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Abstract Background Childhood, adolescent, and young adult (CAYA) cancer survivors, at risk for late effects, including cancer-related fatigue, cardiovascular issues, and psychosocial challenges, may benefit from interventions stimulating behaviour adjustments. Three nurse-led eHealth interventions (REVIVER) delivered via video calls and elaborating on person-centred care, cognitive behaviour therapy and/or motivational interviewing were developed. These interventions target: 1) fatigue management, 2) healthier lifestyle behaviours, and 3) self-efficacy and self-management. This study aimed to assess the feasibility and potential effectiveness of the REVIVER interventions for CAYA cancer survivors and healthcare professionals. Methods In a single-group mixed methods design, CAYA cancer survivors aged 16–54, more than five years post-treatment, were enrolled. Feasibility, assessed via Bowen's outcomes for feasibility studies, included acceptability, practicality, integration and implementation, demand and adherence. Qualitative data from semi-structured interviews and a focus group interview with survivors and healthcare professionals supplemented the evaluation. Paired sample t-tests assessed changes in self-reported quality of life, fatigue, lifestyle, self-management, and self-efficacy at baseline (T0), post-intervention (T1), and 6-month follow-up (T2). Results The interventions and video consults were generally acceptable, practical, and successfully integrated and implemented. Success factors included the nurse consultant (i.e., communication, approach, and attitude) and the personalised approach. Barriers included sustainability concerns, technical issues, and short intervention duration. Regarding demand, 71.4%, 65.4%, and 100% of eligible CAYA cancer survivors engaged in the fatigue (N = 15), lifestyle (N = 17) and empowerment (N = 3) intervention, respectively, with 5, 5 and 2 participants interviewed, correspondingly. Low interest (demand) in the empowerment intervention (N = 3) and dropout rates of one-third for both fatigue and empowerment interventions were noted (adherence). Improvements in quality of life, fatigue (fatigue intervention), lifestyle (lifestyle intervention), self-efficacy, and self-management were evident among survivors who completed the fatigue and lifestyle interventions, with medium and large effect sizes observed immediately after the intervention and six months post-intervention. Conclusions Our study demonstrates the feasibility of nurse-led video coaching (REVIVER interventions) despite lower demand for the empowerment intervention and lower adherence to the fatigue and empowerment interventions. The medium and high effect sizes found for those who completed the interventions hold potential clinical significance for future studies investigating the effectiveness of the REVIVER interventions.

