ME Association November Summary of ME/CFS Published Research | 10 December 2019

December 10, 2019

Charlotte Stephens, Research Correspondent, ME Association.

The Index of Published ME/CFS Research has been updated to take account of the research published during November 2019.

The Index is a convenient way to locate and read the most recent studies and also those that were published previously.

The Index lists studies by subject matter and author, with links to PubMed or the relevant Journal.

It is free to download, comes with an interactive contents table and is an A-Z list of all the most important studies (and selected key documents and articles).

You can also find the index in the Research section of the website together with all the summary research reviews that the ME Association has published.

ME/CFS Research Published in November 2019

1. Daniels J et al. (2019)
‘Prevalence and Treatment of Chronic Fatigue Syndrome/ME and Co-morbid Severe Health Anxiety'.
Journal of the International Neuropsychological Society [Epub ahead of print]

Background: Chronic Fatigue Syndrome/ME (CFS/ME) is a debilitating condition that affects 0.2–0.4% of the population. Health focussed anxiety is common across medical conditions, and may be relevant in CFS/ME. This study sought to identify the prevalence and impact of health anxiety (HA) in CFS/ME and evaluate the effectiveness of Cognitive Behavioural Therapy for HA in CFS/ME.

Method: Cross sectional questionnaire methods and case-series design were used to achieve study aims.

Results: Analysis indicated that 41.9% of the CFS/ME clinic sample experienced threshold levels of health anxiety, which was associated with elevated symptom severity across several dimensions.  Stepwise multiple regression indicated physical functioning and depression accounted for 23.8% of variance in fatigue; depression, fatigue and HA, accounted for 32.9% of variance in physical functioning. Large effect sizes and clinically significant changes were generated in the treatment study.

Conclusion: HA is common in CFS/ME and likely to exacerbate fatigue and physical functioning. This study identifies HA as an important target for treatment, trial findings should be further replicated on a larger scale.

2. Eaton-Fitch N et al. (2019)
A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome.
Systematic Review 8 (279).

Background: Compromised natural killer (NK) cell cytotoxic function is a well-documented and consistent feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Other outcomes evaluated in NK cells of ME/CFS patients, however, remain equivocal. The aim of this study was to conduct a systematic review of the literature regarding NK cell phenotype, receptor expression, cytokine production and cytotoxicity in ME/CFS patients and determine the appropriateness as a model for ME/CFS.

Methods: Medline (EBSCOHost), Scopus, EMBASE and PubMed databases were systematically searched to source relevant papers published between 1994 and March 2018. This review included studies examining NK cells’ features in ME/CFS patients compared with HC following administration of specific inclusion and exclusion criteria. Secondary outcomes included genetic analysis in isolated NK cells or quality of life assessment. Quality assessment was completed using the Downs and Black checklist in addition to The Joanna Briggs Institute checklist.

Results: Seventeen eligible publications were included in this review. All studies were observational case control studies. Of these, 11 investigated NK cell cytotoxicity, 14 investigated NK cell phenotype and receptor profiles, three examined NK cell cytokine production, six investigated NK cell lytic protein levels and four investigated NK cell degranulation. Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications. Other outcomes investigated differed between studies.

Conclusion: A consistent finding among all papers included in this review was impaired NK cell cytotoxicity, suggesting that it is a reliable and appropriate cellular model for continued research in ME/CFS patients. Aberrations in NK cell lytic protein levels were also reported. Although additional research is recommended, current research provides a foundation for subsequent investigations. It is possible that NK cell abnormalities can be used to characterise a subset of ME/CFS due to the heterogeneity of both the illness itself and findings between studies investigating specific features of NK function.

3. Eguchi A et al. (2019)
Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.
Brain, Behaviour and Immunity [Epub ahead of print].

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.

4. Fatt SJ et al. (2019)
Parasympathetic activity is reduced during slow-wave sleep, but not resting wakefulness, in patients with chronic fatigue syndrome.
Journal of Clinical Sleep Medicine [Epub ahead of print].

Objectives: Physiological dearousal characterized by an increase in parasympathetic nervous system activity is important for good-quality sleep. Previous research shows that nocturnal parasympathetic activity (reflected by heart rate variability [HRV]) is diminished in individuals with chronic fatigue syndrome (CFS), suggesting hypervigilant sleep. This study investigated differences in nocturnal autonomic activity across sleep stages and explored the association of parasympathetic activity with sleep quality and self-reported physical and psychological wellbeing in individuals with CFS.

