Abstract
Purpose
A role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CFS.
Methods
Sera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated.
Findings
Overall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease.
Implications
The results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.
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Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
Article
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
Alex A. Kashi 1,Ronald W. Davis 1,2 and Robert D. Phair 3,*
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
Departments of Biochemistry and Genetics, Stanford University, Stanford, CA 94305, USA
Integrative Bioinformatics Inc., Mountain View, CA 94041, USA
Received: 24 May 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.
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Abstracts 2 December 2018 - April 2019

4/12/2019

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Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome
Amit K Saha, Brendan R Schmidt, Julie Wilhelmy, Vy Nguyen, Justin Do, Vineeth C Suja, Mohsen Nemat-Gorgani, Anand K Ramasubramanian and Ronald W Davis
Blood 2018 132:4874; doi: https://doi.org/10.1182/blood-2018-99-117260 
    Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide, with the capacity to persist for several years. ME/CFS is characterized by disabling fatigue of at least 6 months, accompanied serious fatigue and musculoskeletal pain, in addition to impaired short-term memory or concentration, and unrefreshing sleep or extended post-exertional. While the etiology of the disease is still debated, evidence suggest oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes. The shape of erythrocytes change from biconcave discoid to an ellipsoid due shear flow in microcapillaries that provides a larger specific surface area-to-volume ratio for optimal microvascular perfusion and tissue oxygenation establishing the importance not only of total hematocrit but also of the capacity for large deformations in physiology. Clinically, ME/CFS patients show normal arterial oxygen saturation but nothing much is known about microvascular perfusion. In this work, we tested the hypothesis that the erythrocyte deformability in ME/CFS is adversely affected, using a combination of biophysical and biochemical techniques.
We tested the deformability of RBCs using a high-throughput microfluidic device which mimics blood flow through microcapillaries. We perfused RBCs (suspension in plasma) from ME/CFS patients and from age and sex matched healthy controls (n=9 pairs of donors) through a high-throughput microfluidic platform of 5µm width and 3-5 µm height. We recorded the movement of the cells at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by the cells to completely enter the test channels), average transit velocity (velocity of the cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that RBCs from ME/CFS patients had higher entry time (~12%, p<0.0001), lower average transit velocity (~17%, p<0.0001) and lower elongation index (~14%, p<0.0001) as compared to RBCs from healthy controls. Taken together, this data shows that RBCs from ME/CFS patients have reduced deformability. To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates.
To understand the basis for differences in deformability, we investigated the changes in the fluidity of the membrane using a lateral diffusion assay using pyrenedecanoic acid (PDA), and observed that RBCs from ME/CFS patients have lower membrane fluidity (~30%, p<0.01). Apart from the fluidity, Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the RBC plasma membrane (~18%, p<0.0001). Higher levels of reactive oxygen species (ROS) in RBCs from ME/CFS patients (~30%, p<0.008) were also observed, as compared to healthy controls. Using scanning electron microscopy (SEM), we also observed changes in RBC morphology between ME/CFS patients and healthy controls (presence of different morphological subclasses like biconcave disc, leptocyte, acanthocyte and burr cells; area and aspect ratio; levels of RBC aggregation). Despite these changes in RBC physiology, the hemoglobin levels remained comparable between healthy donors and ME/CFS patients. Finally, preliminary studies show that RBCs from recovering ME/CFS patients do not show such differences in cellular physiology, suggesting a connection between RBC deformability and disease severity.
Taken together, our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress, and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease.
Sleep problems and fatigue as predictors for the onset of chronic widespread pain over a 5- and 18-year perspective
Katarina Aili, Maria Andersson, Ann Bremander, Emma Haglund’ Ingrid Larsson and Stefan Bergman
BMC Musculoskeletal Disorders201819:390 https://doi.org/10.1186/s12891-018-2310-5
Received: 16 March 2018 Accepted: 19 October 2018 Published: 3 November 2018
Abstract
Background
Previous research suggests that sleep problems may be an important predictor for chronic widespread pain (CWP). With this study we investigated both sleep problems and fatigue as predictors for the onset of CWP over a 5-year and an 18-year perspective in a population free from CWP at baseline.
Methods
To get a more stable classification of CWP, we used a wash-out period, including only individuals who had not reported CWP at baseline (1998) and three years prior baseline (1995). In all, data from 1249 individuals entered the analyses for the 5-year follow-up and 791 entered for the 18-year follow-up. Difficulties initiating sleep, maintaining sleep, early morning awakening, non-restorative sleep and fatigue were investigated as predictors separately and simultaneously in binary logistic regression analyses.
Results
The results showed that problems with initiating sleep, maintaining sleep, early awakening and non-restorative sleep predicted the onset of CWP over a 5-year (OR 1.85 to OR 2.27) and 18-year (OR 1.54 to OR 2.25) perspective irrespective of mental health (assessed by SF-36) at baseline. Also fatigue predicted the onset of CWP over the two-time perspectives (OR 3.70 and OR 2.36 respectively) when adjusting for mental health. Overall the effect of the sleep problems and fatigue on new onset CWP (over a 5-year perspective) was somewhat attenuated when adjusting for pain at baseline but remained significant for problems with early awakening, non-restorative sleep and fatigue. Problems with maintaining sleep predicted CWP 18 years later irrespective of mental health and number of pain regions (OR 1.72). Reporting simultaneous problems with all four aspects of sleep was associated with the onset of CWP over a five-year and 18-yearperspective, irrespective of age, gender, socio economy, mental health and pain at baseline. Sleep problems and fatigue predicted the onset of CWP five years later irrespective of each other.
