BackgroundGiven the absence of restorative treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), testing of alternative interventions may offer new options to help these debilitated individuals.ObjectiveTo explore in an 8-week pilot randomized trial the potential benefit of two non-invasive treatments, hydrogen water (H2) and app-based heart rate variability biofeedback (HRV-BF), for the symptoms and functional limitations in ME/CFS.MethodsA three-arm, randomized, non-blinded design was adopted. Subjects were randomized to receive H2, HRV-BF or a combined condition of both treatments. The study was administered at a single site, Stony Brook University. Participants were recruited via online advertising and announcements on support group websites. 39 subjects participated in the study. All participant activities were completed in their homes.Intervention: Two daily treatments were self-administered by participants: 2-3 glasses of hydrogen-producing drinking water and/or heart rate variability biofeedback.MethodsA three-arm, randomized, non-blinded design was adopted. Subjects were randomized to receive H2, HRV-BF or a combined condition of both treatments. The study was administered at a single site, Stony Brook University. Participants were recruited via online advertising and announcements on support group websites. 39 subjects participated in the study. All participant activities were completed in their homes.Intervention: Two daily treatments were self-administered by participants: 2-3 glasses of hydrogen-producing drinking water and/or heart rate variability biofeedback.ResultsNo significant post-intervention differences between the three groups were found. However, pre-post comparisons revealed significant improvements on the Fatigue Severity Scale (95% CI: [-0.66, -0.01]; p = .043) and the SF36 Physical Function subscale (95% CI: [5.19, 20.22]; p = 0.002) in the H2 group. For the single intervention conditions, compliance was higher for H2 treatment (94.6%) in comparison to HRV-BF (81.5%).ConclusionThe interventions of molecular hydrogen (H2) and app-based heart rhythm biofeedback (HRV-BF) did not yield improvements across conditions; however, pre-post improvements in physical function and fatigue in the H2 condition suggest that extended treatment may yield a more discernable benefit.Trial registration: ClinicalTrials.gov identifier: NCT05397626.ConclusionThe interventions of molecular hydrogen (H2) and app-based heart rhythm biofeedback (HRV-BF) did not yield improvements across conditions; however, pre-post improvements in physical function and fatigue in the H2 condition suggest that extended treatment may yield a more discernable benefit.Trial registration: ClinicalTrials.gov identifier: NCT05397626.

Background Limited published data suggests that absence of uplifts (minor pleasant events) is associated with clinical worsening in patients with chronic fatigue syndrome (CFS). The current study aimed to assess the relation of illness worsening to the trajectories of social and non-social uplifts and hassles in a six-month prospective study in CFS. Methods Participants were primarily in their 40s, female, white, and ill for over a decade. All participants (N = 128) met criteria for CFS. The interview-based global impression of change rating was used to classify individual outcomes as improved, unchanged, or worsened at six- month follow-up. Uplifts and hassles, both social and non-social, were assessed with the Combined Hassles and Uplifts Scale (CHUS). The CHUS was administered weekly in online diaries over six months. Linear mixed effect models were utilized to examine linear trends for hassles and uplifts. Results No significant differences were found between the three global outcome groups for age, sex, or illness duration; however, work status was significantly lower for the non-improved groups ( p < 0.001). Non-social hassles intensity showed an increasing slope for the worsened group ( p = 0.03) and a decreasing slope ( p = 0.05) for the improved group. For the worsened group, a downward trend was found for frequency of non-social ( p = 0.01) uplifts. Conclusion Individuals with worsening as compared to improving illness in CFS show significantly different six-month trajectories for weekly hassles and a deficit in uplifts. This may have clinical implications for behavioral intervention. Trial registration ClinicalTrials.gov ID: NCT02948556.

