Evidence-Based Care for People with Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

Chronic fatigue syndrome (CFS), sometimes referred to as myalgic encephalomyelitis (ME) and often as CFS/ME, is an illness characterized by disabling fatigue and other symptoms, typically worsened by activity. The main evidence-based treatments are rehabilitative in nature and include specific types of cognitive behavior therapy (CBT) and graded exercise therapy (GET). In this article, we briefly review the evidence for their safety and effectiveness and propose that much of the controversy about them arises from misunderstandings about their nature and delivery. In particular, we emphasize that successful rehabilitation from CFS/ME does not indicate that the illness is not real. We recommend that rehabilitative treatment always be preceded by a thorough clinical assessment and delivered by appropriately trained therapists working in close collaboration with the patient. We conclude that properly applied rehabilitative treatments offer the best hope of safely improving fatigue and function for patients with CFS/ME. However, we also recognize the need for more research into the treatment of this neglected condition, especially for those most severely disabled by it.

Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study.

INTRODUCTION: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation. METHODS: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM). RESULTS: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not. CONCLUSION: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.

Guided graded exercise self-help for chronic fatigue syndrome: Long term follow up and cost-effectiveness following the GETSET trial.

OBJECTIVE: The GETSET trial found that guided graded exercise self-help (GES) improved fatigue and physical functioning more than specialist medical care (SMC) alone in adults with chronic fatigue syndrome (CFS) 12 weeks after randomisation. In this paper, we assess the longer-term clinical and health economic outcomes. METHODS: GETSET was a randomised controlled trial of 211 UK secondary care patients with CFS. Primary outcomes were the Chalder fatigue questionnaire and the physical functioning subscale of the short-form-36 survey. Postal questionnaires assessed the primary outcomes and cost-effectiveness of the intervention 12 months after randomisation. Service costs and quality-adjusted life years (QALYs) were combined in a cost-effectiveness analysis. RESULTS: Between January 2014 and March 2016, 164 (78%) participants returned questionnaires 15 months after randomisation. Results showed no main effect of intervention arm on fatigue (chi2(1) = 4.8, p = 0.03) or physical functioning (chi2(1) = 1.3, p = 0.25), adjusting for multiplicity. No other intervention arm or time*arm effect was significant. The short-term fatigue reduction was maintained at long-term follow-up for participants assigned to GES, with improved fatigue from short- to long-term follow up after SMC, such that the groups no longer differed. Healthcare costs were £85 higher for GES and produced more QALYs. The incremental cost-effectiveness ratio was £4802 per QALY. CONCLUSIONS: The short-term improvements after GES were maintained at long-term follow-up, with further improvement in the SMC group such that the groups no longer differed at long-term follow-up. The cost per QALY for GES compared to SMC alone was below the usual threshold indicating cost-effectiveness, but with uncertainty around the result.

Sick of the Sick Role: Narratives of What "Recovery" Means to People With CFS/ME.

Little is known about what recovery means to those with chronic fatigue syndrome/myalgic encephalomyelitis, a poorly understood, disabling chronic health condition. To explore this issue, semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10) after a guided self-help intervention, and analyzed via "constant comparison." The meaning of recovery differed between participants-expectations for improvement and deployment of the sick role (and associated stigma) were key influences. While some saw recovery as complete freedom from symptoms, many defined it as freedom from the "sick role," with functionality prioritized. Others redefined recovery, reluctant to return to the lifestyle that may have contributed to their illness, or rejected the concept as unhelpful. Recovery is not always about eliminating all symptoms. Rather, it is a nexus between the reality of limited opportunities for full recovery, yet a strong desire to leave the illness behind and regain a sense of "normality."

Prevalence of comorbid mental and physical illnesses and risks for self-harm and premature death among primary care patients diagnosed with fatigue syndromes.