Conclusion
Sleep problems and fatigue were both important predictors for the onset of CWP over a five-year perspective. Sleep problems was a stronger predictor in a longer time-perspective. The results highlight the importance of the assessment of sleep quality and fatigue in the clinic.
Neural mechanisms supporting the relationship between dispositional mindfulness and pain
Zeidan, Fadela,*; Salomons, Timb; Farris, Suzan R.a; Emerson, Nichole M.a; Adler-Neal, Adriennea; Jung, Youngkyooc; Coghill, Robert C.a,d
PAIN: December 2018 - Volume 159 - Issue 12 - p 2477–2485 
doi: 10.1097/j.pain. 0000000000001344
Abstract
Interindividual differences in pain sensitivity vary as a function of interactions between sensory, cognitive–affective, and dispositional factors. Trait mindfulness, characterized as the innate capacity to nonreactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo analgesia, we sought to determine whether dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six meditation-naive and healthy volunteers completed the Freiburg Mindfulness Inventory and were administered innocuous (35°C) and noxious stimulation (49°C) during perfusion-based functional magnetic resonance imaging. Higher Freiburg Mindfulness Inventory ratings were associated with lower pain intensity (P = 0.005) and pain unpleasantness ratings (P = 0.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive, and affective appraisals. We propose that mindfulness and the posterior cingulate cortex should be considered as important mechanistic targets for pain therapies.
Trait mindfulness, the innate capacity to nonreactively attend to the present moment, was associated with lower pain and brain mechanisms supporting self-referential processes.
aDepartment of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC, United States
bDepartment of Psychology, School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom
cDepartment of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
dDepartment of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Corresponding author. Address: Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, Unites States. Tel.: 336-716-4284; fax: 336-716-4534. E-mail address: fzeidan@wakehealth.edu (F. Zeidan).
Received March 13, 2018 Received in revised form July 03, 2018 Accepted July 09, 2018
© 2018 International Association for the Study of Pain 
Cell: 2018 Sep 6;174(6):1388-1405.e21. doi: 10.1016/j.cell.2018.08.041.
Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.
Zmora N1, Zilberman-Schapira G2, Suez J2, Mor U2, Dori-Bachash M2, Bashiardes S2, Kotler E3, Zur M2, Regev-Lehavi D2, Brik RB2, Federici S2, Cohen Y2, Linevsky R2, Rothschild D3, Moor AE4, Ben-Moshe S4, Harmelin A5, Itzkovitz S4, Maharshak N6, Shibolet O6, Shapiro H2, Pevsner-Fischer M2, Sharon I7, Halpern Z8, Segal E9, Elinav E10.
Abstract
Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
PMID:30193112   DOI: 10.1016/j.cell.2018.08.041
Psychoneuroendocrinology: 2018 Dec 14. pii: S0306-4530(18)30196-3. doi: 10.1016/j.psyneuen.2018.11.032. 
Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.
Russell A1, Hepgul N2, Nikkheslat N3, Borsini A4, Zajkowska Z5, Moll N6, Forton D7, Agarwal K8, Chalder T9, Mondelli V10, Hotopf M11, Cleare A12, Murphy G13, Foster G14, Wong T15, Schütze GA16, Schwarz MJ17, Harrison N18, Zunszain PA19, Pariante CM20.
Abstract
The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.
KEYWORDS:
Chronic fatigue syndrome; Cytokines; Fatigue; Inflammation; Kynurenine; Tryptophan
PMID:30567628  DOI:10.1016/j.psyneuen.2018.11.032
Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial.
JAMA Intern Med.  2018; 178(11):1474-1481 (ISSN: 2168-6114)
Urquhart DM; Wluka AE; van Tulder M; Heritier S; Forbes A; Fong C; Wang Y; Sim MR; Gibson SJ; Arnold C; Cicuttini FM
Importance: Antidepressants at low dose are commonly prescribed for the management of chronic low back pain and their use is recommended in international clinical guidelines. However, there is no evidence for their efficacy.
Objective: To examine the efficacy of a low-dose antidepressant compared with an active comparator in reducing pain, disability, and work absence and hindrance in individuals with chronic low back pain.
Design, Setting, and Participants: A double-blind, randomized clinical trial with a 6-month follow-up of adults with chronic, nonspecific, low back pain who were recruited through hospital/medical clinics and advertising was carried out.
Intervention: Low-dose amitriptyline (25 mg/d) or an active comparator (benztropine mesylate, 1 mg/d) for 6 months.
Main Outcomes and Measures: The primary outcome was pain intensity measured at 3 and 6 months using the visual analog scale and Descriptor Differential Scale. Secondary outcomes included disability assessed using the Roland Morris Disability Questionnaire and work absence and hindrance assessed using the Short Form Health and Labour Questionnaire.