To assess biobehavioral sex differences in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) utilizing a low burden exercise protocol, 22 females and 15 males with ME/CFS and 14 healthy controls underwent two six-min walk tests. Fifteen daily assessments were scheduled for fatigue and function ratings and heart monitoring. Six-min walk tests were conducted on days 8 and 9. The ME/CFS group showed high self-report fatigue and impaired physical function, whereas healthy controls did not show fatigue or function abnormalities. In patients, no significant post-exercise changes were found for heart rate variability (HRV); however, heart rate decreased in ME/CFS males from Day 14 to Day 15 ( p = 0.046). Female patients showed increased fatigue ( p = 0.006) after the initial walk test, but a downward slope ( p = 0.008) in fatigue following the second walk test. Male patients showed a decrease in self-report work limitation in the days after exercise ( p = 0.046). The healthy control group evidenced a decrease in HRV after the walk tests from Day 9–14 ( p = 0.038). This pilot study did not confirm hypotheses that females as compared to males would show slower exercise recovery on autonomic or self-report (e.g. fatigue) measures. A more exertion-sensitive test may be required to document prolonged post-exertional abnormalities in ME/CFS. Trial registration: NCT NCT03331419.

ABSTRACT Objective To test a model of nonimprovement in chronic fatigue syndrome (CFS) using self-report activity patterns (e.g., “push-crash”), uplifts and hassles, and a biological measure of cardiac autonomic function. Activity pattern impacts on symptoms and objective measures of autonomic and physical activity were also examined. Methods This prospective study in CFS collected all data remotely, including 6 months of weekly web diaries that recorded symptom ratings, activity patterns, and hassles and uplifts. In addition, 6 months of weekly heart monitoring and 3 months of daily waking actigraphy data were collected. Improvement or nonimprovement status was assessed using semistructured interviews at the 6-month follow-up. Results A total of 148 individuals (87.2% female) were enrolled, and 12.2% were lost to follow-up. Participants reporting nonimprovement (n = 92), as compared with improvement (n = 38), showed greater autonomic dysfunction (lower heart rate variability, group difference = 5.93 [SE = 2.73] milliseconds; p = .032) and lower mean intensity of behavioral uplifts (group difference = 0.14 [SE = 0.16]; p = .043), but no significant differences in any activity pattern, including push-crash, limiting activity, and healthy pacing. Conclusions This study provided evidence for linking patient-reported nonimprovement to a biological variable indexing autonomic dysfunction and a behavioral measure indicating a deficit in psychological uplifts. These findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS. Trial Registration: ClinicalTrials.gov ID: NCT02948556.

Background: Given the absence of effective medical treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the testing of a new intervention that may ameliorate potentially pathologic levels of oxidative stress, sympathetic arousal, and inflammation may yield symptomatic improvements. Objective: To explore in a pilot study, the possible beneficial effect of molecular hydrogen (H-2) for the symptoms and functional limitations of ME/CFS. Methods: Twenty-three subjects were randomized to H-2 or active placebo which involved drinking up to five glasses daily of hydrogen-enriched water or placebo water for 28 days. Assessments included: (i) self-report fatigue, physical function, and stress; (ii) salivary C-Reactive Protein (inflammation), Uric Acid (antioxidant status), and Alpha-Amylase (sympathetic function); and (iii) heart rate variability (parasympathetic activity). Data were analysed with Wilcoxon rank-sum tests. Results: Completion rate for the primary outcome measure of fatigue severity was 100% for the 11 hydrogen participants and 91.7% (n = 11) for placebo participants. No significant changes were found on self-report or biological variables in the active vs. placebo treatment conditions. A small, but significant reduction in fatigue was found in the placebo condition. Adverse effects led to treatment discontinuation in 27.2% of H-2 subjects. All severe- and moderate-intensity effects were found in the active treatment condition. Adverse effects were not significantly associated with any demographic or symptom variable. Conclusions: Therapeutic molecular hydrogen did not yield improvement on any biological or symptom measure in individuals with ME/CFS. Dosage reduction might benefit any future trial of hydrogen therapy in this illness.

The recently held 3-day virtual conference (8/19–8/21) of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) resembled our in-person meetings in that we...

This commentary identifies recent scientific and clinical milestones that appear to have increased legitimization of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These milestones include government-funded reports recognizing the seriousness of ME/CFS, new initiatives for biomedical research sponsored by the US National Institutes of Health, official endorsement of the ME/CFS name, publication of practitioner primers, and the launch of a new peer-review fatigue journal. These positive developments are tempered by ongoing illness challenges including patient stigma, absence of diagnostic markers, a lack of established treatments, and a dearth of researchers and knowledgeable, interested clinicians.