Methods: Twenty-four patients with medically diagnosed CFS, and 24 matched healthy control individuals participated. Electroencephalography and HRV were recorded during sleep in participants' homes using a minimally invasive ambulatory device. Questionnaires were used to measure self-reported wellbeing and sleep quality.

Results: Sleep architecture in patients with CFS differed from that of control participants in slower sleep onset, more awakenings, and a larger proportion of time spent in slow-wave sleep (SWS). Linear mixed-model analyses controlling for age revealed that HRV reflecting parasympathetic activity (normalized high frequency power) was reduced in patients with CFS compared to control participants, particularly during deeper stages of sleep. Poorer self-reported wellbeing and sleep quality was associated with reduced parasympathetic signaling during deeper sleep, but not during wake before sleep, rapid eye movement sleep, or with the proportion of time spent in SWS.

Conclusions: Autonomic hypervigilance during the deeper, recuperative stages of sleep is associated with poor quality sleep and self-reported wellbeing. Causal links need to be confirmed but provide potential intervention opportunities for the core symptom of unrefreshing sleep in CFS.

5. Friedberg F (2019)
Autonomic markers, chronic fatigue syndrome, and post-exertion states. Journal of Psychosomatic Research 127.


6. Jammes Y and Retornaz F (2019)
Understanding neuromuscular disorders in chronic fatigue syndrome.
F1000Research [Epub ahead of print].

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.

7. Klebek L et al. (2019)
Differentiating post-polio syndrome from myalgic encephalomyelitis and chronic fatigue syndrome.
Fatigue: Biomedicine, Health and Behaviour.

Background: Overlapping and concomitant symptoms among similar chronic illnesses have created difficulties for diagnosis and further treatment. Three such chronically fatiguing illnesses, Post-polio syndrome (PPS), Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS) fall under this category.

Purpose: The aim of this study is to examine and distinguish between core symptoms found in these illnesses (i.e. muscle pain/weakness, fatigue or exhaustion, and autonomic symptoms) via three methods of analysis (DePaul Symptom Questionnaire 2 (DSQ-2), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and machine learning techniques).

Results: Items assessing onset and severity for individuals who reported having PPS were found to have experienced an onset of PPS related symptoms roughly 30 years after the onset of Polio. Items found in the DSQ-2, SF-36 compared all illness groups and found that participants with ME/CFS were more functionally impaired across symptoms than those with PPS. Across all analyses, three domains most commonly differentiated the illnesses (neurocognitive, Post-exertional malaise, and neuroendocrine).

Conclusion: Examining functional impairment amongst chronically fatiguing illnesses using multiple methods of analysis can be an important factor in distinguishing similar illnesses. These findings support further analysis of analogous symptomatology among other chronic illnesses to assist in diagnosis.

8. Lacerda E et al. (2019)
A logistic regression analysis of risk factors in ME/CFS pathogenesis.
BMC Neurology 19 (275).

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.

9. Melvin A et al. (2019)
Circulating levels of GDF15 in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. 
Journal of Translational Medicine [Epub ahead of print].

Background: Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS.

Methods: GDF15 was measured in serum from patients with ME/CFS (n=150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n=150) and a cohort of patients with multiple sclerosis (n=50).

Results: Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~7 months (IQR 6.7-8.8) apart, 720 pg/ml (95% CI=625-816) vs 670 pg/ml (95% CI=598-796), P=0.5. GDF15 levels were 491 pg/ml in controls (95% CI= 429-553), 546 pg/ml (95% CI= 478 to 614) in MS patients, 560 pg/ml (95% CI= 502 to 617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI=531 to 674) in severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P=0.026) with fatigue scores in ME/CFS.

Conclusions: Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.

10. Oka T et al. (2019)
The longitudinal effects of seated isometric yoga on blood biomarkers, autonomic functions, and psychological parameters of patients with chronic fatigue syndrome: a pilot study.
BioPsychoSocial Medicine 13 (28).