Design Parallel-group randomised controlled trial. Methods Participants Adolescents aged 11–17 years, diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome and with no local specialist treatment centre, were referred to a specialist service in South West England. Interventions Fatigue In Teenagers on the interNET in the National Health Service is a web-based myalgic encephalomyelitis/chronic fatigue syndrome-focused cognitive–behavioural therapy programme for adolescents, supported by individualised written, asynchronous electronic consultations with a clinical psychologist/cognitive–behavioural therapy practitioner. The comparator was videocall-delivered activity management with a myalgic encephalomyelitis/chronic fatigue syndrome clinician. Both treatments were intended to last 6 months. Objectives Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for paediatric myalgic encephalomyelitis/chronic fatigue syndrome. Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for those with mild/moderate comorbid mood disorders. From a National Health Service perspective, estimate the cost-effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management over a 12-month horizon. Primary Outcome 36-item Short Form Health Survey Physical Function subscale at 6 months post randomisation. Randomisation Web-based, using minimisation with a random component to balance allocated groups by age and gender. Blinding While the investigators were blinded to group assignment, this was not possible for participants, parents/carers and therapists. Results The treatment of 314 adolescents was randomly allocated, 155 to Fatigue In Teenagers on the interNET in the National Health Service. Mean age was 14 years old and 63% were female. Primary outcome At 6 months, participants allocated to Fatigue In Teenagers on the interNET in the National Health Service were more likely to have improved physical function (mean 60.5, standard deviation 29.5, n = 127) compared to Activity Management (mean 50.3, standard deviation 26.5, n = 138). The mean difference was 8.2 (95% confidence interval 2.7 to 13.6, p = 0.003). The result was similar for participants meeting the National Institute for Health and Care Excellence 2021 diagnostic criteria. Secondary outcomes Fatigue In Teenagers on the interNET in the National Health Service participants attended, on average, half a day more school per week at 6 months than those allocated Activity Management, and this difference was maintained at 12 months. There was no strong evidence that comorbid mood disorder impacted upon the relative effectiveness of the two interventions. Similar improvement was seen in the two groups for pain and the Clinical Global Impression scale, with a mixed picture for fatigue. Both groups continued to improve, and no clear difference in physical function remained at 12 months [difference in means 4.4 (95% confidence interval −1.7 to 10.5)]. One or more of the pre-defined measures of a worsening condition in participants during treatment, combining therapist and patient reports, were met by 39 (25%) participants in the Fatigue In Teenagers on the interNET in the National Health Service group and 42 (26%) participants in the Activity Management group. A small gain was observed for the Fatigue In Teenagers on the interNET in the National Health Service group compared to Activity Management in quality-adjusted life-years (0.002, 95% confidence interval −0.041 to 0.045). From an National Health Service perspective, the costs were £1047.51 greater in the Fatigue In Teenagers on the interNET in the National Health Service group (95% confidence interval £624.61 to £1470.41). At a base cost-effectiveness threshold of £20,000 per quality-adjusted life-year, the incremental cost-effectiveness ratio was £457,721 with incremental net benefit of −£1001 (95% confidence interval −£2041 to £38). Conclusion At 6 months post randomisation, compared with Activity Management, Fatigue In Teenagers on the interNET in the National Health Service improved physical function and school attendance. The additional cost of Fatigue In Teenagers on the interNET in the National Health Service and limited sustained impact mean it is unlikely to be cost-effective. Trial registration This trial is registered as ISRCTN18020851. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/109) and is published in full in Health Technology Assessment; Vol. 28, No. 70. See the NIHR Funding and Awards website for further award information. Plain language summary Why did we do the study? The best evidence for the treatment of adolescents with myalgic encephalomyelitis/chronic fatigue syndrome is cognitive–behavioural therapy for fatigue delivered in person. In the United Kingdom, most adolescents with myalgic encephalomyelitis/chronic fatigue syndrome cannot get this specialist treatment where they live. Fatigue In Teenagers on the interNET in the National Health Service is an online treatment using cognitive–behavioural therapy designed for myalgic encephalomyelitis/chronic fatigue syndrome, which has been shown to work in the Netherlands. To find out if Fatigue In Teenagers on the interNET in the National Health Service would be beneficial in the United Kingdom, we compared Fatigue In Teenagers on the interNET in the National Health Service to Activity Management. Activity Management is the treatment most often offered to children and young people with myalgic encephalomyelitis/chronic fatigue syndrome in the United Kingdom, and aims to avoid peaks in activity (sometimes called ‘pacing’). What was the question? Does Fatigue In Teenagers on the interNET in the National Health Service lead to greater improvements in children and young people with myalgic encephalomyelitis/chronic fatigue syndrome when compared to Activity Management, when both interventions are delivered remotely? What did we do? We compared Fatigue In Teenagers on the interNET in the National Health Service and Activity Management in two comparable groups of children, and measured physical function at 6 months as the main indication of improvement. We measured how much the treatments cost and we asked children and young people, their parents and treatment providers what they thought about the two interventions. What did we find? At 6 months, adolescents saw greater improvements in physical function, and attended half a day more school per week, with Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management. Both interventions were associated with improvements over 12 months, with there being no clear difference between them after that time. However, the Fatigue In Teenagers on the interNET in the National Health Service treatment was more expensive. What does this mean? We have shown that cognitive–behavioural therapy for fatigue can be provided online to children as Fatigue In Teenagers on the interNET in the National Health Service, leading to faster improvement in physical function and greater school attendance compared to Activity Management. However, Fatigue In Teenagers on the interNET in the National Health Service is expensive and is unlikely to be good value for money. Scientific summary Objectives Primary objective To investigate whether cognitive–behavioural therapy (CBT) specifically designed for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and delivered over the internet [Fatigue In Teenagers on the interNET in the National Health Service (FITNET-NHS)] is effective and cost-effective compared to Activity Management for children with ME/CFS who do not have access to a local specialist ME/CFS service. Secondary objectives (1) Estimate the effectiveness of FITNET-NHS compared to Activity Management for those with mild/moderate comorbid mood disorders (anxiety/depression). (2) Estimate the cost-effectiveness of FITNET-NHS compared to Activity Management. (3) Estimate the cost-effectiveness of FITNET-NHS compared to Activity Management for those with mild/moderate comorbid mood disorders (anxiety/depression). Methods Trial design Randomised controlled trial (RCT) comparing FITNET-NHS with Activity Management. Participants were allocated in a 1 : 1 ratio, minimised by age and gender. We conducted an internal pilot (first 12 months) and integrated qualitative methods to optimise recruitment and retention. Participants Adolescents aged 11–17 years with a diagnosis of ME/CFS [defined using National Institute for Health and Care Excellence (NICE) 2007 Criteria], who did not have a local specialist ME/CFS service. To have a confirmed diagnosis, potential participants were required to have been assessed by a paediatrician (or equivalent specialist doctor), and to have had screening bloods taken. We excluded adolescents if: they were not disabled by fatigue; their fatigue was due to another cause (including primary anxiety/depression); they had access to a local specialist service; they were unable to complete video calls or FITNET-NHS treatment modules; they were pregnant. Setting We identified potentially eligible adolescents at referral to the specialist paediatric ME/CFS service at the Royal United Hospital, Bath. Patients were referred to the service by their general practitioner (GP) or paediatrician (or equivalent specialist). Between September 2018 and March 2020, we offered GP surgeries the opportunity to become patient identification centres. In these sites, database searches were conducted to identify potentially eligible adolescents, who were then offered referral to the Bath Royal United Hospital for eligibility assessment. Recruitment Potentially eligible adolescents were contacted by the clinical team by telephone to discuss the opportunity to take part in the FITNET-NHS trial. Interested adolescents were sent study information, including a link to the Revised Children’s Anxiety and Depression Scale (RCADS) questionnaire. Eligibility assessment Adolescents who were interested were invited to an eligibility assessment conducted by a specialist nurse. The nurse checked if: (1) they had debilitating persistent or relapsing fatigue for at least 3 months, but not life-long; (2) fatigue was not the result of ongoing exertion and not substantially alleviated by rest; (3) they had post-exertional malaise (and increase in fatigue and other symptoms after exertion); and (4) their fatigue was severe enough to cause substantial reduction in previous levels of occupational, educational, social or personal activities. The recruiting nurse checked that the screening blood tests had been done within the previous 12 months and were normal. The nurse then assessed whether the adolescent had comorbid mental health problems or a primary mental health problem. Patients were asked to complete the RCADS. Those scoring within the borderline or above the age-/gender-validated threshold answered further questions to determine if they were at risk of harm and whether their anxiety/depression was sufficiently severe to explain the fatigue. This enabled us to ensure that those recruited had a diagnosis of ME/CFS from a specialist but also had 3 months of disabling fatigue plus one further symptom and did not have an exclusionary diagnosis and therefore had ME/CFS according to the contemporary United Kingdom (UK) guideline. Consent If adolescents were eligible and interested in taking part in the FITNET-NHS trial, consent and assent (patients aged 11–15 years) were obtained using an online form. Randomisation We used an automated web randomisation service operated by Bristol Trials Centre. Participants were allocated in a 1 : 1 ratio. Allocation used minimisation to balance by age and gender with a random component to preserve allocation concealment. Blinding It was not possible to blind the participant, family or the clinical service. The investigators (including the senior statistician who wrote the statistical analysis plan) were blinded to treatment allocation. The study statistician was unblinded as they reported to the Data Safety and Monitoring Committee. Interventions