Results: Of the 146 randomized participants (90 [61.6%] male; mean [SD] age, 54.8 [13.7] years), 118 (81%) completed 6-month follow-up. Treatment with low-dose amitriptyline did not result in greater pain reduction than the comparator at 6 (adjusted difference, -7.81; 95% CI, -15.7 to 0.10) or 3 months (adjusted difference, -1.05; 95% CI, -7.87 to 5.78), independent of baseline pain. There was no statistically significant difference in disability between the groups at 6 months (adjusted difference, -0.98; 95% CI, -2.42 to 0.46); however, there was a statistically significant improvement in disability for the low-dose amitriptyline group at 3 months (adjusted difference, -1.62; 95% CI, -2.88 to -0.36). There were no differences between the groups in work outcomes at 6 months (adjusted difference, absence: 1.51; 95% CI, 0.43-5.38; hindrance: 0.53; 95% CI, 0.19-1.51), or 3 months (adjusted difference, absence: 0.86; 95% CI, 0.32-2.31; hindrance: 0.78; 95% CI, 0.29-2.08), or in the number of participants who withdrew owing to adverse events (9 [12%] in each group; χ2 = 0.004; P = .95).
Conclusions and Relevance: This trial suggests that amitriptyline may be an effective treatment for chronic low back pain. There were no significant improvements in outcomes at 6 months, but there was a reduction in disability at 3 months, an improvement in pain intensity that was nonsignificant at 6 months, and minimal adverse events reported with a low-dose, modest sample size and active comparator. Although large-scale clinical trials that include dose escalation are needed, it may be worth considering low-dose amitriptyline if the only alternative is an opioid.
Trial Registration: anzctr.org.au Identifier: ACTRN12612000131853. PreMedline Identifier: 30285054
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Front. Pediatr., 08 January 2019 | https://doi.org/10.3389/fped.2018.00412 
Estimating Prevalence, Demographics, and Costs of ME/CFS Using Large Scale Medical Claims Data and Machine Learning


Ashley R. Valdez1, Elizabeth E. Hancock1, Seyi Adebayo1, David J. Kiernicki1, Daniel Proskauer2, ohn R. Attewell3, Lucinda Bateman4, Alfred DeMaria Jr.5, Charles W. Lapp6, Peter C. Rowe7 and Charmian Proskauer8*
  • 1Optum Enterprise Analytics, UnitedHealth Group, Minneapolis, MN, United States
  • 2Optum Technology, UnitedHealth Group, Minneapolis, MN, United States
  • 3Innovation, Research, and Development, UnitedHealth Group, Minneapolis, MN, United States
  • 4Bateman Horne Center, Salt Lake City, UT, United States
  • 5Bureau of Infectious Disease and Laboratory Sciences, Massachusetts Department of Public Health, Boston, MA, United States
  • 6Hunter-Hopkins Center, Charlotte, NC, United States
  • 7Children's Center Chronic Fatigue Clinic, Johns Hopkins University School of Medicine, Baltimore, MD, United States
  • 8Massachusetts ME/CFS & FM Association, Quincy, MA, United States
Techniques of data mining and machine learning were applied to a large database of medical and facility claims from commercially insured patients to determine the prevalence, gender demographics, and costs for individuals with provider-assigned diagnosis codes for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). The frequency of diagnosis was 519–1,038/100,000 with the relative risk of females being diagnosed with ME or CFS compared to males 1.238 and 1.178, respectively. While the percentage of women diagnosed with ME/CFS is higher than the percentage of men, ME/CFS is not a “women's disease.” Thirty-five to forty percent of diagnosed patients are men. Extrapolating from this frequency of diagnosis and based on the estimated 2017 population of the United States, a rough estimate for the number of patients who may be diagnosed with ME or CFS in the U.S. is 1.7 million to 3.38 million. Patients diagnosed with CFS appear to represent a more heterogeneous group than those diagnosed with ME. A machine learning model based on characteristics of individuals diagnosed with ME was developed and applied, resulting in a predicted prevalence of 857/100,000 (p > 0.01), or roughly 2.8 million in the U.S. Average annual costs for individuals with a diagnosis of ME or CFS were compared with those for lupus (all categories) and multiple sclerosis (MS), and found to be 50% higher for ME and CFS than for lupus or MS, and three to four times higher than for the general insured population. A separate aspect of the study attempted to determine if a diagnosis of ME or CFS could be predicted based on symptom codes in the insurance claims records. Due to the absence of specific codes for some core symptoms, we were unable to validate that the information in insurance claims records is sufficient to identify diagnosed patients or suggest that a diagnosis of ME or CFS should be considered based solely on looking for presence of those symptoms. These results show that a prevalence rate of 857/100,000 for ME/CFS is not unreasonable; therefore, it is not a rare disease, but in fact a relatively common one.
Metabolites 2018, 8(4), 90; https://doi.org/10.3390/metabo8040090 
Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology
Arnaud Germain 1 David Ruppert 2, Susan M. Levine 1 and Maureen R. Hanson 1,* 
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
2Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA
*
Received: 17 September 2018 / Revised: 30 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018 
Abstract 
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin. View Full-Text 
Keywords: ME/CFS; plasma; metabolomics; biomarkers; diagnostics 





J Pain Res. 2018 Nov 21;11:2981-2990. doi: 10.2147/JPR.S169499. eCollection 2018.