BACKGROUND: Fatigue syndromes (FSs) affect large numbers of individuals, yet evidence from epidemiological studies on adverse outcomes, such as premature death, is limited. METHODS: Cohort study involving 385 general practices in England that contributed to the Clinical Practice Research Datalink (CPRD) with linked inpatient Hospital Episode Statistics (HES) and Office for National Statistics (ONS) cause of death information. A total of 10 477 patients aged 15 years and above, diagnosed with a FS during 2000-2014, were individually matched with up to 20 comparator patients without a history of having a FS. Prevalence ratios (PRs) were estimated to compare the FS and comparison cohorts on clinical characteristics. Adjusted hazard ratios (HRs) for subsequent adverse outcomes were estimated from stratified Cox regression models. RESULTS: Among patients diagnosed with FSs, we found elevated baseline prevalence of: any psychiatric illness (PR 1.77; 95% CI 1.72-1.82), anxiety disorders (PR 1.92; 1.85-1.99), depression (PR 1.89; 1.83-1.96), psychotropic prescriptions (PR 1.68; 1.64-1.72) and comorbid physical illness (PR 1.28; 1.23-1.32). We found no significant differences in risks for: all-cause mortality (HR 0.99; 0.91-1.09), natural death (HR 0.99; 0.90-1.09), unnatural death (HR 1.00; 0.59-1.72) or suicide (HR 1.68; 0.78-3.63). We did, however, observe a significantly elevated non-fatal self-harm risk: HR 1.83; 1.56-2.15. CONCLUSIONS: The absence of elevated premature mortality risk is reassuring. The raised prevalence of mental illness and increased non-fatal self-harm risk indicate a need for enhanced assessment and management of psychopathology associated with fatigue syndromes.

Protocol for a multicentre randomised controlled parallel-group trial to compare the effectiveness of remotely delivered cognitive-behavioural and graded exercise interventions with usual care alone to lessen the impact of fatigue in inflammatory rheumatic diseases (LIFT).

INTRODUCTION: Fatigue remains pervasive, disabling and challenging to manage across all inflammatory rheumatic diseases (IRDs). Non-pharmacological interventions, specifically cognitive-behavioural approaches (CBAs) and graded exercise programmes designed to support and increase exercise, are valuable treatments which help patients with IRD to manage their fatigue. Yet, healthcare systems have encountered substantial barriers to the implementation of these therapeutic options. Lessening the Impact of Fatigue in Inflammatory Rheumatic Diseases: a Randomised Trial (LIFT) is designed to give insights into the effectiveness of a remotely delivered standardised intervention for a range of patients with IRD. It will also enable the exploration of putative moderating factors which may allow for the future triage of patients and to investigate the precise mediators of treatment effect in IRD-related fatigue. METHODS AND ANALYSIS: LIFT is a pragmatic, multicentre, three-arm randomised, controlled trial, which will test whether adapted CBA and personalised exercise programme interventions can individually reduce the impact and severity of fatigue. This will be conducted with up to 375 eligible patients diagnosed with IRD and interventions will be delivered by rheumatology healthcare professionals, using the telephone or internet-based audio/video calls. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been granted by Wales REC 7 (17/WA/0065). Results of this study will be disseminated through presentation at scientific conferences and in scientific journal. A lay summary of the results will be sent to participants. TRIAL REGISTRATION NUMBER: NCT03248518; Pre-results.

Tutorial: The practical application of longitudinal structural equation mediation models in clinical trials.

The study of mediation of treatment effects, or how treatments work, is important to understanding and improving psychological and behavioral treatments, but applications often focus on mediators and outcomes measured at a single time point. Such cross-sectional analyses do not respect the implied temporal ordering that mediation suggests. Clinical trials of treatments often provide repeated measures of outcomes and, increasingly, of mediators as well. Repeated measurements allow the application of various types of longitudinal structural equation mediation models. These provide flexibility in modeling, including the ability to incorporate some types of measurement error and unmeasured confounding that can strengthen the robustness of findings. The usual approach is to identify the most theoretically plausible model and apply that model. In the absence of clear theory, we put forward the option of fitting a few theoretically plausible models, providing a type of sensitivity analysis for the mediation hypothesis. In this tutorial, we outline how to fit several longitudinal mediation models, including simplex, latent growth and latent change models. This will allow readers to learn about one type of model that is of interest, or about several alternative models, so that they can take this sensitivity approach. We use the Pacing, Graded Activity, and Cognitive Behavioral Therapy: A Randomized Evaluation (PACE) trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) as a motivating example and describe how to fit and interpret various longitudinal mediation models using simulated data similar to those in the PACE trial. The simulated data set and Mplus code and output are provided. (PsycINFO Database Record

The International Collaborative on Fatigue Following Infection (COFFI).

