Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome

Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.

Alcohol intolerance and myalgic encephalomyelitis/chronic fatigue

BACKGROUND The literature is mixed about the occurrence of alcohol intolerance among patients with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS).Surveys that asked respondents with ME/CFS whether they experienced alcohol intolerance within a recent time frame might produce inaccurate results because respondents may indicate that the symptom was not present if they avoid alcohol due to alcohol intolerance.AIM To overcome this methodologic problem,participants in the current study were asked whether they have avoided alcohol in the past 6 mo,and if they had,how severe their alcohol intolerance would be if they were to drink alcohol.METHODS The instrument used was a validated scale called the DePaul symptom questionnaire.Independent t-tests were performed among the alcohol intolerant or not alcohol intolerant group.The alcohol intolerant group had 208 participants,and the not alcohol intolerant group had 96 participants.RESULTS Using specially designed questions to properly identify those with alcohol intolerance,those who experienced alcohol intolerance vs those who did not experience alcohol intolerance experienced more frequent/severe symptoms and domains.In addition,using a multiple regression analysis,the orthostatic intolerance symptom domain was related to alcohol intolerance.CONCLUSION The findings from the current study indicated that those with ME/CFS are more likely to experience alcohol intolerance.In addition,those with this symptom have more overall symptoms than those without alcohol intolerance.

Effects of Exercise on Behavior and Peripheral Blood Lymphocyte Apoptosis in a Rat Model of Chronic Fatigue Syndrome

This study examined the effects of exercise on behavior and peripheral blood leukocyte apoptosis in a rat model of chronic fatigue syndrome （CFS）. Thirty-six healthy male Sprague-Dawley rats were equally randomized into 3 groups： the control group, CFS model group and the exercise group in terms of body weight. A total of 25 rats entered the final statistical analysis due to 11 deaths during the study. CFS model was established by subjecting the rats in CFS model group and exercise group to electric shock, chronic restraint stress and cold water swim. Besides, rats in the exercise group took rtmning wheel exercise. After a week of conditioning feeding, model construction and running wheel exercise were performed simultaneously, and lasted for 23 consecutive days. The behavior experiments, including running wheel exercise, open-field test, tail suspension test and Morris water maze test, were conducted, either before or after the model establishment. Rats were sacrificed and peripheral blood was obtained for the assessment of lymphocyte apoptosis index by flow cytometry （FCM）. It was found that as compared with those in the control group, the weight of the rats was decreased obviously （P〈0.01）, the mobility time in the open-field and the tail suspension tests was shortened significantly （P〈0.01）, the time to locate the platform was enhanced （P〈0.01） and the cell apoptosis index was increased substantially （P〈0.01） in the CSF model group. Meanwhile, in comparison to the model group, the behavior in the open-field and the tail suspension tests was improved significantly （P〈0.05）, and the apoptosis index decreased remarkably （P〈0.01） in the exercise group. It is concluded that sport intervention can prevent lymphocyte apoptosis and improve animal behavior rather than the memory.

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

BACKGROUND Fibromyalgia(FM)and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS)are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers.Despite patient heterogeneity linked to patient subgroups and variation in disease severity,anomalies are found in the blood and plasma of these patients when compared with healthy control groups.The seeming specificity of these“plasma factors”,as recently reported by Ron Davis and his group at Stanford University,CA,United States,and observations by our group,have led to the proposal that induced pluripotent stem cells(iPSCs)may be used as metabolic sensors for FM and ME/CFS,a hypothesis that is the basis for this indepth review.AIM To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.METHODS A PRISMA(Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids.The MeSH terms“metabolomic”or“metabolites”in combination with FM and ME/CFS disease terms were screened against the PubMed database.Only original studies applying omics technologies,published in English,were included.The data obtained were tabulated according to the disease and type of body fluid analyzed.Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.RESULTS Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids.In vitro cell-based assays have the potential to be developed as screening platforms,providing evidence for the existence of factors in patient body fluids capable of altering morphology,differentiation state and/or growth patterns.Moreover,they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients.The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust,reproducible reporter systems of metabolic diseases,including ME/CFS and FM.Furthermore,culturing iPSCs,or their mesenchymal stem cell counterparts,in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.CONCLUSION This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

Effect of intradermal needle at five-zang Back-Shu points on treatment of chronic fatigue syndrome