Given the cancelation of the 2020 in-person IACFS/ME conference due to COVID restrictions, the Board decided to plan an alternative, if shortened, virtual meeting to gauge interest from the ME/CFS ...

Functional Somatic Symptoms (FSS) are symptoms for which an underlying pathology cannot be found. High negative affect (NA) has been linked to the etiology of FSS, but little is known about the role of Positive Affect (PA).The aim of this study was to test if PA is related to current and future lower levels of FSS. We also examined the interactions between PA and NA, and PA and sex on FSS.Data from the Dutch Tracking Adolescents' Individual Lives Survey (TRAILS) cohort were used (N = 1247 cases, 60% females, mean age T5 = 22.2, T6 = 25.6). PA was measured with the PANAS schedule and FSS with the Adult Self Report questionnaire (ASR). A Principal Component Analysis (PCA) was performed on the physical complaints subscale of the ASR. Regression analyses with bootstrapping were performed to assess the associations and interactions.PA had a significant negative association with current FSS when adjusted for NA, age, sex and socioeconomic status (B = −0.004; BCa 95% CI = [−0.006; −0.002]), but the association was not significant longitudinally. No interactions were found. In secondary analysis, PA was significantly related to the component "General Physical Symptoms" (B = −0.019; BCa 95% CI = [−0.0028; −0.011]) but not to the component "Gastrointestinal Symptoms" (B = −0.008; BCa 95% CI = [−0.016;0.001]) in the cross-sectional analysis.In conclusion, high PA was significantly related to current lower levels of FSS, but the effect was small. Further research on individual variations in affect is needed to obtain more insight in their contribution to FSS.

Introduction The main objective was to evaluate the efficacy of an 8-session, group-based comprehensive smoking cessation and trauma management (CSC-T) treatment among daily smokers (≥5 cigarettes/day) exposed to the World Trade Center (WTC) disaster with elevated WTC-related post-traumatic stress disorder (PTSD) symptoms. Methods Participants (N = 90) were randomly assigned to CSC-T (N = 44; 63.6% white; 27.3% female; mean age = 51.32 ± 7.87) or comprehensive smoking cessation (CSC) alone (N = 46; 71.7% white; 28.3% female; mean age = 48.74 ± 10.66), which was comparable in length and time. Assessments included a diagnostic clinical interview and self-report measures of PTSD and respiratory symptoms, and smoking behavior, and biologically confirmed smoking abstinence. Evaluations occurred at a baseline visit, each treatment session, and at 1-, 2-, 4-, 12-, and 26-weeks post-treatment. Results The two treatments did not differ in regard to PTSD symptom improvement. After quit day (week 6), the two groups had similar 7-day (~15%) and 6-month (~20%) abstinence rates as well as average number of cigarettes smoked, and PTSD and respiratory symptoms. Conclusions It is possible that the Cognitive Behavioral Therapy skills specific to quitting smoking, group-based support, and degree of therapist contact, that were available in both treatments may have played a role in equalizing the abstinence rates between the two conditions. Although the current study found no evidence that the CSC-T was superior to the CSC alone treatment, the abstinence rates observed were high relative to previous trials of smokers with diagnosed PTSD. Further development of smoking cessation programs tailored to the needs of smokers with PTSD symptoms continues to be needed. Implications This study suggests that a CSC program aids in smoking abstinence for smokers with PTSD symptoms and that incorporating trauma management skills, may not add additional benefits for abstinence and PTSD and respiratory symptom relief. Further work is needed to improve smoking cessation efforts for smokers with PTSD symptoms.