A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndromediagnosis from healthy controls.
Lukkahatai N1, Walitt B2, Deandrés-Galiana EJ3, Fernández-Martínez JL3, Saligan LN2.
Abstract
OBJECTIVES:
Fibromyalgia syndrome (FMS) is a chronic and often debilitating condition that is characterized by persistent fatigue, pain, bowel abnormalities, and sleep disturbances. Currently, there are no definitive prognostic or diagnostic biomarkers for FMS. This study attempted to utilize a novel predictive algorithm to identify a group of genes whose differential expression discriminated individuals with FMS diagnosis from healthy controls.
METHODS:
Secondary analysis of gene expression data from 28 women with FMS and 19 age-and race-matched healthy women. Expression of discriminatory genes were identified using fold-change differential and Fisher's ratio (FR). Discriminatory accuracy of the differential expression of these genes was determined using leave-one-out-cross-validation. Functional networks of the discriminating geneswere described from the Ingenuity's Knowledge Base.
RESULTS:
The small-scale signature contained 57 genes whose expressions were highly discriminatory of the FMS diagnosis. The combination of these high discriminatory genes with FR higher than 1.45 provided a leave-one-out-cross-validation accuracy for the FMS diagnosis of 85.11%. The discriminatory genes were associated with 3 canonical pathways: hepatic stellate cell activation, oxidative phosphorylation, and airway pathology related to COPD.
CONCLUSION:
The discriminating genes, especially the 2 with the highest accuracy, are associated with mitochondrial function or oxidative phosphorylation and glutamate signaling. Further validation of the clinical utility of this finding is warranted.
KEYWORDS:
chronic pain; machine learning; medically unexplained symptoms; microarray
PMID:30538537  PMCID: PMC6255277 DOI:10.2147/JPR.S169499
Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy
Christina Mueller& Joanne C. Lin& Sulaiman Sheriff& Andrew A. Maudsley& Jarred W. Younger

Springer Science+Business Media, LLC, part of Springer Nature 2019
Brain Imaging and Behaviour  https://doi.org/10.1007/s11682-018-0029-4
Abstract
Previous neuroimaging studies have detected markers of neuroin flammatio n in patients wit h Myalgi c Encephalo myelitis /Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflamma tion, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is
elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imagin g (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), an d compared
between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups.
Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the c erebellum (all p < 0.05), which was not attributable to increased body temperature or d iffe rences in cereb ral perfusion. Brain temperature increases converged with elevated LAC/CR in
the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormaliti es in ME/CFS patients in widely distributed regions. Our f indings may indicate that ME/CFS involves neuroinflammation.
Front. Pediatr., 15 February 2019 | https://doi.org/10.3389/fped.2019.00026 
Impaired Health-Related Quality of Life in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Impact of Core Symptoms


Maria Roma, Colleen L. Marden, Marissa A. K. Flaherty, Samantha E. Jasion, Erica M. Cranston and Peter C. Rowe*
  • Division of General Pediatrics and Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Objective: The objectives of this study were to compare the health-related quality of life (HRQOL) of a North American population of adolescents and young adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to (1) healthy controls (HC), (2) adolescents with ME/CFS in other countries, and (3) other forms of pediatric chronic illness, and (4) to examine the influence of the core illness symptoms in the Institute of Medicine (IOM) case definition on impaired HRQOL.
Study design: Cross-sectional study comparing individuals with ME/CFS referred to a tertiary care Chronic Fatigue clinic and HC. Eligible participants were age 10–30 years and met the Fukuda criteria for CFS. HC were eligible if they were age 10–30 years, with self-reported good, very good, or excellent general health. Pediatric HRQOL was measured using the PedsQL (Pediatric Quality of Life Inventory) and other validated instruments.
Results: We enrolled 55 consecutive ME/CFS patients (46 F) aged 10–23 years. From a pool of 69 potential HC we selected 55 with similar age and gender distribution for comparison. The total and subscale scores on the PedsQL and on all other measures of HRQOL indicated significantly worse function among those with ME/CFS (all P < 0.001). The self-reported frequency of post-exertional malaise (PEM) was significantly associated with the severity of impaired HRQOL (P < 0.001). Cognitive impairment had a weaker association with the PedsQL score (P = 0.02). Orthostatic intolerance was present in 96% of the ME/CFS population. Of the 55 who satisfied the Fukuda criteria, 47 (85%) also satisfied the IOM criteria for the diagnosis. Those meeting the IOM criteria had worse PedsQL total scores than those meeting just the Fukuda criteria (P < 0.001).
Conclusions: HRQOL was substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America, consistent with reports from other continents. HRQOL was also lower in ME/CFS than has been described in children with asthma, diabetes mellitus, epilepsy, eosinophilic gastroenteritis, and cystic fibrosis. The findings of this study lend further support to the inclusion of PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS.
Metabolites 2018, 8(4), 90; https://doi.org/10.3390/metabo8040090
Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology
Arnaud Germain 1,David Ruppert 2,Susan M. Levine 1 andMaureen R. Hanson 1,* 
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA
Received: 17 September 2018 / Revised: 30 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
 Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin. 