Fatigue In Teenagers on the interNET in the National Health Service (FITNET-NHS) This is a web-based modular specialist CBT programme designed to be used by adolescents with ME/CFS and their parents. We adapted the Dutch FITNET platform for UK adolescents. FITNET-NHS is delivered using asynchronous individualised e-consultations within the web-based platform. Contact is weekly initially and then becomes less frequent. The therapist works with patients and parents separately. FITNET-NHS has psycho-educational and CBT chapters for patients and a parallel programme for parents. There are 19 chapters. Chapters 1–3 introduce ME/CFS, CBT and the role of therapists; Chapter 4 discusses treatment goals; Chapters 5–19 are about cognitive and behavioural strategies. There are diaries for patients that are visible to the therapist. FITNET-NHS is individualised for patients. Chapters 5–19 are unlocked (made available) by the therapist according to clinical presentation, needs and formulation. Fidelity was assessed in clinical supervisions. Activity Management Participants and their families received information on ME/CFS, Activity Management, sleep and symptoms management. Participants could use an online app to record their activity. Activity Management was delivered via videocall. In the initial assessment, participants had a detailed assessment of physical and cognitive activity. The participant and therapist agreed a ‘baseline’ of activity, which is the average level of activity. Participants were asked to record activity, and then, when activity was stable, to increase activity gradually in a flexible and individual way. The initial assessment was 90 minutes (but this could be split into two shorter sessions). Follow-up video calls (60 minutes each) were organised 2–6 weeks apart. In November 2017, the number of follow-up sessions was increased from 3 to 6 in response to participant feedback. Fidelity was assessed using a checklist of mandatory, flexible and prohibited elements. Data sources Adolescent- and parent-completed measures, collected online using research electronic data capture. Therapist reports. Routinely collected data from local systems and from NHS Digital. Qualitative interviews with adolescents, parents and therapists. Measures Primary outcome Disability measured using the 36-item Short Form Health Survey Physical Function subscale (SF-36-PFS) measured 6 months after randomisation. We included outcome data returned in a 5-to-9-month window post randomisation. Secondary outcomes (Measured at 3, 6 and 12 months unless specified): Physical function (3 and 12 months); fatigue [Chalder fatigue scale and checklist individual strength (CIS) fatigue scale]; school attendance (self-reported days per week attending school, or whether receiving home tuition); mental health {RCADS; pain [visual analogue scale (VAS)]; Clinical Global Impression Scale; quality of life [EuroQol-5 Dimensions Youth (EQ-5D-Y)]; parent-completed resource use questionnaire; parent-completed work productivity and activity impairment questionnaire general health (WPAI:GH)}. Demographic data were collected at recruitment and included: age, sex, postcode, ethnicity, symptoms, months since illness onset, presence of comorbid illnesses. Harms/adverse events We prospectively collected the following data: (1) clinician-reported serious deterioration in health, (2) a decrease of ≥ 20 in SF-36-PFS between baseline and 3, 6 or 12 months or scores of ‘much’ or ‘very much’ worse on the Clinical Global Impression scale or (3) withdrawal from treatment because of feeling worse. Safety outcomes were reported to the Data Safety Monitoring Committee. Resource use data In addition to study documentation and patient/parent questionnaires, we used patient-level data recorded on the Royal United Hospitals Bath NHS Trusts electronic patient record system (Millennium). We obtained secondary care data on outpatient visits, inpatient visits and emergency department attendances from NHS Digital. Costs were valued using 2019/20 prices. Analysis Sample size Our sample size of 314 participants (assuming 15% attrition) gives 90% power at 5% significance to detect a 10-point (0.4 standard deviation) difference for the SF-36-PFS for our primary outcome. The original sample size was powered to detect a difference in the subgroup with mental health problems, but this was revised during the study. Statistical methods We used an intention-to-treat analysis in study participants who completed the primary outcome. We used multivariable linear regression analysis adjusting for baseline values of the outcome, age and gender. The treatment effect was estimated as an adjusted difference between sample means. We conducted the following pre-planned sensitivity analyses: we adjusted for variation across participants in the time between randomisation and the 6-month outcome; the primary analysis was repeated with an additional binary covariate distinguishing participants recruited before or after 1 September 2019 (distinguishing those with a 6-month assessment before or during the COVID-19 pandemic); we repeated the analysis in those who completed one or more modules/sessions of their allocated intervention. We conducted a sensitivity analysis for participants with ME/CFS according to the NICE (2021) criteria. We adapted the regression model used for the primary analysis to the secondary outcome variables. We estimated the effectiveness of FITNET-NHS compared with Activity Management in participant subgroups defined by the presence or absence of anxiety or depression (defined by the RCADS). Health economic analysis We used an intention-to-treat approach and multiple imputation by chained equation to minimise bias due to missing data. We combined cost and quality-adjusted life-year (QALY) data to calculate an incremental cost-effectiveness ratioand an incremental net monetary benefit (iNMB) statistic. We performed a subgroup analysis to explore the interaction between comorbid anxiety/depression and cost-effectiveness. Prespecified sensitivity analyses include conducting a complete-case analysis and repeating the primary analysis using the tariff paid by Clinical Commissioning Groups instead of reference costs. Qualitative methods We integrated qualitative methods into the pilot and main phase of the trial to explore trial conduct, recruitment and intervention acceptability. We analysed recruitment to trial consultations and conducted in-depth interviews with recruiters, trial therapists and participants. Results were used to improve recruitment and make small changes to the interventions. Qualitative analysis was ongoing and iterative, commencing soon after data collection. Audio recordings were transcribed, checked and imported into NVivo (QSR International, Warrington, UK). The data were systematically assigned codes and analysed thematically using techniques of constant comparison. Results Of 892 referrals between 1 November 2016 and 31 October 2020, 550 were eligible, of which 155 were allocated to FITNET-NHS and 159 to Activity Management. 265 adolescents were included in the primary analysis (127 for FITNET-NHS and 138 for Activity Management). The baseline characteristics were similar between the treatment arms. 147 participants had either comorbid depression or anxiety (145 depression, 34 anxiety and 32 both). The number completing 80% or more of expected modules/sessions was lower for FITNET-NHS participants (58, 38%) compared to Activity Management participants (124, 78%). Participants in the FITNET-NHS group had a greater improvement in physical function compared to the Activity Management group at 6 months [mean difference 8.2, 95% confidence interval (CI) 2.7 to 13.6]. The sensitivity analyses confirmed the primary analysis. This was true for participants with ME/CFS defined using the NICE (2021) criteria. At 6 months, those allocated to FITNET-NHS were, on average, attending half a day more of school per week compared to Activity Management, and this difference was maintained at 12 months. They experienced less fatigue (with the CIS fatigue measure) at both 6 and 12 months. There was no strong evidence that either treatment was more effective in those with comorbid depression/anxiety, and similar levels of improvement were noted for pain, the Clinical Global Improvement Score, and fatigue measured using the Chalder Fatigue Scale. Participants continued to improve between 6 and 12 months in both treatment arms, and there was little difference in physical function between the two treatment arms at 12 months. Fatigue In Teenagers on the interNET in the National Health Service participants had a small gain in QALYs (0.002, 95% CI −0.041 to 0.045) compared to Activity Management but substantially higher mean costs (£1047.51, 95% CI £624.61 to £1470.41). In the primary analysis, from an NHS perspective, at a threshold of £20,000 per QALY, the iNMB was −£1001.74 (95% CI −£2041.31 to £37.83), indicating that FITNET-NHS is unlikely to be cost-effective. The wide Cis show there is considerable uncertainty in this result. The subgroup analysis suggests that FITNET-NHS is more likely to be cost-effective among those with comorbid anxiety and depression at baseline. In the qualitative interviews, families felt online treatment could fit around everyday life and reduce the increase in symptoms that can accompany travelling to face-to-face appointments. However, some participants still preferred in-person treatment and found it difficult to build a rapport with therapists online. Personalised contact with a therapist was valued in both treatments and remains essential even in online treatment. The reading and writing required on the FITNET-NHS platform was difficult for younger children and those with cognitive symptoms such as brain fog; therefore, adaptations may be needed for these groups. Therapists felt they had to develop a different set of skills to engage patients online. Conclusions Despite the fact that adolescents are more likely to have better physical function at 6 months and attend more school (at 6 and 12 months) after receiving FITNET-NHS compared to Activity Management, FITNET-NHS is unlikely to be cost-effective. This study is consistent with previous RCTs that demonstrated the effectiveness of CBT for children and young people with ME/CFS. It is the first study to attempt to look at cost-effectiveness. The high additional cost of FITNET-NHS and limited substantial sustained impact mean that it may not be a cost-effective use of NHS funds. Alternatively, it is possible that the EQ-5D-Y is not sensitive enough to appropriately reflect the improvements in physical function and school attendance. Most participants in the FITNET-NHS group did not complete 80% or more of the recommended treatment modules. While our qualitative data suggest that FITNET-NHS was acceptable to most patients, it was considered burdensome by some. Implications for health care This study strengthens the evidence that CBT is effective for adolescents with ME/CFS and should be the first line of treatment offered. FITNET-NHS is an intensive treatment approach and is unlikely to be cost-effective. However, the online approach was popular with patients and families. Recommendations for research Would a shorter intervention with less intensive therapist input increase retention and reduce costs without jeopardising effectiveness? We need a validated health economic measure for children and young people that is sensitive to change. Further research needs to be conducted on the best method to deliver remote treatment. A large implementation study in the Netherlands suggested that many patients (and therapists) prefer a mixture of face-to-face and online treatment. Trial registration This trial is registered as ISRCTN18020851. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/109) and is published in full in Health Technology Assessment; Vol. 28, No. 70. See the NIHR Funding and Awards website for further award information.