Objective:To observe the effect of intradermal needle therapy on back-shu points of five zang organs in treating chronic fatigue syndrome(CFS)and provide evidence for the usage of unilateral back-shu point.Methods:Patients were randomly divided into bilateral back-shu point group,unilateral back-shu point group and non-acupoint group,remove shedding cases,each group remaining 30 patients.In bilateral back-shu point group,both sides of back-shu points of five zang organs were selected.In unilateral back-shu point group,only one side was selected,left or right alternately.The location where non-acupoint group inserted by intradermal needles were outward from the back-shu points,left or right alternately.Fatigue Scale-14(FS-14)was used to evaluate the fatigue level and the scores’improvement of physical fatigue and mental fatigue revealed the therapeutic effect on body constituents and spirits of CFS patient.Results:After the 8-week intradermal needle therapy,the total effective rate was 83.33%in the bilateral back-shu point group,which was 76.67%in the unilateral back-shu point group and 50.00%in the non-acupoint group.The curative effects of the two groups whose back-shu points of five zang organs were inserted by intradermal needles were better than the non-acupoint group(P<0.05).There was no significant difference in clinical efficacy between the bilateral back-shu point group and the unilateral back-shu point group(P>0.05).There were statistical differences in FS-14 questionnaires including total,physical and mental scores between before and after the treatment in both the two back-shu point groups(P<0.05).Only the scores of total and physical fatigue in decreased in non-acupoint group(P<0.05),which means it couldn’t help to alleviate mental fatigue statistically(P>0.05).Conclusions:(1)The intradermal needle therapy on back-shu points of five zang organs for CFS has a satisfying clinical efficacy in curing tiredness.It can help to reduce both physical and mental fatigue for the patients.Hence,it can regulate both body constituents and spirits simultaneously.(2)Needling the unilateral acupoints can get similar clinical efficacy to the bilateral points.It reveals that we can cut cost by reducing the consumption of the amount of intradermal needles used on one side.(3)Both the groups of back-shu points get better clinical efficacy than the non-acupoint group dramatically.The reason of why the intradermal needle can treat CFS maybe that back-shu points of five zang organs can regulate the functions of five zang organs characteristically.

Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms

Although myalgic encephalomyelitis(ME) and chronic fatigue syndrome(CFS) are considered to be synonymous,the definitional criteria for ME and CFS define two distinct,partially overlapping,clinical entities.ME,whether defined by the original criteria or by the recently proposed criteria,is not equivalent to CFS,let alone a severe variant of incapacitating chronic fatigue.Distinctive features of ME are:muscle weaknessand easy muscle fatigability,cognitive impairment,circulatory deficits,a marked variability of the symptoms in presence and severity,but above all,post-exertional "malaise":a(delayed) prolonged aggravation of symptoms after a minor exertion.In contrast,CFS is primarily defined by(unexplained) chronic fatigue,which should be accompanied by four out of a list of 8 symptoms,e.g.,headaches.Due to the subjective nature of several symptoms of ME and CFS,researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes.However,various characteristic symptoms,e.g.,post-exertional "malaise" and muscle weakness,can be assessed objectively using wellaccepted methods,e.g.,cardiopulmonary exercise tests and cognitive tests.The objective measures acquired by these methods should be used to accurately diagnose patients,to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially.

A Comparative Study of Antifatigue Effects of Taurine and Vitamin C on Chronic Fatigue Syndrome

Vitamin C and taurine (TR) are well known as active components for fatigue recovery. However, the mechanism of the anti-fatigue effects of vitamin C and TR is still unclear. Our study was designed to evaluate the anti-fatigue activities of vitamin C and TR in an animal test for fatigue and to compare the activities between vitamin C and TR. Materials and Methods: Vitamin C, TR or their combination were orally administrated to mice once daily for 15 days, and then metabolic activities such as blood glucose, triglyceride (TG), lactate, and lactate dehydrogenase (LDH) as well as antioxidant activities such as malondialdehyde (MDA) and superoxide dismutase (SOD) were determined (evaluated) after forced swimming test (FST). Results: Compared with the control group, C100, C200, and T50 showed a tendency to decrease mobility in FST. Moreover, TG (C100, C200, T200), LDH (C200), lactic acid (C100) and MDA (C50, C100, C200) levels were inhibited by vitamin C and TR. Conclusions: These results suggest that vitamin C and TR have anti-fatigue activities in mice, with vitamin C providing a stronger effect.

Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome:A systematic review and comparison of pathogenesis

Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977.It is well-documented that about 10%of patients properly treated with antibiotics never fully recover,but instead go on to develop a chronic illness dubbed,posttreatment Lyme disease syndrome(PTLDS)characterized by severe fatigue,cognitive slowing,chronic pain,and sleep difficulties.This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome(ME/CFS),a strikingly similar syndrome.In the majority of the PTLDS studies,at least four of the six major symptoms of ME/CFS were also noted,including substantial impairment in activity level and fatigue for more than 6 months,post-exertional malaise,and unrefreshing sleep.In one of the included PTLDS articles,26 of the 29 ME/CFS symptoms were noted.This study adds to the expanding literature on the post-active phase of infection syndromes,which suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 ’long-haulers’?