BACKGROUND: The purpose of the Collaborative on Fatigue Following Infection (COFFI) is for investigators of post-infection fatigue (PIF) and other syndromes to collaborate on these enigmatic and poorly understood conditions by studying relatively homogeneous populations with known infectious triggers. Utilizing COFFI, pooled data and stored biosamples will support both epidemiological and laboratory research to better understand the etiology and risk factors for development and progression of PIF. METHODS: COFFI consists of prospective cohorts from the UK, Netherlands, Norway, USA, New Zealand and Australia, with some cohorts closed and some open to recruitment. The 9 cohorts closed to recruitment total over 3,000 participants, including nearly 1000 with infectious mononucleosis (IM), > 500 with Q fever, > 800 with giardiasis, > 600 with campylobacter gastroenteritis (CG), 190 with Legionnaires disease and 60 with Ross River virus. Follow-ups have been at least 6 months and up to 10 years. All studies use the Fukuda criteria for defining chronic fatigue syndrome (CFS). RESULTS: Preliminary analyses indicated that risk factors for non-recovery from PIF included lower physical fitness, female gender, severity of the acute sickness response, and autonomic dysfunction. CONCLUSIONS: COFFI (https://internationalcoffi.wordpress.com/) is an international collaboration which should be able to answer questions based on pooled data that are not answerable in the individual cohorts. Possible questions may include the following: Do different infectious triggers different PIF syndromes (e.g., CFS vs. irritable bowel syndrome)?; What are longitudinal predictors of PIF and its severity?

Review of systematic reviews of non-pharmacological interventions to improve quality of life in cancer survivors.

OBJECTIVES: Over two million people in the UK are living with and beyond cancer. A third report diminished quality of life. DESIGN: A review of published systematic reviews to identify effective non-pharmacological interventions to improve the quality of life of cancer survivors. DATA SOURCES: Databases searched until May 2017 included PubMed, Cochrane Central, EMBASE, MEDLINE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO. STUDY SELECTION: Published systematic reviews of randomised trials of non-pharmacological interventions for people living with and beyond cancer were included; included reviews targeted patients aged over 18. All participants had already received a cancer diagnosis. Interventions located in any healthcare setting, home or online were included. Reviews of alternative therapies or those non-English reports were excluded. Two researchers independently assessed titles, abstracts and the full text of papers, and independently extracted the data. OUTCOMES: The primary outcome of interest was any measure of global (overall) quality of life. ANALYTICAL METHODS: Quality assessment assessing methdological quality of systematic reviews (AMSTAR) and narrative synthesis, evaluating effectiveness of non-pharmacological interventions and their components. RESULTS: Of 14 430 unique titles, 21 were included in the review of reviews. There was little overlap in the primary papers across these reviews. Thirteen reviews covered mixed tumour groups, seven focused on breast cancer and one focused on prostate cancer. Face-to-face interventions were often combined with online, telephone and paper-based reading materials. Interventions included physical, psychological or behavioural, multidimensional rehabilitation and online approaches. Yoga specifically, physical exercise more generally, cognitive behavioural therapy (CBT) and mindfulness-based stress reduction (MBSR) programmes showed benefit in terms of quality of life. CONCLUSIONS: Exercise-based interventions were effective in the short (less than 3-8 months) and long term. CBT and MBSR also showed benefits, especially in the short term. The evidence for multidisciplinary, online and educational interventions was equivocal.

Response to the editorial by Dr Geraghty.

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial.

BACKGROUND: Graded exercise therapy is an effective and safe treatment for chronic fatigue syndrome, but it is therapist intensive and availability is limited. We aimed to test the efficacy and safety of graded exercise delivered as guided self-help. METHODS: In this pragmatic randomised controlled trial, we recruited adult patients (18 years and older) who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome from two secondary-care clinics in the UK. Patients were randomly assigned to receive specialist medical care (SMC) alone (control group) or SMC with additional guided graded exercise self-help (GES). Block randomisation (randomly varying block sizes) was done at the level of the individual with a computer-generated sequence and was stratified by centre, depression score, and severity of physical disability. Patients and physiotherapists were necessarily unmasked from intervention assignment; the statistician was masked from intervention assignment. SMC was delivered by specialist doctors but was not standardised; GES consisted of a self-help booklet describing a six-step graded exercise programme that would take roughly 12 weeks to complete, and up to four guidance sessions with a physiotherapist over 8 weeks (maximum 90 min in total). Primary outcomes were fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale); both were self-rated by patients at 12 weeks after randomisation and analysed in all randomised patients with outcome data at follow-up (ie, by modified intention to treat). We recorded adverse events, including serious adverse reactions to trial interventions. We used multiple linear regression analysis to compare SMC with GES, adjusting for baseline and stratification factors. This trial is registered at ISRCTN, number ISRCTN22975026. FINDINGS: Between May 15, 2012, and Dec 24, 2014, we recruited 211 eligible patients, of whom 107 were assigned to the GES group and 104 to the control group. At 12 weeks, compared with the control group, mean fatigue score was 19·1 (SD 7·6) in the GES group and 22·9 (6·9) in the control group (adjusted difference -4·2 points, 95% CI -6·1 to -2·3, p<0·0001; effect size 0·53) and mean physical function score was 55·7 (23·3) in the GES group and 50·8 (25·3) in the control group (adjusted difference 6·3 points, 1·8 to 10·8, p=0·006; 0·20). No serious adverse reactions were recorded and other safety measures did not differ between the groups, after allowing for missing data. INTERPRETATION: GES is a safe intervention that might reduce fatigue and, to a lesser extent, physical disability for patients with chronic fatigue syndrome. These findings need confirmation and extension to other health-care settings. FUNDING: UK National Institute for Health Research Research for Patient Benefit Programme and the Sue Estermann Fund.