Objectives: Different SARS-CoV-2 variants can differentially affect the prevalence of Post Covid-19 Condition (PCC). This prospective study assesses prevalence and severity of symptoms three months after an Omicron infection, compared to Delta, test-negative and population controls. This study also assesses symptomology after reinfection and breakthrough infections. Methods: After a positive SARS-CoV-2 test, cases were classified as Omicron or Delta based on ≥ 85% surveillance prevalence. Three months after enrolment, participants indicated point prevalence for 41 symptoms and severity, using validated questionnaires for four symptoms. PCC prevalence was estimated as the difference in prevalence of at least one significantly elevated symptom, identified by permutation test, in cases compared to population controls. Results: At three months follow-up, five symptoms and severe dyspnea were significantly elevated in Omicron cases (n = 4138) compared to test-negative (n = 1672) and population controls (n = 2762). PCC prevalence was 10·4% for Omicron cases and 17·7% for Delta cases (n = 6855). In Omicron cases, severe fatigue and dyspnea were more prevalent in reinfected than primary infected, while severity of symptoms did not significantly differ between cases with a booster or primary vaccination course. Conclusions: Prevalence of PCC is 41% lower after Omicron than Delta at three months. Reinfection seems associated with more severe long-term symptoms compared to first infection.

AbstractThe ‘Oslo Chronic Fatigue Consortium’ consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brain's response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.

Abstract Background Currently, there is limited evidence about the long-term impact on physical, social and emotional functioning, i.e. health-related quality of life (HRQL) after mild or moderate COVID-19 not requiring hospitalization. We compared HRQL among persons with initial mild, moderate or severe/critical COVID-19 at 1 and 12 months following illness onset with Dutch population norms and investigated the impact of restrictive public health control measures on HRQL. Methods RECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled adult participants after confirmed SARS-CoV-2 diagnosis. HRQL was assessed with the Medical Outcomes Study Short Form 36-item health survey (SF-36). SF-36 scores were converted to standard scores based on an age- and sex-matched representative reference sample of the Dutch population. Differences in HRQL over time were compared among persons with initial mild, moderate or severe/critical COVID-19 using mixed linear models adjusted for potential confounders. Results By December 2021, 349 persons were enrolled of whom 269 completed at least one SF-36 form (77%). One month after illness onset, HRQL was significantly below population norms on all SF-36 domains except general health and bodily pain among persons with mild COVID-19. After 12 months, persons with mild COVID-19 had HRQL within population norms, whereas persons with moderate or severe/critical COVID-19 had HRQL below population norms on more than half of the SF-36 domains. Dutch-origin participants had significantly better HRQL than participants with a migration background. Participants with three or more COVID-19 high-risk comorbidities had worse HRQL than part participants with fewer comorbidities. Participants who completed the SF-36 when restrictive public health control measures applied reported less limitations in social and physical functioning and less impaired mental health than participants who completed the SF-36 when no restrictive measures applied. Conclusions Twelve months after illness onset, persons with initial mild COVID-19 had HRQL within population norms, whereas persons with initial moderate or severe/critical COVID-19 still had impaired HRQL. Having a migration background and a higher number of COVID-19 high-risk comorbidities were associated with worse HRQL. Interestingly, HRQL was less impaired during periods when restrictive public health control measures were in place compared to periods without.