Keywords: ME/CFS; plasma; metabolomics; biomarkers; diagnostics
International Journal of Immunopathology and Pharmacology Volume 33: 1–8 © The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/2058738418820402 journals.sagepub.com/home/iji
Changes in the transcriptome of  circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/ chronic fatigue syndrome
Eiren Sweetman1, Margaret Ryan2, Christina Edgar1,  Angus MacKay1, Rosamund Vallings3 and Warren Tate1
Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood disease affecting 0.2%–2% of the global population. To gain insight into the pathophysiology of ME/CFS in New Zealand, we examined the transcriptomes of peripheral blood mononuclear cells by RNA-seq analysis in a small well-characterized patient group (10 patients), with age/gender-matched healthy controls (10 control subjects). Twenty-seven gene transcripts were increased 1.5- to sixfold and six decreased three- to sixfold in the patient group (P < 0.01). The top enhanced gene transcripts, IL8, NFΚBIA and TNFAIP3, are functionally related to inflammation, and significant changes were validated for IL8 and NFΚBIA by quantitative polymerase chain reaction (qPCR). Functional network analysis of the altered gene transcripts (P < 0.01) detected interactions between the products related to inflammation, circadian clock function, metabolic dysregulation, cellular stress responses and mitochondrial function. Ingenuity pathway analysis (P < 0.05) provided further insights into the dysfunctional physiology, highlighting stress and inflammation pathways. This analysis provides novel insights into the molecular changes in ME/CFS and contributes to the understanding of the pathophysiological mechanisms of the disease.
Journal of Epidemiological Research 2019, Vol. 5, No. 1 ORIGINAL ARTICLES
Incidence rates of brain cancer following an outbreak of Chronic Fatigue Syndrome
Cheng-Te Major Lin1, Naji Younes1, Paul H. Levine∗2,3 1Milken Institute School of Public Health, The George Washington University, Washington, United States 2College of Public Health, University of Nebraska, NE, United States 3The National Cancer Institute, National Institutes of Health, MD, United States
Received: May 14, 2018 Accepted: July 30, 2018 OnlinePublished: August 24, 2018 DOI:10.5430/jer.v5n1p1 URL:https://doi.org/10.5430/jer.v5n1p1
ABSTRACT
Previous studies utilizing data from the Nevada Cancer Registry suggested a transient increase in non-Hodgkin’s lymphoma (NHL) and brain cancer in northern Nevada following an outbreak of Chronic Fatigue Syndrome (CFS) in that area which was not seen in southern Nevada which had no reported CFS outbreaks. A subsequent study from the National Cancer Institute (NCI) using data from the NCI’s Surveillance, Epidemiology and End Results (SEER) Program and Medicare documented the association between CFS and NHL on a national basis but no other cancer association was seen. Since brain cancer has a younger age distribution than NHL, we returned to the Nevada Cancer Registry and used ten more years of data and additional analyses to determine if there was an association between CFS and brain cancer by age. This study confirmed the increased incidence of brain cancer following the outbreak in northern Nevada but not southern Nevada with the increase limited to the under 65 age group, thus explaining why the SEER-Medicare analysis only analyzing data in the 65 and above age group did not detect this association. KeyWords: Chronic Fatigue Syndrome, Brain cancer, Incidence, Nevada
To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis: a position paper of ESGBOR, the ESCMID study group for Lyme borreliosis
R.B. Dessau et alPlumX Metrics
DOI: https://doi.org/10.1016/j.cmi.2017.08.025
Published online: September 05, 2017Accepted: August 29, 2017Received in revised form: August 26, 2017Received: April 5, 2017
Figures


Abstract
Background
Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management.
Aim
The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB.
Sources
This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations.
Implications
The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi. Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value.
Keywords: 
Antibody testing, Borrelia burgdorferi, Laboratory diagnosis, Lyme borreliosis, Polymerase chain reaction, Serology
∗Key references for suggested further reading are 1, 2, 14, 15, 16, 19 and 39.
© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd.
Original Research ARTICLE Front. Pediatr., 21 February 2019 | https://doi.org/10.3389/fped.2019.00021 
Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service
Katherine S. Rowe*
  • Department of General Medicine, Royal Children's Hospital, Melbourne, VIC, Australia
Aim: To determine the reported duration of illness, the functional and educational long-term outcomes, predictive factors for recovery and seek feedback regarding management in pediatric/adolescent myalgic encepahalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods: A cohort observational study of 784 young people, mean age 14.6 (6–18) years, with ME/CFS diagnosed at a specialist pediatric hospital and receiving regular care, was conducted with follow-up for a mean 8 (range 1–21) years after onset. Baseline symptoms, history, depression and anxiety questionnaires were available from 418. The remaining 366, did not have similar standardized baseline information. Questionnaires requested functional rating, persistent symptoms, duration of illness if “recovered,” social engagement and school/work attendance. Feedback was sought regarding management, support services, useful information, helpful interventions or personnel and use of alternative therapies. Reported recovery and function were compared with baseline information and between the two groups.