In the literature, patient reactions associated with PEM have included increased symptoms of pain and fatigue, [1–3] abnormal cardiopulmonary responses to exercise, [4, 5] decreases in physical activity behaviors, [2, 6, 7] changes in cognitive function [8, 9] and up-regulation of numerous biological variables. [10, 11] Although a number of studies have been conducted, consistent results and/or replication of findings have been rare. [12]

Background: Chronic fatigue syndrome (CFS) is a complex chronic condition with large negative impact on patients' function and quality of life. Efficacy and cost-effectiveness of cognitive behavioral intervention remain inconclusive. Objective: To evaluate the cost-utility of a home-based fatigue selfmanagement (FSM) intervention as compared to usual care among primary care patients with severe CFS. Methods: An economic evaluation alongside of a randomized controlled study design was used. Cost and utility data were collected from 137 patients with severe CFS at baseline and 1-year follow-up. The FSM group (n = 89) received self-delivered cognitive behavioral self-management intervention and the usual care group (n = 48) received regular medical care. Cost was measured by total costs (direct, indirect, and intervention costs) during the follow-up period. Quality-adjusted life years (QALY), as the utility measure, were derived from the Medical Outcomes Survey Short Form-36. A societal perspective was adopted. Bootstrapped incremental costutility ratios (ICURs) and net monetary benefit (NMB) were calculated as measures of cost-effectiveness. Results: Baseline individual characteristics were similar between the two groups. The intervention was well received by the participants with only minimum attrition. At the end of one-year postintervention, FSM dominated usual care in terms of ICUR in both the intention-to-treat analysis and the complete-cases-only analysis. Net monetary benefit analysis showed that FSM has higher probability of achieving positive net monetary across the entire range of possible societal willingness to pay for fatigue symptom management. Conclusions: In primary care patients with severe CFS, the low-cost FSM appears to be a cost-effective treatment.

Purpose: To identify patient change attributions arising from a home self-management intervention in severe chronic fatigue syndrome (CFS).Methods: This multi-method study of 126 participants with severe CFS collected data through phone interviews at 3-month follow-up in a self-management trial reported previously. Patient ratings (ranging from very much worse to very much better), were elicited on the global impression of change scale followed by this question: 'Why do you think you are: "worse", "unchanged", "improved"', etc.? The open-ended responses from participants were thematically organized and analyzed as study data.Results: Most improved participants referenced behavioral changes that included: increased relaxation, coping and stress reduction (44%), pacing (e.g. more rest, less exercise; 33%), and more physical activity/exercise (25%). For participants reporting 'unchanged' global ratings, the majority (63%) attributed their status to one or more of the following: nothing will help/illness acceptance/illness fluctuates without overall change (29%), everything is the same (24%) or does not know (17%). Participants with worsened global ratings most often attributed their decline to: changes in sleep (40.5%), deteriorating health (35%), specific life events (30%), and/or stress (30%). Treatment-assigned participants as compared to no treatment controls were significantly more likely (p = <. 05) to cite increased awareness, relaxation/coping/stress reduction and pacing as their reasons for change. The frequency of active vs. passive coping categories also distinguished improved from non-improved patients.Conclusions: Patient attributions could be utilized by the clinician to shift patient perceptions of their illness status in a constructive direction, possibly leading to an enhanced quality of life.

Purpose: To assess the efficacy of fatigue self-management for severe chronic fatigue syndrome (CFS).Methods: This randomized trial enrolled 137 patients with severe CFS. Participants were randomized to one of three conditions: fatigue self-management with web diaries and actigraphs (FSM:ACT); fatigue self-management with less expensive paper diaries and pedometers (FSM:CTR); or an usual care control condition (UC). The primary outcome assessed fatigue severity at 3-month follow-up. Analysis was by intention-to-treat.Results: At 3-month follow-up, the FSM:CTR condition showed significantly greater reduction in fatigue severity compared to UC (p=.03; d=.58). No significant improvement was found at 12-month follow-up for the FSM:ACT or the FSM:CTR condition as compared to UC (p>.10). The combined active treatment conditions revealed significantly reduced fatigue at 3-month follow-up (p=.03), but not at 12-month follow-up (p=.24) compared to UC. Clinically significant improvements were found for 24-28% of the intervention groups as compared to 9% of the UC group. Attrition at 12-month follow-up was low (<8%).Conclusion: Home-based self-management for severe CFS appeared to be less effective in comparison to findings reported for higher functioning groups. Home-based management may be enhanced by remotely delivered interventional feedback.