A significant number of SARS-CoV-2 (COVID-19) pandemic patients have developed chronic symptoms lasting weeks or months which are very similar to those described for myalgic encephalomyelitis/chronic fatigue syndrome. This study reviews the current literature and understanding of the role that mitochondria, oxidative stress and antioxidants may play in the understanding of the pathophysiology and treatment of chronic fatigue. It describes what is known about the dysfunctional pathways which can develop in mitochondria and their relationship to chronic fatigue. It also reviews what is known about oxidative stress and how this can be related to the pathophysiology of fatigue, as well as examining the potential for specific therapy directed at mitochondria for the treatment of chronic fatigue in the form of antioxidants. This study identifies areas which require urgent, further research in order to fully elucidate the clinical and therapeutic potential of these approaches.

Acupuncture for Chronic Fatigue Syndrome:An Overview of Systematic Reviews

Objective To evaluate the quality of the existing studies and summarize evidence of important outcomes of meta-analyses/systematic reviews(MAs/SRs)of CFS.Methods Potentially eligible studies were searched in the following electronic databases from inception to 1 September,2019:Chinese Biomedical Literature Database(CBM),China Science and Technology Journal Database(VIP),China National Knowledge Infrastructure(CNKI),WanFang Database(WF),Web of Science,Embase,PubMed and Cochrane Library.Grades of Recommendation,Assessment,Development,and Evaluation(GRADE)was used to evaluate the quality of evidence.The methodological quality of the literature was evaluated by A Measure Tool to Assess Systematic Reviews-2(AMSTAR-2)and the quality of the report was assessed by Preferred Reporting Items for Systematic Reviews and Meta-analyses(PRISMA).The intra-class correlation coefficient was used to assess the consistency of the reviewers,with an overall intraclass correlation coefficient score of 0.967.Results Ten MAs/SRs were included.The overall conclusions were that acupuncture had good safety and efficacy in the treatment of CFS,but some of these results were contradictory.The GRADE indicated that out of the 17 outcomes,high-quality evidence was provided in 0(0%),moderate in 3(17.65%),low in 10(58.82%),and very low in 4(23.53%).The results of AMSTAR-2 showed that the methodological quality of all included studies was critically low.The PRISMA statement revealed that 8 articles(80%)were in line with 20 of the 27-item checklist,and 2 articles(20%)matched with 10-19 of the 27 items.Conclusion We found that acupuncture on treating CFS has the advantage for efficacy and safety,but the quality of SRs/MAs of acupuncture for CFS need to be improved.

Survey: Third of Japanese Suffer Chronic Fatigue

三分之一以上的日本人患慢性疲劳症,其严重程度使许多人下得不停工辍学。周末健康部长说。 健康部所进行的对3015名年龄在15岁和65岁之间的调查对象的全国性调查显示36％的被调查人至少经受了6个月之久的疲劳症。

Impact of Strokes: The Burden of Care, Post-CVA Fatigue & Caregiver Role Strain

Strokes and cerebral vascular accidents (CVAs) and related disease events are an unfortunate circumstance that inflicts individuals around the world and impacts people every day as individuals and their caregivers. The consequences of these strokes or CVA events are life-changing for all those involved. As a result of long-term disability related to strokes, the caregiver may undergo many emotional, psychological, and physical factors that impact their daily lives. There is a relatively short period of time to react to the necessary change and as a result there may be differences in coping associated with these unexpected health circumstances. Many stoke victims experience motor, cognitive, emotional, and psycho-social deficits and their caregivers may not be prepared for these abrupt life altering effects. The impact for caregivers, factors impacting strokes, and solutions for care will be addressed in the paper. Evidence suggests that post fatigue stroke (PFS) may be triggered by a dysfunction of the stress system. Family caregivers with a low level of social engagement may be more likely to perceived stress, and increased risk for caregiver role strain.

Fatigue is not associated with vitamin D deficiency in inflammatory bowel disease patients