Background: In a previous randomized controlled trial, we found that practicing seated isometric yoga regularly for 2 months improved the fatigue of patients with chronic fatigue syndrome (CFS) who are resistant to conventional therapy. The aim of this pilot study was to investigate the possible mechanisms behind this finding by comparing blood biomarkers, autonomic nervous function, and psychological indices before versus after an intervention period of seated isometric yoga practice.

Methods: Fifteen patients with CFS who did not show satisfactory improvements after at least 6 months of conventional therapy practiced seated isometric yoga (biweekly 20-min sessions with a yoga instructor and daily practice at home) for 2 months. The longitudinal effects of seated isometric yoga on fatigue, blood biomarkers, autonomic function, and psychological state were investigated by comparing the following parameters before and after the intervention period: Fatigue severity was assessed by the Chalder fatigue scale (FS) score. Levels of the blood biomarkers cortisol, DHEA-S, TNF-α, IL-6, prolactin, carnitine, TGF-β1, BDNF, MHPG, HVA, and α-MSH were measured. The autonomic nervous functions assessed were heart rate (HR) and HR variability. Psychological indices included the 20-item Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale (HADS).

Results: Practicing seated isometric yoga for 2 months resulted in significant reductions in the Chalder FS (P = 0.002) and HADS-depression (P = 0.02) scores. No significant changes were observed in any other parameter evaluated. The change in Chalder FS score was not correlated with the change in HADS-depression score. However, this change was positively correlated with changes in the serum TNF-α levels (P = 0.048), the high frequency component of HR variability (P = 0.042), and TAS-20 scores (P = 0.001).

Conclusions: Regular practice of seated isometric yoga for 2 months reduced the fatigue and depressive symptom scores of patients with CFS without affecting any other parameters we investigated. This study failed to identify the markers responsible for the longitudinal fatigue-relieving effect of seated isometric yoga. However, considering that the reduced fatigue was associated with decreased serum TNF-α level and TAS-20 scores, fatigue improvement might be related to reduced inflammation and improved alexithymia in these patients.

11. Parslow RM et al. (2019)
Developing and pretesting a new patient reported outcome measure for paediatric Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME): cognitive interviews with children.
Journal of Patient Rep Outcomes 3 (1): 67.

Background: There is a lack of patient derived, child specific outcome measures to capture what health outcomes are important to children with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). We developed a new Patient Reported Outcome Measure (PROM) for paediatric CFS/ME through qualitative research with children. This study aimed to pre-test the new measure through cognitive interviews with children with CFS/ME.

Methods: Cognitive interviews were undertaken in children's homes or over Skype. The Three-Step Test-Interview (TSTI) method was used to assess the quality of the draft PROM with children with CFS/ME to identify problems with initial content and design and test modifications over subsequent interview rounds. Children were purposively sampled from a single specialist paediatric CFS/ME service in England.

Results: Twenty-four children and their parents took part. They felt the new measure captured issues relevant to their condition and preferred it to the generic measures they completed in clinical assessment. Changes were made to item content and phrasing, timeframe and response options and tested through three rounds of interviews.

Conclusions: Cognitive interviews identified problems with the draft PROM, enabling us to make changes and then confirm acceptability in children aged 11-18. Further cognitive interviews are required with children 8-10 years old to examine the acceptability and content validity and provide evidence for age related cut offs of the new PROM to meet FDA standards. This study demonstrates the content validity of the new measure as relevant and acceptable for children with CFS/ME. The next stage is to undertake a psychometric evaluation to support the reduction of items, confirm the structure of the PROM and provide evidence of the data quality, reliability and validity.

12. Polo O et al. (2019)
Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Fatigue: Biomedicine, Helath and Behaviour.

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.

13. Roca-Espiau M et al. (2019)
Muscle-tendon weakness contributes to chronic fatigue syndrome in Gaucher's disease.
Journal of Orthopeadic Surgeon Research 14 (1): 383.

Background: Chronic fatigue (CFg) is a prevalent symptom in Gaucher disease (GD) at diagnosis (79%) and remains in a quarter of patients after years of therapy. Bone abnormalities are present in over 70% and peripheral neuropathy in about 11% of the patients, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors such as muscle-tendinous weakness could have influence in the development of CFg.