Results: Follow-up data were returned from 81.8%. There was no significant difference in functional score (if reported recovery) or illness duration related to provision of baseline data. The mean duration of illness was 5 (range 1–15) years in the 50% who reported recovery. By 5 years 38% and by 10 years 68% reported recovery. At 10 years the mean functional score was 8/10 (range 2–10) with 5% scoring <6. Depression, anxiety or severity of illness at diagnosis was not predictive of non-recovery. Designing and monitoring their own management plan that included educational, social, physical and enjoyable activities, as well as having symptom management and understanding professionals were highly valued. However, remaining engaged in an education system that flexibly accommodated their illness and aspirations was consistently reported as crucial for long term functioning.
Conclusions: ME/CFS in young people has a mean duration of 5 years (1–15) with 68% reporting recovery by 10 years. All improved functionally with 5% remaining very unwell and a further 20% significantly unwell. There were no obvious baseline predictors for recovery. However, depression, anxiety, orthostatic intolerance and to a lesser extent pain at follow up were identified as hampering recovery or function. Supportive professionals, remaining engaged in education and management strategies were identified as helpful.
Front. Pediatr., 21 January 2019 | https://doi.org/10.3389/fped.2018.00435
The Importance of Accurate Diagnosis of ME/CFS in Children and Adolescents: A Commentary
Keith James Geraghty* and Charles Adeniji
  • Division of Population Health, Health Services Research and Primary Care, Centre for Primary Care, University of Manchester, Manchester, United Kingdom


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness that causes a range of debilitating symptoms. While most research has focused on adults, the illness also presents in children and adolescents. Many physicians find it difficult to diagnose the illness. In this commentary paper, we discuss a range of salient themes that have emerged from our ongoing research into the prevalence of ME/CFS in children and adolescents. We discuss reasons why pediatric prevalence estimates vary widely in the literature, from almost 0% to as high as 3%. We argue that there is considerable misdiagnosis of pediatric cases and over-inflation of estimates of pediatric ME/CFS. Many children and teenagers with general fatigue and other medical complaints may meet loose diagnostic criteria for ME/CFS. We make recommendations for improving epidemiological research and identifying pediatric ME/CFS in clinical practice.
Introduction
Children and adolescents with suspected myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) regularly present with persistent fatigue, sleep disturbance, and an array of other symptoms, such as headaches and cognitive difficulties (1). ME/CFS is noted for being a major cause of long-term school absence and has profound negative ramifications for social development, educational achievement, and future employment (2, 3). The illness is associated with co-morbid anxiety and depression (4). It is known that children with chronic health problems exhibit higher rates of distress, anxiety, and depression (5). Taking these factors together, it is vital that young patients with this illness are correctly identified, so that they might receive a speedy diagnosis and appropriate medical care and social support.
Epidemiological studies report a wide range of prevalence estimates of ME/CFS in this age group. Some estimates are as low as 0.1% (6), while others suggest rates of 2.6% (7); and rates for CFS-like illness go as high as 4.4% (8). Girls are at greater risk of developing ME/CFS, particularly post-puberty (9). This wide spread in prevalence estimates appears to result from researchers using different diagnostic criteria to classify cases and applying different methods to sample and identify cases, such as postal or telephone questionnaires, community-based surveys, and clinical interviews. Given the general lack of consistency in methodologies applied, inconsistency in prevalence estimates is not surprising. However, such inconsistency suggests a problem with the methods used to identify young ME/CFS sufferers. It is clear, with estimates as low as 0.1% and as high as 3–4%, many young patients are being misdiagnosed, either under or over. Misdiagnosis in this vulnerable group has profound implications, since a false positive diagnosis may lead to inappropriate labeling of a child with ME/CFS and improper intervention with treatment (10), while under-diagnosis might mean a child or teen not receiving the care they require. If researchers are unable to reliably identify pediatric cases of ME/CFS, how confident can we be that clinicians are able to diagnose cases at the clinic level? We know doctors often find it difficult to diagnose ME/CFS and adult sufferers commonly wait an average of 5 years for a diagnosis (11).
Initiating Care of a Patient With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Charles W. Lapp*
  • Hunter-Hopkins Center PLLC, Charlotte, NC, United States
This paper introduces the primary care physician to the unique and challenging aspects of initially diagnosing and managing a complex condition for which there are a plethora of symptoms, few physical findings, no known cause, and no specific treatments. While daunting, the rewards are many, and those who pursue an interest in ME/CFS find themselves at the forefront of medicine.
The approach to any complex problem is to break it down into small steps, and ME/CFS is no exception. The first office visit should be devoted to a history of the present illness, a physical examination, and collection of exclusionary laboratory tests. On follow-up the differential diagnosis and a treatment plan can be addressed. Many individuals with ME/CFS have been humiliated or dismissed by other providers, so one will need to be as non-judgmental as possible and acknowledge that ME/CFS is not a psychological condition but a real illness. They need reassurance that you will work with them to seek a unifying diagnosis and prioritize management.
Metabolites 2018, 8(4), 90; doi:10.3390/metabo8040090
Article
Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology
Arnaud Germain 1,David Ruppert 2,Susan M. Levine 1 and Maureen R. Hanson 1,* 
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA
Received: 17 September 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.
Lyme Disease Emergence After Invasion of the Blacklegged Tick
Ixodes scapularis, Ontario, Canada, 2010-2016
Manisha A. Kulkarni; Isha Narula; Andreea M. Slatculescu; Curtis Russell
Emerging Infectious Diseases. 2019;25(2):328-332. 