Abstract Background Fatigue is the most frequent and burdensome symptom of patients with diffuse glioma. It is closely linked to decreased health-related quality of life and symptoms such as depression and sleep disturbances. Currently, there is no evidence-based treatment that targets severe fatigue in patients with brain tumours. Cognitive behavioural therapy is aimed at fatigue-maintaining beliefs and behaviour. This therapy has been proven effective in reducing severe fatigue in cancer survivors and patients with multiple sclerosis. A blended therapy program combines sessions with a therapist with therapist-guided web-based therapy modules. The aim of this randomized controlled trial is to determine the efficacy of blended cognitive behavioural therapy in treating severe fatigue in patients with diffuse glioma. Methods We will include a maximum of 100 patients with diffuse glioma with clinically and radiologically stable disease and severe fatigue (i.e. Checklist Individual Strength, subscale fatigue severity ≥ 35). Patients will be randomized to blended cognitive behavioural therapy or a waiting list condition. The 12-week intervention GRIP on fatigue consists of five patient-therapist sessions and five to eight individualized web-based therapy modules supported by email contact. The primary outcome measure is fatigue severity. Secondary outcome measures include sleep quality, health-related quality of life, depression, anxiety, functional impairment and subjective and objective cognitive functioning. Primary and secondary outcome measures will be assessed at baseline and after 14 and 24 weeks. Magnetoencephalography and MRI will be used to evaluate potential biomarkers for intervention success. This trial has a Bayesian design: we will conduct multiple interim analyses to test for efficacy or futility of the trial. This is the first trial within the GRIP trial platform: a platform developing four to five different interventions for the most common symptoms in patients with diffuse glioma. Discussion The results of the GRIP on fatigue trial will provide information about the efficacy of this intervention on fatigue in patients with diffuse glioma. Multiple other outcomes and possible predictors of treatment success will also be explored. Trial registration Netherlands Trial Register NL8711 . Registered on 14 June 2020.

Abstract Background Fatigue is often reported by patients with childhood cancer both during and after cancer treatment. Several instruments to measure fatigue exist, although none are specifically validated for use in childhood cancer survivors (CCS). The aim of the current study was to present norm values and psychometric properties of the Checklist Individual Strength (CIS) and Short Fatigue Questionnaire (SFQ) in a nationwide cohort of CCS. Methods In total, 2073 participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Normative data, construct validity, structural validity, and internal consistency were calculated for the CIS and SFQ. In addition, reliability and a cutoff score to indicate severe fatigue were determined for the SFQ. Results Correlations between CIS/SFQ and vitality measures asking about fatigue were high (>0.8). Correlations between CIS/SFQ and measures of different constructs (sleep, depressive emotions, and role functioning emotional) were moderate (0.4–0.6). Confirmatory factor analysis resulted in a four‐factor solution for the CIS and a one‐factor solution for the SFQ with Cronbach's alpha for each (sub)scale showing good to excellent values (>0.8). Test–retest reliability of the SFQ was adequate (Pearson's correlation = 0.88; ICC = 0.946; weighted Cohen's kappa item scores ranged 0.31–0.50) and a cut‐off score of 18 showed good sensitivity and specificity scores (92.6% and 91.3%, respectively). Conclusion The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS. The CIS can be used as a tool to assess the multiple fatigue dimensions in CCS.

Abstract Background Insomnia is common in people with long-term medical conditions and is related to increased mortality and morbidity. Cognitive behavioral therapy for insomnia (CBT-I) is first choice treatment and effective for people with insomnia and comorbid long-term medical conditions. However, CBT-I has some limitations as it might not always be available or appeal to patients with medical conditions. Furthermore, a small proportion of patients do not respond to CBT-I. Preliminary evidence and clinical experience suggest that low-dose amitriptyline (AM) might be an effective alternative to treat insomnia in patients with medical comorbidity. In this randomized controlled trial, we will determine whether AM is non-inferior to the first choice treatment for insomnia, CBT-I. Methods/design This study will test if treatment with low-dose amitriptyline for insomnia in patients with medical comorbidity is non-inferior to CBT-I in a multicenter randomized controlled non-inferiority trial. Participants will be 190 adults with a long-term medical condition and insomnia. Participants will be randomly allocated to one of two intervention arms: 12 weeks AM (starting with 10 mg per day, and if ineffective at 3 weeks, doubling this dose) or 12 weeks of CBT-I consisting of 6 weekly sessions and a follow-up session 6 weeks later. The primary outcome is subjective insomnia severity, measured with the Insomnia Severity Index (ISI). The primary endpoint is at 12 weeks. Secondary outcomes include sleep quality (e.g., sleep efficiency), questionnaires on daytime functioning (physical functioning and impairment of functioning), and symptoms (e.g., fatigue, pain, anxiety) at 12 weeks and 12 months post treatment and relapse of insomnia until 12 months after treatment. Discussion Irrespective of the outcome, this study will be a much-needed contribution to evidence based clinical guidelines on the treatment of insomnia in patients with medical comorbidity. Trial registration Dutch Trial Register NTR NL7971 . Registered on 18 August 2019

Abstract Background More than half of the adults with visual impairment experience severe symptoms of fatigue, with a negative impact on daily life. Since there is no evidence-based treatment to reduce fatigue in adults with visual impairment, we developed E-nergEYEze, an eHealth intervention based on cognitive behavioral therapy and self-management tailored to the needs of visually impaired adults. The aim is to describe the study protocol of a randomized controlled trial testing E-nergEYEze. Methods A randomized controlled trial will be conducted to investigate the cost-effectiveness and cost-utility of E-nergEYEze to reduce fatigue severity compared to care as usual from a healthcare and societal perspective. A total of 172 severely fatigued adults with visual impairment will be recruited and randomized to either the E-nergEYEze intervention plus care as usual or to care as usual only (ratio 1:1). Inclusion criteria are having a visual impairment, experiencing severe fatigue (Checklist Individual Strength – subscale Fatigue Severity: CIS-FS > 35), being 18 years or older, understanding the Dutch language, and having access to the internet. The intervention consists of one face-to-face session and a computer training followed by internet-based modules with information and assignments on coping with fatigue. During this 5-month intervention, participants will be digitally supported by a social worker. All measurements will be administered at baseline, after 6 and 12 months, and additionally, those related to cost-effectiveness at 3 and 9 months. The primary outcome is fatigue severity (CIS-FS). Discussion Severe fatigue on top of visual impairment compromises quality of life and is associated with incremental societal costs that largely determine the economic burden of low vision or blindness. E-nergEYEze contributes to the evidence base of potentially feasible interventions to reduce the important health-related consequences of vision loss and could fulfill the gap in knowledge, skills and treatment options for low vision services. Trial registration Dutch Trial Register NTR7764 . Registered on 28 May 2019.