AIM To investigate if vitamin D deficiency is associated with fatigue in patients with inflammatory bowel disease(IBD).METHODS IBD patients were recruited from nine hospitals in the southeastern and western regions of Norway to participate in a multicenter cross-sectional study lasting from March 2013 to April 2014. Data were collected by interviews, from medical records and laboratory tests. The Fatigue Questionnaire(FQ) was used to measure fatigue. Linear and logistic regression models were applied to explore the possible association between vitamin D deficiency and total fatigue scores and chronic fatigue, respectively. The analyses were adjusted for age, gender, disease activity, depressive symptoms and sleep disturbance.RESULTS In total, 405 patients were included in the analyses, of which 227(56%) had Crohn's disease(CD) and 178(44%) had ulcerative colitis(UC). Vitamin D deficiency(< 50 nmol/L) was present in half(203/405) of the patients. Chronic fatigue was reported by 116(29%) of all included patients with substantial fatigue reported by 194(48%). Vitamin D levels were neither associated with total fatigue nor with chronic fatigue. Higher total fatigue scores and chronic fatigue were both associated with increased disease activity scores in patients with UC and CD, but not with increased CRP or fecal calprotectin. In UC patients, female gender was associated with fatigue in the univariate analysis, but no such difference was found when adjusted for elevated disease activity scores. Sleep disturbance and more depressive symptoms were associated with total fatigue scores in both UC and CD patients, but with chronic fatigue only in CD patients.CONCLUSION In this study, no significant association between fatigue and vitamin D deficiency in IBD patients was revealed.

Moxibustion upregulates hippocampal progranulin expression

In China,moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome,but its mechanisms are largely unknown.More recently,the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome,and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis.In the present study,we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms.Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome.The acupoints Guanyuan（CV4） and Zusanli（ST36,bilateral） were simultaneously administered moxibustion.Untreated chronic fatigue syndrome rats and normal rats were used as controls.Results from the forced swimming test,open field test,tail suspension test,real-time PCR,enzyme-linked immunosorbent assay,and western blot assay showed that moxibustion treatment decreased m RNA expression of corticotropin-releasing hormone in the hypothalamus,and adrenocorticotropic hormone and corticosterone levels in plasma,and markedly increased progranulin m RNA and protein expression in the hippocampus.These findings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome,at least in part,by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.

针刺调控慢性疲劳综合征中枢机制研究进展

Chronic fatigue syndrome is a neurological disorder characterized by extreme fatigue that lasts for a long time and doesn't alleviate with rest.The number of the cases has been increasing during the era of COVID-19 pandemic.Acupuncture may have some effect on chronic fatigue syndrome,but its mechanism remains unclear.This article was to summarize the specific manifestations of abnormal central mechanism in patients with chronic fatigue syndrome through laboratory tests and neuroimaging.It was found from the laboratory evaluation that there were changes in the structure of the frontal cortex,thalamus and other brain tissues;factors,including IFN-a and IL-10 in cerebrospinal fluid were found abnormal;results of oxidative and nitrosative stress and changes in neurobiochemical substances,e.g.hypothalamus hormone levels and neurotransmitter concentrations,were observed.With magnetic resonance imaging and positron emission tomography,it was shown that the partial brain of persons with chronic fatigue syndrome had morphological changes with diminished grey matter and white;changes in cerebral blood flow velocity caused by decreased perfusion and functional activity with abnormal connectivity in brain were detected.In addition,there was significant decrease in glucose metabolism accompanied with neuroinflammatory response;metabolic disorders of serotonergic,cholinergic,glutamatergic and yaminobutyric acid energy neurotransmitters were also discovered.The regulatory effect of acupuncture on the above central neurological abnormalities in chronic fatigue syndrome model animals was elaborated,and the direction for further research was analyzed in order to provide ideas for further research on the central mechanism of acupuncture treatment for chronic fatigue syndrome.

Development and Validation of A Lao Juan(劳倦)Questionnaire

Objectives： Lao Juan （LJ, 劳倦） is a syndrome described in Chinese medicine （CM） that manifests with fatigue, fever, spontaneous sweating, indigestion, work-induced pain, weakness of the limbs, and shortness of breath. The present study was conducted to examine the reliability and validity of a Lao Juan Questionnaire （LJQ）. Methods： A total of 151 outpatients and 73 normal subjects were asked to complete the LJQ. Seventy-three normal subjects were additionally asked to complete the Chalder Fatigue Scale （CFS）. Twelve clinicians determined whether the 151 outpatients exhibited LJ or not. The internal consistency and construct validity for the LJQ were estimated using data from the outpatient subjects. The CFS data were used to examine the concurrent validity of the LJQ. Total LJQ scores and the clinicians＇ diagnoses of the outpatients were used to perform receiver operating characteristics （ROC） curve analyses and to define an optimum cut-off score for the LJQ. Results： The 19-item LJQ had satisfactory internal consistency （α =0.828） and concurrent validity, with significant correlations between the LJQ and the CFS subscales. In the test of construct validity using principal component analysis, a total of six factors were extracted, and the overall variance explained by all factors was 59.5%. In ROC curve analyses, the sensitivity, specificity, and area under the curve were 76.0%, 59.2%, and 0.709, respectively. The optimum cut-off score was defined as six points. Conclusions： Our results suggest that the LJQ is a reliable and valid instrument for evaluating LJ.