 Abstract
Analysis of surveillance data for 2010–2016 in eastern Ontario, Canada, demonstrates the rapid northward spread of Ixodes scapularis ticks and Borrelia burgdorferi, followed by increasing human Lyme disease incidence. Most spread occurred during 2011–2013. Continued monitoring is essential to identify emerging risk areas in this region.
Introduction
Lyme disease (LD) is the most reported vectorborne disease in North America, where it is caused by Borrelia burgdorferi sensu stricto and principally transmitted by the blacklegged tick (Ixodes scapularis).[1] With northward expansion of I. scapularis tick populations from endemic areas in the United States, LD is rapidly emerging in parts of central and eastern Canada.[2–4] Although several studies have mapped blacklegged tick populations across Canada and developed models to predict future spread of ticks and LD risk,[2,3] little is known about the extent of human LD in relation to tick vector distributions at a fine geographic scale. We examined spatiotemporal trends in the occurrence and expansion of I. scapularis ticks, B. burgdorferi–infected ticks, and human LD cases over a 7-year period to elucidate the process of LD emergence in eastern Ontario, Canada.


Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods
Michael B. VanElzakker*, Sydney A. Brumfield and Paula S. Lara Mejia
  • Division of Neurotherapeutics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying. The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement. The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable. We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies. We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.
Front. Pediatr., 21 February 2019 | https://doi.org/10.3389/fped.2019.00021
Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service
Katherine S. Rowe*
  • Department of General Medicine, Royal Children's Hospital, Melbourne, VIC, Australia

Aim: To determine the reported duration of illness, the functional and educational long-term outcomes, predictive factors for recovery and seek feedback regarding management in pediatric/adolescent myalgic encepahalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods: A cohort observational study of 784 young people, mean age 14.6 (6–18) years, with ME/CFS diagnosed at a specialist pediatric hospital and receiving regular care, was conducted with follow-up for a mean 8 (range 1–21) years after onset. Baseline symptoms, history, depression and anxiety questionnaires were available from 418. The remaining 366, did not have similar standardized baseline information. Questionnaires requested functional rating, persistent symptoms, duration of illness if “recovered,” social engagement and school/work attendance. Feedback was sought regarding management, support services, useful information, helpful interventions or personnel and use of alternative therapies. Reported recovery and function were compared with baseline information and between the two groups.
Results: Follow-up data were returned from 81.8%. There was no significant difference in functional score (if reported recovery) or illness duration related to provision of baseline data. The mean duration of illness was 5 (range 1–15) years in the 50% who reported recovery. By 5 years 38% and by 10 years 68% reported recovery. At 10 years the mean functional score was 8/10 (range 2–10) with 5% scoring <6. Depression, anxiety or severity of illness at diagnosis was not predictive of non-recovery. Designing and monitoring their own management plan that included educational, social, physical and enjoyable activities, as well as having symptom management and understanding professionals were highly valued. However, remaining engaged in an education system that flexibly accommodated their illness and aspirations was consistently reported as crucial for long term functioning.
Conclusions: ME/CFS in young people has a mean duration of 5 years (1–15) with 68% reporting recovery by 10 years. All improved functionally with 5% remaining very unwell and a further 20% significantly unwell. There were no obvious baseline predictors for recovery. However, depression, anxiety, orthostatic intolerance and to a lesser extent pain at follow up were identified as hampering recovery or function. Supportive professionals, remaining engaged in education and management strategies were identified as helpful.
Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Maximillian J. Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Daniel Clark, Richard Kwiatek and Kade Davison
Journal of Translational Medicine201917:80
https://doi.org/10.1186/s12967-019-1836-0
Published: 14 March 2019
Abstract
Background
There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established.
Methods
16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days.
Results
WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of − 6.3% to − 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls.
Conclusion
The decrease in WR at VT of 6.3–9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS.
Front. Endocrinol., 20 March 2018 | https://doi.org/10.3389/fendo.2018.00097
Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study


Begoña Ruiz-Núñez1,2*, Rabab Tarasse1, Emar F. Vogelaar3, D. A. Janneke Dijck-Brouwer1 and Frits A. J. Muskiet1
  • 1Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
  • 2Healthy Institute, Madrid, Spain
  • 3European Laboratory of Nutrients, Bunnik, Netherlands
Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation. We studied 98 CFS patients (21–69 years, 21 males) and 99 age- and sex-matched controls (19–65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation. Most remarkably, CFS patients exhibited similar thyrotropin, but lower free triiodothyronine (FT3) (difference of medians 0.1%), total thyroxine (TT4) (11.9%), total triiodothyronine (TT3) (12.5%), %TT3 (4.7%), sum activity of deiodinases (14.4%), secretory capacity of the thyroid gland (14.9%), 24-h urinary iodine (27.6%), and higher % reverse T3 (rT3) (13.3%). FT3 below the reference range, consistent with the “low T3 syndrome,” was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% confidence interval = 1.00–6.54). Most observations persisted in two sensitivity analyses with more stringent cutoff values for body mass index, high-sensitive C-reactive protein (hsCRP), and WBC. We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4, and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with, e.g., T3 and iodide supplements might be indicated.