Abstract Background Fear of cancer recurrence, depressive symptoms, and cancer-related fatigue are prevalent symptoms among cancer survivors, adversely affecting patients’ quality of life and daily functioning. Effect sizes of interventions targeting these symptoms are mostly small to medium. Personalizing treatment is assumed to improve efficacy. However, thus far the empirical support for this approach is lacking. The aim of this study is to investigate if systematically personalized cognitive behavioral therapy is more efficacious than standard cognitive behavioral therapy in cancer survivors with moderate to severe fear of cancer recurrence, depressive symptoms, and/or cancer-related fatigue. Methods The study is designed as a non-blinded, multicenter randomized controlled trial with two treatment arms (ratio 1:1): (a) systematically personalized cognitive behavioral therapy and (b) standard cognitive behavioral therapy. In the standard treatment arm, patients receive an evidence-based diagnosis-specific treatment protocol for fear of cancer recurrence, depressive symptoms, or cancer-related fatigue. In the second arm, treatment is personalized on four dimensions: (a) the allocation of treatment modules based on ecological momentary assessments, (b) treatment delivery, (c) patients’ needs regarding the symptom for which they want to receive treatment, and (d) treatment duration. In total, 190 cancer survivors who experience one or more of the targeted symptoms and ended their medical treatment with curative intent at least 6 months to a maximum of 5 years ago will be included. Primary outcome is limitations in daily functioning. Secondary outcomes are level of fear of cancer recurrence, depressive symptoms, fatigue severity, quality of life, goal attainment, therapist time, and drop-out rates. Participants are assessed at baseline (T0), and after 6 months (T1) and 12 months (T2). Discussion To our knowledge, this is the first randomized controlled trial comparing the efficacy of personalized cognitive behavioral therapy to standard cognitive behavioral therapy in cancer survivors. The study has several innovative characteristics, among which is the personalization of interventions on several dimensions. If proven effective, the results of this study provide a first step in developing an evidence-based framework for personalizing therapies in a systematic and replicable way. Trial registration The Dutch Trial Register (NTR) NL7481 (NTR7723). Registered on 24 January 2019.

Abstract (1) To evaluate the prevalence of severe and chronic fatigue in subjects with and without chronic disease; (2) to assess to which extent multi-morbidity contributes to severe and chronic fatigue; and (3) to identify predisposing and associated factors for severe and chronic fatigue and whether these are disease-specific, trans-diagnostic, or generic. The Dutch Lifelines cohort was used, including 78,363 subjects with (n = 31,039, 53 ± 12 years, 33% male) and without (n = 47,324, 48 ± 12 years, 46% male) ≥ 1 of 23 chronic diseases. Fatigue was assessed with the Checklist Individual Strength-Fatigue. Compared to participants without a chronic disease, a higher proportion of participants with ≥ 1 chronic disease were severely (23% versus 15%, p

Background Fatigue in immune thrombocytopenia (ITP) is frequent and burdensome, but we lack the knowledge to help these patients. Aim The aim of the study is to explore the role of disease activity and other potentially modifiable factors in fatigue. Method This cross-sectional study included adult chronic ITP patients (n = 59). Univariable linear regression (corrected for confounders) was used to determine the relationship between disease activity (platelet count 0.50) were found for physical and functional well-being and fatigue, and physical activity and fatigue. Other significant relations with fatigue (effect size 0.30–0.47) included skin and organ bleeding, emotional and social well-being, vitamin D, and disease activity. Notably, the models with disease activity and disease-specific factors explained 50%. Vitamin D alone explained 12% of the variance in fatigue. Conclusion Transdiagnostic (non-disease-specific) rather than disease-specific factors explained a large part of the variance in ITP-related fatigue. Many factors related to fatigue are potentially modifiable and should be investigated as targets for interventions.

Introduction A substantial proportion of individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), report persisting symptoms weeks and months following acute infection. Estimates on prevalence vary due to differences in study designs, populations, heterogeneity of symptoms and the way symptoms are measured. Common symptoms include fatigue, cognitive impairment and dyspnoea. However, knowledge regarding the nature and risk factors for developing persisting symptoms is still limited. Hence, in this study, we aim to determine the prevalence, severity, risk factors and impact on quality of life of persisting symptoms in the first year following acute SARS-CoV-2 infection.Methods and analysis The LongCOVID-study is both a prospective and retrospective cohort study being conducted in the Netherlands, with a one year follow-up. Participants aged 5 years and above, with self-reported positive or negative tests for SARS-CoV-2 will be included in the study. The primary outcome is the prevalence and severity of persistent symptoms in participants that tested positive for SARS-CoV-2 compared with controls. Symptom severity will be assessed for fatigue (Checklist Individual Strength (CIS subscale fatigue severity)), pain (Rand-36/SF-36 subscale bodily pain), dyspnoea (Medical Research Council (mMRC)) and cognitive impairment (Cognitive Failure Questionnaire (CFQ)). Secondary outcomes include effect of vaccination prior to infection on persistent symptoms, loss of health-related quality of life (HRQoL) and risk factors for persisting symptoms following infection with SARS-CoV-2.Ethics and dissemination The Utrecht Medical Ethics Committee (METC) declared in February 2021 that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (METC protocol number 21-124/C). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in a peer-reviewed journal.

Abstract Background A debilitating late effect for childhood cancer survivors (CCS) is cancer-related fatigue (CRF). Little is known about the prevalence and risk factors of fatigue in this population. Here we describe the methodology of the Dutch Childhood Cancer Survivor Late Effect Study on fatigue (DCCSS LATER fatigue study). The aim of the DCCSS LATER fatigue study is to examine the prevalence of and factors associated with CRF, proposing a model which discerns predisposing, triggering, maintaining and moderating factors. Triggering factors are related to the cancer diagnosis and treatment during childhood and are thought to trigger fatigue symptoms. Maintaining factors are daily life- and psychosocial factors which may perpetuate fatigue once triggered. Moderating factors might influence the way fatigue symptoms express in individuals. Predisposing factors already existed before the diagnosis, such as genetic factors, and are thought to increase the vulnerability to develop fatigue. Methodology of the participant inclusion, data collection and planned analyses of the DCCSS LATER fatigue study are presented. Results Data of 1955 CCS and 455 siblings was collected. Analysis of the data is planned and we aim to start reporting the first results in 2022. Conclusion The DCCSS LATER fatigue study will provide information on the epidemiology of CRF and investigate the role of a broad range of associated factors in CCS. Insight in associated factors for fatigue in survivors experiencing severe and persistent fatigue may help identify individuals at risk for developing CRF and may aid in the development of interventions.