Methods: We have evaluated the fiber structure and elasticity of muscle-tendinous unit by strain-elastography (S-ELA) and analyzed their influence in the CFg. S-ELA study was performed in Achilles tendon in 25 type 1 and two type 3 GD patients, all of them with fatigue and were on enzymatic replacement therapy for mean 13 years; simultaneously, bone marrow burden by MRI and calcaneus ultrasound densitometry were evaluated. Blood cell counts, plasma biomarkers, GBA1 genotyping, and SF36 quality of life scale (QoL) were also performed.

Results: All patients showed a normal Achilles tendinous structure. Abnormal stiff grade 2-3 was found in 17/27 (62.9%); in 11/27 (40.7%) of patients, the alteration was bilateral. There were no correlations between the S-ELA results to other variables; nevertheless, a significant correlation between the degree of tendon hardness and the low score on the QoL scales (p = 0.0035) was found. The S-ELA is a sensitive painless, fast, and low cost method to detect muscle-tendinous subclinical dysfunction that could contribute to CFg in GD. The identification of subclinical tendon alteration would be a sign of alarm, focused on the risk of development of bone complications.

Conclusions: Intratendinous alteration in strain-elastography is an independent variable in GD patients with persistent fatigue.

14. Sepulveda N et al. (2019)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections.
Frontiers in Immunology 10:2684.

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.

15. Van Campen LMC and Visser FC (2019)
The Effect of Curcumin in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Disparate Responses in Different Disease Severities.
Pharmacovigilance and Pharmacoepidemiology 2 (1).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a chronic and often disabling disease. Although the exact pathophysiological mechanism of ME/CFS is unknown, immunological abnormalities may play an important role. Curcumin is an herb with powerful anti-oxidative and anti-inflammatory properties. Therefore, we hypothesized that curcumin would have favorable effects on symptomatology in ME/CFS patients.

In an open trial among 65 ME/CFS participants, 6 stopped the use of curcumin because of side effects and 8 did not complete the end of study questionnaire. Before and 8 weeks after the use of curcumin complexed with phosphatidyl choline-, 500 mg bid, participants completed the CDC inventory for assessment of Chronic Fatigue Syndrome. The CDC questions (n=19) were scored and divided into 2 parts: the first being specific for CFS complaints (n=9), the second being scores of less specific symptoms (n=10); denoted as CDC other score.

Results showed that 8 weeks of curcumin significantly decreased the CDC CFS-related symptom scores and CDC other scores, especially in patients with mild disease. Conclusion: in this open-labeled study 8 week curcumin use in a phosphatidyl choline complex reduced ME/CFS symptomatology, especially in patients with mild disease severity.

16. Van der Vaart R et al. (2019)
Implementing guided ICBT for chronic pain and fatigue: A qualitative evaluation among therapists and managers.
Internet Interventions 18.

Introduction: Internet-based cognitive behavioural therapy (ICBT) for chronic pain and chronic fatigue syndrome (CFS) has a high potential to increase the number of patients who can receive an evidence-based treatment aimed to reduce symptoms and/or disability and to lower burden on (mental) health care. However, implementing a new behaviour-change intervention, and especially an online intervention, has shown to be a challenge. This study aimed to identify factors influencing the implementation process of ICBT for chronic pain and CFS in mental health care.

Methods: A qualitative study using semi-structured interviews with therapists and managers from twelve mental health care clinics was conducted. Questions and analysis were guided by the Consolidated Framework for Implementation Research (CFIR), covering five domains: (1) the implemented intervention, (2) individual characteristics of the users, (3) the inner setting of implementation, (4) the outer setting, and (5) the implementation process.

Results: In all five domains important facilitators and barriers were found. Key themes were: (1) the quality of the content, its perceived effectiveness and usability, (2) the attitude, self-efficacy and ability to learn new skills among therapists, and motivation to start online treatment among patients, (3) internal communication within a team, existing workload, and top-down support from the management, (4) availability of reimbursement options and marketing strategies, and (5) involvement of all key stakeholders, steering towards independence of the implementation sites during the process and adequate training of therapists.

Conclusions: This study provides insight in the challenge of implementing ICBT for chronic pain and CFS in daily clinical practice. Several lessons can be learned from the interviews with therapists and managers which can also be more broadly applied to (ICBT) implementation projects in general. Development of practical tools to support the implementation process would be a valuable next step to overcome certain challenges at forehand and to properly prepare for those expected to come along.

17. Venturini L et al. (2019)
Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study.
Oxidative Medicine and Cellular Longevity.

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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