Health care resource use by patients before and after a diagnosis of chronic fatigue syndrome (CFS/ME): a clinical practice research datalink study.

BACKGROUND: Our aim was to investigate patterns of health care resource use by patients before and after a diagnosis of CFS/ME, as recorded by Clinical Practice Research Datalink (CPRD) GP practices in the UK. METHODS: We used a case-control study design in which patients who had a first recorded diagnosis of CFS/ME during the period 01/01/2001 to 31/12/2013 were matched 1:1 with controls by age, sex, and GP practice. We compared rates of GP consultations, diagnostic tests, prescriptions, referrals, and symptoms between the two groups from 15 years (in adults) or 10 years (in children) before diagnosis to 10 years after diagnosis. RESULTS: Data were available for 6710 adult and 916 child (age <18 years) matched case-control pairs. Rates of GP consultations, diagnostic tests, prescriptions, referrals, and symptoms spiked dramatically in the year when a CFS/ME diagnosis was recorded. GP consultation rates were 50% higher in adult cases compared to controls 11-15 years before diagnosis (rate ratio (RR) 1.49 (95% CI 1.46, 1.52)) and 56% higher 6-10 years after diagnosis (RR 1.56 (1.54, 1.57)). In children, consultation rates in cases were 45% higher 6-10 years before diagnosis (RR 1.45 (1.40, 1.51)) and 62% higher 6-10 years after diagnosis (RR 1.62 (1.54, 1.70)). For adults and children, rates of tests, prescriptions, referrals, and symptoms were higher in cases compared to controls for up to 10 years before and after diagnosis. CONCLUSIONS: Adults and children with CFS/ME have greater health care needs than the rest of the population for at least ten years before their diagnosis, and these higher levels of health care resource use continue for at least ten years after diagnosis.

Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study.

Objective Trends in recorded diagnoses of chronic fatigue syndrome (CFS, also known as 'myalgic encephalomyelitis' (ME)) and fibromyalgia (FM) in the UK were last reported more than ten years ago, for the period 1990-2001. Our aim was to analyse trends in incident diagnoses of CFS/ME and FM for the period 2001-2013, and to investigate whether incidence might vary by index of multiple deprivation (IMD) score. Design Electronic health records cohort study. Setting NHS primary care practices in the UK. Participants Participants: Patients registered with general practices linked to the Clinical Practice Research Datalink (CPRD) primary care database from January 2001 to December 2013. Main outcome measure Incidence of CFS/ME, FM, post-viral fatigue syndrome (PVFS), and asthenia/debility. Results The overall annual incidence of recorded cases of CFS/ME was 14.8 (95% CI 14.5, 15.1) per 100,000 people. Overall annual incidence per 100,000 people for FM was 33.3 (32.8-33.8), for PVFS 12.2 (11.9, 12.5), and for asthenia/debility 7.0 (6.8, 7.2). Annual incidence rates for CFS/ME diagnoses decreased from 17.5 (16.1, 18.9) in 2001 to 12.6 (11.5, 13.8) in 2013 (annual percent change -2.8% (-3.6%, -2.0%)). Annual incidence rates for FM diagnoses decreased from 32.3 (30.4, 34.3) to 27.1 (25.5, 28.6) in 2007, then increased to 38.2 (36.3, 40.1) per 100,000 people in 2013. Overall annual incidence of recorded fatigue symptoms was 2246 (2242, 2250) per 100,000 people. Compared with the least deprived IMD quintile, incidence of CFS/ME in the most deprived quintile was 39% lower (incidence rate ratio (IRR) 0.61 (0.50, 0.75)), whereas rates of FM were 40% higher (IRR 1.40 (0.95, 2.06)). Conclusion These analyses suggest a gradual decline in recorded diagnoses of CFS/ME since 2001, and an increase in diagnoses of fibromyalgia, with opposing socioeconomic patterns of lower rates of CFS/ME diagnoses in the poorest areas compared with higher rates of FM diagnoses.