ORIGINAL RESEARCH |2 APRIL 2019
B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Øystein Fluge, MD, PhD; Ingrid G. Rekeland, MD; Katarina Lien, MD; Hanne Thürmer, MD, PhD; Petter C. Borchgrevink, MD, PhD; Christoph Schäfer, MD; Kari Sørland, RN; Jörg Aßmus, PhD; Irini Ktoridou-Valen, MD; Ingrid Herder, MD; Merethe E. Gotaas, MD; Øivind Kvammen, MD; Katarzyna A. Baranowska, MD, PhD; Louis M.L.J. Bohnen, MD; Sissel S. Martinsen, RN; Ann E. Lonar, RN; Ann-Elise H. Solvang, RN; Arne E.S. Gya, RN; Ove Bruland, PhD; Kristin Risa, MSc; Kine Alme, MSc; Olav Dahl, MD, PhD; Olav Mella, MD, PhD
Abstract
Background:
Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective:
To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS.
Design:
Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942)
Setting:
4 university hospitals and 1 general hospital in Norway.
Patients:
151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years.
Intervention:
Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74).
Measurements:
Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures.
Results:
Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, −5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, −0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.
Limitation:
Self-reported primary outcome measures and possible recall bias.
Conclusion:
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.
Published: Ann Intern Med. 2019.
DOI: 10.7326/M18-1451
©2019 American College of Physicians
Front. Pediatr., 22 March 2019 
Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Todd E. Davenport1,2*, Mary Lehnen1, Staci R. Stevens2, J. Mark VanNess2,3, Jared Stevens2 and Christopher R. Snell2
  • 1Department of Physical Therapy, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, United States
  • 2Workwell Foundation, Ripon, CA, United States
  • 3Department of Health, Exercise, and Sport Sciences, College of the Pacific, University of the Pacific, Stockton, CA, United States
Post-exertional malaise (PEM) is the hallmark clinical feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PEM involves a constellation of substantially disabling signs and symptoms that occur in response to physical, mental, emotional, and spiritual over-exertion. Because PEM occurs in response to over-exertion, physiological measurements obtained during standardized exertional paradigms hold promise to contribute greatly to our understanding of the cardiovascular, pulmonary, and metabolic states underlying PEM. In turn, information from standardized exertional paradigms can inform patho-etiologic studies and analeptic management strategies in people with ME/CFS. Several studies have been published that describe physiologic responses to exercise in people with ME/CFS, using maximal cardiopulmonary testing (CPET) as a standardized physiologic stressor. In both non-disabled people and people with a wide range of health conditions, the relationship between exercise heart rate (HR) and exercise workload during maximal CPET are repeatable and demonstrate a positive linear relationship. However, smaller or reduced increases in heart rate during CPET are consistently observed in ME/CFS. This blunted rise in heart rate is called chronotropic intolerance (CI). CI reflects an inability to appropriately increase cardiac output because of smaller than expected increases in heart rate. The purposes of this review are to (1) define CI and discuss its applications to clinical populations; (2) summarize existing data regarding heart rate responses to exercise obtained during maximal CPET in people with ME/CFS that have been published in the peer-reviewed literature through systematic review and meta-analysis; and (3) discuss how trends related to CI in ME/CFS observed in the literature should influence future patho-etiological research designs and clinical practice.
April 2019, Volume 34, Issue 2, pp 385–415|  Metabolic Brain Disease
Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?
  • Gerwyn Morris,Michael Maes,Michael Berk,Basant K. Puri
Abstract
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
Systematic Review of the Efficacy and Safety of Gabapentin and Pregabalin for Pain in Children and Adolescents
Oluwaseun Egunsola, PhD; Claire E. Wylie, PhD; Kate M. Chitty, PhD; Nicholas A. Buckley, MD
Anesth Analg. 2019;128(4):811-819. 
Abstract
The barriers to opioid use in some countries necessitate the need to identify suitable alternatives or adjuncts for pain relief. The gabapentinoids (gabapentin and pregabalin) are approved for the management of persistent pain in adults, but not in children. Searches were conducted in Embase, Medline, Scopus, and Web of Science up until November 2017, for randomized controlled trials that investigated the analgesic effects of gabapentin or pregabalin in children and adolescents <18 years of age. A total of 7 publications were identified, 5 regarding gabapentin as prophylactic postsurgical pain relief for either adenotonsillectomy (n = 3) or scoliosis surgery (n = 2), and 1 for gabapentin treatment of chronic regional pain syndrome/neuropathic pain. One study investigated the efficacy of pregabalin as a treatment for fibromyalgia. Based on the studies' primary outcomes alone, neither of the chronic pain studies involving gabapentin and pregabalin showed significant efficacy compared with amitriptyline or placebo, respectively. Two of the prophylactic gabapentin studies for adenotonsillectomy and idiopathic scoliosis surgery reported significantly fewer children requiring analgesia and lower opioid requirement, respectively, compared with placebo. Two of the identified clinical trials (conducted by the same first author) on the efficacy of gabapentin for prophylactic postadenotonsillectomy pain relief were omitted from narrative synthesis due to clear evidence of fabricated data. Overall, this review identified a paucity of evidence for the analgesic effect and safety of gabapentinoids in children. We also suggest audit of any current evidence-based practice and clinical guidelines that have cited the research studies with fabricated data.

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