Abstract Background Cognitive behavioural therapy (CBT) has been found to be effective in reducing fatigue severity in MS patients directly following treatment. However, long-term effects are inconsistent leaving room for improvement. In addition, individual face-to-face CBT draws heavily on limited treatment capacity, and the travel distance to the treatment centre can be burdensome for patients. Therefore, we developed “MS Fit”, a blended CBT for MS-related fatigue, based on a face-to-face CBT protocol found effective in a previous study, and “MS Stay Fit”, internet-based booster sessions to improve long-term effectiveness of CBT for MS-related fatigue. This article presents the protocol of two randomised clinical trials (RCTs) conducted within one study investigating (1) the non-inferiority of MS Fit compared with evidence-based face-to-face CBT for MS-related fatigue and (2) the effectiveness of MS Stay Fit on the long-term outcome of fatigue compared with no booster sessions. Methods/design The first part of this study is an observer-blinded non-inferiority multicentre RCT, in which 166 severely fatigued MS patients will be randomly assigned (1:1 ratio, computer-generated sequence) to either face-to-face CBT or blended CBT (MS Fit) for fatigue. The primary endpoint is at 20 weeks after baseline. After this post-treatment assessment, patients will be randomly assigned again (1:1 ratio, computer generated sequence) to either MS Stay Fit consisting of two booster sessions at 2 and 4 months after end of treatment or no booster sessions. The primary endpoint of the second study is 52 weeks after baseline. Primary outcome measure in both studies is fatigue severity assessed with the fatigue severity subscale of the Checklist Individual Strength (CIS20r). Outcomes will be assessed at baseline (T0), at the end of treatment (T20), and after 39 and 52 weeks (T39 and T52). Discussion If MS Fit is found to be non-inferior to face-to-face CBT, it will improve the accessibility of this treatment. In addition, the study aims to test whether it is possible to improve long-term effectiveness of CBT for MS-related fatigue with MS Stay Fit. Trial registration Dutch Trial Register (NTR6966), registered 18 January 2018 https://www.trialregister.nl/trial/6782 World Health Organization (WHO) Trial Registration Data Set All items from the WHO Trial Registration Data Set can be found within the protocol.

Introduction: Psychological distress and fatigue are common in persons with diabetes, adversely affecting quality of life and complicating diabetes self-management. Offering diabetes-specific self-guided cognitive behavioral therapy (CBT) may be helpful for persons with diabetes and mild symptoms of psychological distress and fatigue. We are the first to test the feasibility and user experiences of a web-based self-help app called ‘MyDiaMate’ in adults with type 1 and type 2 diabetes. Methods and materials: MyDiaMate was developed in close collaboration with persons with diabetes and professionals, building on elements from existing (guided) diabetes-specific CBT interventions. The study was advertised, offering free access to the app for adults with diabetes for a period of three months. Feasibility and user experiences were tested in a non-randomized study with pre- and post- measurements and interviews in a small sample.. In addition usage of the app was studied using log-data.. Results: In total N = 55 adults with diabetes signed up for the study. Mean age was M = 42.7 (SD = 15.6), mostly women (n = 39, 70.9%), higher educated (n = 36, 65.5%), and diagnosed with type 1 diabetes (n = 37, 67.3%). About half reported current or a history of psychological complaints. All the participants completed baseline assessments, and n = 32 participants (58%) completed the follow-up questionnaire. Main reasons for participating in the study were: to preserve or improve mental fitness (40.6%), curiosity (25.0%) and wanting to contribute to research (34.4%). No major technical issues were encountered in accessing or using the app. The app was opened at least once by n = 51 participants, median use of the modules was 28 min (1–80) within a period of 1 to 92 days (median = 10). Almost all participants (n = 50, 98.0%) opened the basic module ‘Diabetes in balance’, of whom 32 (62.7%) completed this module. ‘My mood’ and ‘My energy’ were opened by n = 40 (78.4%) and n = 32 (62.7%) participants, respectively, and completed by n = 21 (52.5%) and n = 9 (28.1%) of the participants. Of all participants, 40.6% would recommend the app to others living with diabetes. Conclusions: This study confirmed the feasibility of MyDiaMate as a diabetes-specific self-guided app for adults wishing to preserve or improve their psychological health. While user experiences were overall positive, further tailoring the content to individual needs and preferences could enhance uptake, usage and appreciation. Future research should explore its effectiveness in a randomized controlled trial.

Introduction: A common approach to personalizing psychological interventions is the allocation of treatment modules to individual patients based on cut-off scores on questionnaires, which are mostly based on group studies. However, this way, intraindividual variation and temporal dynamics are not taken into account. Automated individual time series analyses are a possible solution, since these can identify the factors influencing the targeted symptom in a specific individual, and associated modules can be allocated accordingly. The aim of this study was to illustrate how automated individual time series analyses can be applied to personalize cognitive behavioral therapy for cancer-related fatigue in cancer survivors and how this procedure differs from allocating modules based on questionnaires. Methods: This study was a case report series (n = 3). Patients completed ecological momentary assessments at the start of therapy, and after three treatment modules (approximately 14 weeks). Assessments were analyzed with AutoVAR, an R package that automates the process of finding optimal vector autoregressive models. The results informed the treatment plan. Results: Three cases were described. From the ecological momentary assessments and automated time series analyses three individual treatment plans were constructed, in which the most important predictor for cancer-related fatigue was treated first. For two patients, this led to the treatment ending after the follow-up ecological momentary assessments. One patient continued treatment until six months, the standard treatment time in regular treatment. All three treatment plans differed from the treatment plans informed by questionnaire scores. Discussion: This study is one of the first to apply time series analyses in systematically personalizing psychological treatment. An important strength of this approach is that it can be used for every modular cognitive behavioral intervention where each treatment module addresses specific maintaining factors. Whether or not personalized CBT is more efficacious than standard, non-personalized CBT remains to be determined in controlled studies comparing it to usual care.