The purpose of this mixed methods study was to identify participants’ attributions for their global impression of change ratings in a behavioral intervention for unexplained chronic fatigue and chronic fatigue syndrome. At 3-month follow-up, participants (N = 67) were asked “Why do you think you are (improved, unchanged, worse)?” Improved patients pointed to specific behavioral changes, unchanged patients referred to a lack of change in lifestyle, and worsened patients invoked stress and/or specific life events. Identifying patient perceptions of behaviors associated with patient global impression of change–rated improvement and non-improvement may assist in developing more effective management strategies in clinical care.

Purpose: To assess fatigue severity in World Trade Center (9/11) responders 13 years later. Methods: The participant pool consisted of male 9/11 responders enrolled in the Stony Brook World Trade Center Health Program (WTC-HP), one of five centers of excellence established by the Centers for Disease Control and Prevention. Fatigue severity was assessed with the Fatigue Severity Scale. WTC-related medical conditions were certified by a physician and diagnoses of 9/11-related post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) were determined with the Structured Clinical Interview for DSM-IV (SCID). Results: High fatigue severity was reported by 20.8% of the sample (N = 1079) and was significantly associated with PTSD, major depressive disorder, sleep apnea, gastro-esophageal reflux disease, upper respiratory disease, and lower respiratory disease. These associations remained significant for PTSD, major depressive disorder and lower respiratory disease when adjusted for medications, age and BMI. Only 17.3% of the high fatigue subgroup did not have an identified medical or psychiatric diagnosis. Fewer fatigued (21.1%) than non-fatigued (72.0%) responders rated their physical health as 'good' or 'very good.' Also fewer fatigued (33.9%) than non-fatigued (54.1%) responders were employed full-time (p < .0001). Conclusions: This study found clinically elevated fatigue in a high percentage of a male WTC responder cohort that prior to 9/11/2001 would be considered a ` healthy worker cohort.' To better understand the pathophysiology of fatigue, newer methodologies such as symptom provocation (e.g. exercise) designs may be useful.

A well-validated diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is essential for research and clinical care. To that end, the US Department of Health and Human Services (D...

In celebration of our first anniversary issue, I am happy to report that our quarterly issues have been filled to their page limits with peer review articles consistent with our publishing agreement. This first issue of 2014 contains an interesting diversity of empirical studies and a narrative review. The research team of Lauren Krupp and colleagues present a brief narrative review of fatigue in multiple sclerosis. My initial reaction, as a CFS researcher, was to reflect on the arbitrary nature of the term “medically unexplained” as used for symptoms and illnesses not linked to an objective marker. Although fatigue is the most prominent symptom of MS, it is not medically understood or “explained” in any objective, mechanistic sense. Fatigue in MS appears to be a complex symptom with multiple etiologies, including overall neurological impairment, pain, sleep disturbance, and depression. Thus, understanding fatigue in MS presents challenges similar to those confronted by CFS researchers. Perhaps this is one reason why the “unexplained” term is falling into disuse: dichotomous thinking about the nature of fatigue in illness is not useful. The next paper on “coincidence anticipation timing” (CAT) by Michael Duncan and colleagues represents a new area of inquiry for the journal. CAT is a technical term often applied to athletic performance. It refers to the ability to predict when a critical event occurs and then respond to it in a predetermined manner. For example, batting a baseball or hitting a tennis ball with a racquet requires precise timing combined with the correct action. The study found that a standard 100 mg dose of caffeine could significantly improve CAT and reduce perceived exertion during submaximal cycling in comparison to a placebo control condition. This may have implications for enhancing perceptual motor skill performance in sports. Two articles on CFS/ME examine clinical guidelines and several case definitions of the illness. S.C. Johnston et al. reviewed the pros and cons of different sets of guidelines and the adequacy of case definitions within these guidelines. Finally, Leonard Jason’s research team presents a controlled study of symptom severity in CFS/ME patients in comparison to controls. Employing frequency and severity requirements, their algorithm identified three symptoms that accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise. The authors conclude that both frequency and severity