HF-Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization.

We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post-translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.

A UK based review of recommendations regarding the management of chronic fatigue syndrome.

OBJECTIVES: Chronic fatigue syndrome (CFS) is a controversial illness, with apparent disagreements between medical authorities and patient support organisations regarding safe and effective treatments. The aim of this study was to measure the extent of different views regarding treatments, comparing patient support organisations and medical authorities in the UK. METHODS: Two independent raters analysed two groups of resources: UK patient support websites and both medical websites and textbooks. A 5-point Likert scale was developed with the question 'With what strength does the source recommend these treatments?' The various treatments were divided into the following four groups: complementary and alternative medicine (CAM), pharmacological, rehabilitative, and pacing therapies. RESULTS: There were significant differences between the scores for patient support organisations and medical sources for all 4 treatment groups. The results for supporting CAM were 74% (patient group) vs 16% (medical source) (p<0.001), 71% vs 42% for pharmacological (p=0.01), 28% vs 94% for rehabilitative (p<0.001) and 91% vs 50% for pacing treatments (p=0.001). CONCLUSIONS: There were substantially different treatment recommendations between patient support organisations and medical sources. Since expectations can determine response to treatment, these different views may reduce the engagement in and effectiveness of rehabilitative therapies recommended by national guidelines and supported by systematic reviews.

Graded Exercise Therapy Guided Self-Help Trial for Patients with Chronic Fatigue Syndrome (GETSET): Protocol for a Randomized Controlled Trial and Interview Study.

BACKGROUND: Chronic fatigue syndrome, also known as myalgic encephalomyelitis (CFS/ME), is characterized by chronic disabling fatigue and other symptoms, which are not explained by an alternative diagnosis. Previous trials have suggested that graded exercise therapy (GET) is an effective and safe treatment. GET itself is therapist-intensive with limited availability. OBJECTIVE: While guided self-help based on cognitive behavior therapy appears helpful to patients, Guided graded Exercise Self-help (GES) is yet to be tested. METHODS: This pragmatic randomized controlled trial is set within 2 specialist CFS/ME services in the South of England. Adults attending secondary care clinics with National Institute for Health and Clinical Excellence (NICE)-defined CFS/ME (N=218) will be randomly allocated to specialist medical care (SMC) or SMC plus GES while on a waiting list for therapist-delivered rehabilitation. GES will consist of a structured booklet describing a 6-step graded exercise program, supported by up to 4 face-to-face/telephone/Skype™ consultations with a GES-trained physiotherapist (no more than 90 minutes in total) over 8 weeks. The primary outcomes at 12-weeks after randomization will be physical function (SF-36 physical functioning subscale) and fatigue (Chalder Fatigue Questionnaire). Secondary outcomes will include healthcare costs, adverse outcomes, and self-rated global impression change scores. We will follow up all participants until 1 year after randomization. We will also undertake qualitative interviews of a sample of participants who received GES, looking at perceptions and experiences of those who improved and worsened. RESULTS: The project was funded in 2011 and enrolment was completed in December 2014, with follow-up completed in March 2016. Data analysis is currently underway and the first results are expected to be submitted soon. CONCLUSIONS: This study will indicate whether adding GES to SMC will benefit patients who often spend many months waiting for rehabilitative therapy with little or no improvement being made during that time. The study will indicate whether this type of guided self-management is cost-effective and safe. If this trial shows GES to be acceptable, safe, and comparatively effective, the GES booklet could be made available on the Internet as a practitioner and therapist resource for clinics to recommend, with the caveat that patients also be supported with guidance from a trained physiotherapist. The pragmatic approach in this trial means that GES findings will be generalizable to usual National Health Service (NHS) practice. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRTCTN): 22975026; http://www.isrctn.com/ISRCTN22975026 (Archived by WebCite at http://www.webcitation.org/6gBK00CUX).