BackgroundInternet-based cognitive behavior therapy (I-CBT) for adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been shown to be effective in a randomized controlled trial (RCT; Fatigue in Teenagers on the Internet [FITNET]). FITNET can cause a significant reduction in fatigue and disability. ObjectiveWe aimed to investigate whether FITNET treatment implemented in routine clinical care (IMP-FITNET) was as effective, using the outcomes of the FITNET RCT as the benchmark. MethodsOutcomes of CFS/ME adolescents who started IMP-FITNET between October 2012 and March 2018 as part of routine clinical care were compared to the outcomes in the FITNET RCT. The primary outcome was fatigue severity assessed posttreatment. The secondary outcomes were self-reported physical functioning, school attendance, and recovery rates. Clinically relevant deterioration was assessed posttreatment, and for this outcome, a face-to-face CBT trial was used as the benchmark. The attitude of therapists toward the usability of IMP-FITNET was assessed through semistructured interviews. The number of face-to-face consultations during IMP-FITNET was registered. ResultsOf the 384 referred adolescents with CFS/ME, 244 (63.5%) started IMP-FITNET, 84 (21.9%) started face-to-face CBT, and 56 (14.6%) were not eligible for CBT. Posttreatment scores for fatigue severity (mean 26.0, SD 13.8), physical functioning (mean 88.2, SD 15.0), and full school attendance (mean 84.3, SD 26.5) fell within the 95% CIs of the FITNET RCT. Deterioration of fatigue and physical functioning after IMP-FITNET was observed at rates of 1.2% (n=3) and 4.1% (n=10), respectively, which is comparable to a waiting list condition (fatigue: 1.2% vs 5.7%, χ21=3.5, P=.06; physical functioning: 4.1% vs 11.4%, χ21=3.3, P=.07). Moreover, 41 (16.8%) IMP-FITNET patients made use of face-to-face consultations. ConclusionsIMP-FITNET is an effective and safe treatment for adolescents with CFS/ME in routine clinical care.

Summary: Background: Concerns about long-lasting symptoms attributed to Lyme borreliosis (LB) are widespread in the Western world, while such symptoms are highly prevalent in the general population. Methods: In the largest prospective study to date, adults with physician-confirmed LB were included at the start of antibiotic treatment. Primary outcomes, prevalence of persistent symptoms and symptom severity, were assessed using three-monthly standardised questionnaires during one year. Persistent symptoms were defined as impaired scores for fatigue (CIS, subscale fatigue), cognitive impairment (CFQ) or pain (SF-36, subscale bodily pain) ≥6 months, with onset

Abstract The FITNET-NHS Trial is a UK, national, trial investigating whether an online cognitive behavioural therapy program (FITNET-NHS) for treating chronic fatigue syndrome/ME in adolescents is clinically effective and cost-effective in the NHS. At the time of writing (September 2019), the trial was recruiting participants. This article presents an update to the planned sample size and data collection duration previously published within the trial protocol. Trial registration ISRCTN, ID: 18020851. Registered 8 April 2016.

Abstract Background After antibiotic treatment of Lyme borreliosis, a subset of patients report persistent symptoms, also referred to as post-treatment Lyme disease syndrome. The reported prevalence of persistent symptoms varies considerably, and its pathophysiology is under debate. The LymeProspect study has been designed to investigate the prevalence, severity, and a wide range of hypotheses on the etiology of persistent symptoms among patients treated for Lyme borreliosis in the Netherlands. Methods LymeProspect is a prospective, observational cohort study among adults with proven or probable Lyme borreliosis, either erythema migrans or disseminated manifestations, included at the start of antibiotic treatment. During one year of follow-up, participants are subjected to questionnaires every three months and blood is collected repeatedly during the first three months. The primary outcome is the prevalence of persistent symptoms after treatment, assessed by questionnaires online focusing on fatigue (CIS, subscale fatigue severity), pain (SF-36, subscale pain) and neurocognitive dysfunction (CFQ). Potential microbiological, immunological, genetic, epidemiological and cognitive-behavioral determinants for persistent symptoms are secondary outcome measures. Control cohorts include patients with long-lasting symptoms and unconfirmed Lyme disease, population controls, and subjects having reported a tick bite not followed by Lyme borreliosis. Discussion This article describes the background and design of the LymeProspect study protocol. This study is characterized by a prospective, explorative and multifaceted design. The results of this study will provide insights into the prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis, and may provide a rationale for preventive and treatment recommendations. Trial registration NTR4998 (Netherlands Trial Register). Date of registration: 13 February 2015.

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. Keywords: Internet-based cognitive behavioural therapy, Implementation, Pain, Chronic fatigue syndrome, Qualitative evaluation

Abstract Background Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. Methods Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA. Results In CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls. Conclusions In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra. Trial Registration: ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014

Fatigue is a frequent complaint in kidney transplant recipients (KTR), often accompanied by poor quality of life (QoL). The role of nutrition as determinant of fatigue in KTR is largely unexplored. The aims of this study are to examine the association of protein intake with fatigue and QoL in KTR and to identify other determinants of fatigue. This cross-sectional study is part of the TransplantLines Cohort and Biobank Study (NCT03272841). Protein intake was calculated from urinary urea nitrogen (UUN) in 24-h urine samples. Fatigue was assessed by the Checklist Individual Strength (CIS) questionnaire; moderate and severe fatigue were defined as a CIS score of 20–34 and ≥ 35, respectively. QoL was assessed with the RAND-36-Item Health Survey (RAND-36). Associations of protein intake with fatigue and QoL were analyzed using multinomial logistic and linear regression analyses. We included 730 stable outpatient KTR (median age 58 year [IQR 48–65], 57% male) with a mean protein intake of 82.2 ± 21.3 g/d. Moderate and severe fatigue were present in 254 (35%) and 245 (34%) of KTR. Higher protein intake was significantly associated with lower risk of moderate fatigue (OR 0.89 per 10 g/d; 95%CI 0.83–0.98, p = 0.01), severe fatigue (OR 0.85; 95%CI 0.78–0.92, p < 0.001) and was associated with higher physical component summary score of QoL (β 0.74 per 10 g/d; 95%CI 0.39–1.09, p < 0.001). Higher BMI, a history of dialysis, glomerulonephritis as primary kidney disease and a history of combined organ transplantation were also associated with severe fatigue. In conclusion, amongst the potential modifiable factors of fatigue, higher protein intake is independently associated with lower risk of moderate and severe fatigue and with better QoL in KTR. These findings underline the need to incorporate nutritional assessment in the diagnostic work-up of fatigue. Intervention studies are needed to assess the benefits and safety of higher protein intake in KTR.

Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale-originally designed to assess a positive response bias-are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ's MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ's discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias-as detected by the MD subscale-has a small but significant moderating effect on the CTQ's discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables.