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, Kashfia Chowdhury, , , , Emilia Caverly, Lisa French, , Anne Klepacz, Mathew Raynor, et al.
Efficacy and Mechanism Evaluation, Volume 8, pp 1-46; https://doi.org/10.3310/eme08150

Abstract:
Background Keratoconus is a disease of the cornea affecting vision that is usually first diagnosed in the first three decades. The abnormality of corneal shape and thickness tends to progress until the patient reaches approximately 30 years of age. Epithelium-off corneal cross-linking is a procedure that has been demonstrated to be effective in randomised trials in adults and observational studies in young patients. Objectives The KERALINK trial examined the efficacy and safety of epithelium-off corneal cross-linking, compared with standard care by spectacle or contact lens correction, for stabilisation of progressive keratoconus. Design In this observer-masked, randomised, controlled, parallel-group superiority trial, 60 participants aged 10–16 years with progressive keratoconus were randomised; 58 participants completed the study. Progression was defined as a 1.5 D increase in corneal power measured by maximum or mean power (K2) in the steepest corneal meridian in the study eye, measured by corneal tomography. Setting Referral clinics in four UK hospitals. Interventions Participants were randomised to corneal cross-linking plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision, and were monitored for 18 months. Main outcome measures The primary outcome was K2 in the study eye as a measure of the steepness of the cornea at 18 months post randomisation. Secondary outcomes included keratoconus progression, visual acuity, keratoconus apex corneal thickness and quality of life. Results Of 60 participants, 30 were randomised to the corneal cross-linking and standard-care groups. Of these, 30 patients in the corneal cross-linking group and 28 patients in the standard-care group were analysed. The mean (standard deviation) K2 in the study eye at 18 months post randomisation was 49.7 D (3.8 D) in the corneal cross-linking group and 53.4 D (5.8 D) in the standard-care group. The adjusted mean difference in K2 in the study eye was –3.0 D (95% confidence interval –4.93 D to –1.08 D; p = 0.002), favouring corneal cross-linking. Uncorrected and corrected differences in logMAR vision at 18 months were better in eyes receiving corneal cross-linking: –0.31 (95% confidence interval –0.50 to –0.11; p = 0.002) and –0.30 (95% confidence interval –0.48 to –0.11; p = 0.002). Keratoconus progression in the study eye occurred in two patients (7%) randomised to corneal cross-linking compared with 12 (43%) patients randomised to standard care. The unadjusted odds ratio suggests that, on average, patients in the corneal cross-linking group had 90% (odds ratio 0.1, 95% confidence interval 0.02 to 0.48; p = 0.004) lower odds of experiencing progression than those receiving standard care. Quality-of-life outcomes were similar in both groups. No adverse events were attributable to corneal cross-linking. Limitations Measurements of K2 in those eyes with the most significant progression were in some cases indicated as suspect by corneal topography device software. Conclusions Corneal cross-linking arrests progression of keratoconus in the great majority of young patients. These data support a consideration of a change in practice, such that corneal cross-linking could be considered as first-line treatment in progressive disease. If the arrest of keratoconus progression induced by corneal cross-linking is sustained in longer follow-up, there may be particular benefit in avoiding the later requirement for contact lens wear or corneal transplantation. However, keratoconus does not continue to progress in all patients receiving standard care. For future work, the most important questions to be answered are whether or not (1) the arrest of keratoconus progression induced by corneal cross-linking is maintained in the long term and (2) the proportion of those receiving standard care who show significant progression increases with time. Trial registration Current Controlled Trials ISRCTN17303768 and EudraCT 2016-001460-11. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 15. See the NIHR Journals Library website for further project information. The trial sponsor is University College London. This research was otherwise supported in part by the NIHR Moorfields Biomedical Research Centre and the NIHR Moorfields Clinical Research Facility, London, United Kingdom.
, Emma Mckenzie, Zara Rasoul, , , , Rebecca Jones, , Rumana Omar, Sally Finning, et al.
Public Health Research, Volume 9, pp 1-80; https://doi.org/10.3310/phr09100

Abstract:
Background Little is known about the effectiveness of befriending for people with intellectual disability and whether or not befriending improves depressive symptoms and social outcomes. Objective This pilot trial aimed to assess the feasibility and acceptability of conducting a future full-scale randomised controlled trial of one-to-one befriending for people with intellectual disability who had depressive symptoms. Design This was a parallel-group, two-armed randomised controlled trial incorporating an exploratory economic analysis and a mixed-methods process evaluation. Outcome assessments were conducted at baseline and at 6 months post randomisation by a research assistant who was blind to allocation. We aimed to approach 50 participants, with a view to recruiting 40. Setting Participants with intellectual disability were recruited from one NHS trust and from referrals to two community befriending services. The intervention was delivered by community befriending services. Participants Adults with mild or moderate intellectual disability with a score on the Glasgow Depression Scale for people with a Learning Disability of ≥ 5 were included. Those attending a day service/college for ≥ 3 days a week were excluded. Volunteers were aged ≥ 18 years and had no history of prior convictions. Intervention Participants in the intervention group were matched with a volunteer befriender and were expected to meet once per week for 1 hour, over 6 months. Volunteers recorded activities in a logbook. Volunteers received training and regular supervision. Both groups received usual care and a resource booklet of local activities. Main outcome measures The feasibility outcomes and progression criteria were recruitment of at least 70% of participants approached; matching of at least 70% of participants in the intervention group to a volunteer; a dropout rate of < 30% of participants and volunteers; adherence to the intervention (10 meetings between pairs); acceptability of the intervention; and feasibility of collecting data on costs and resource use for an economic evaluation. Changes in depressive symptoms (primary clinical outcome: Glasgow Depression Scale) and self-esteem, quality of life, social participation, social support, health-related quality of life and service use were recorded at 6 months. Outcomes in volunteers were also assessed. Results We recruited only 16 participants with intellectual disability (40% of target) and 10 volunteers. Six of the eight (75%) participants in the intervention group were matched with a befriender and there was good adherence (mean number of meetings attended 11.8; range 1–21 meetings). Going to a cafe/restaurant and having a conversation were the most frequent activities. All participants were retained at follow-up, but two volunteers dropped out. Trial procedures and the intervention might be acceptable, but modifications were suggested. Data on costs and resource use were obtained, but there were discrepancies in the health-related quality-of-life data. Limitations Delays to the study prevented the use of alternative recruitment strategies and the planned 12-month follow-up could not be completed. Conclusions Recruitment was not feasible, but other feasibility outcomes were more positive. Future work Evaluating befriending for people with intellectual disability could be explored through alternative study designs, such as observational studies. Trial registration Current Controlled Trials ISRCTN63779614. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 9, No. 10. See the NIHR Journals Library website for further project information.
Martin J Wildman, , , Chin Maguire, , Marlene Hutchings, , , , , et al.
Programme Grants for Applied Research, Volume 9, pp 1-146; https://doi.org/10.3310/pgfar09110

Abstract:
Background People with cystic fibrosis frequently have low levels of adherence to inhaled medications. Objectives The objectives were to develop and evaluate an intervention for adults with cystic fibrosis to improve adherence to their inhaled medication. Design We used agile software methods to develop an online platform. We used mixed methods to develop a behaviour change intervention for delivery by an interventionist. These were integrated to become the CFHealthHub intervention. We undertook a feasibility study consisting of a pilot randomised controlled trial and process evaluation in two cystic fibrosis centres. We evaluated the intervention using an open-label, parallel-group randomised controlled trial with usual care as the control. Participants were randomised in a 1 : 1 ratio to intervention or usual care. Usual care consisted of clinic visits every 3 months. We undertook a process evaluation alongside the randomised controlled trial, including a fidelity study, a qualitative interview study and a mediation analysis. We undertook a health economic analysis using both a within-trial and model-based analysis. Setting The randomised controlled trial took place in 19 UK cystic fibrosis centres. Participants Participants were people aged ≥ 16 years with cystic fibrosis, on the cystic fibrosis registry, not post lung transplant or on the active transplant list, who were able to consent and not using dry-powder inhalers. Intervention People with cystic fibrosis used a nebuliser with electronic monitoring capabilities. This transferred data automatically to a digital platform. People with cystic fibrosis and clinicians could monitor adherence using these data, including through a mobile application (app). CFHealthHub displayed graphs of adherence data as well as educational and problem-solving information. A trained interventionist helped people with cystic fibrosis to address their adherence. Main outcome measures Randomised controlled trial – adjusted incidence rate ratio of pulmonary exacerbations meeting the modified Fuchs criteria over a 12-month follow-up period (primary outcome); change in percentage adherence; and per cent predicted forced expiratory volume in 1 second (key secondary outcomes). Process evaluation – percentage fidelity to intervention delivery, and participant and interventionist perceptions of the intervention. Economic modelling – incremental cost per quality-adjusted life-year gained. Results Randomised controlled trial – 608 participants were randomised to the intervention (n = 305) or usual care (n = 303). To our knowledge, this was the largest randomised controlled trial in cystic fibrosis undertaken in the UK. The adjusted rate of exacerbations per year (primary outcome) was 1.63 in the intervention and 1.77 in the usual-care arm (incidence rate ratio 0.96, 95% confidence interval 0.83 to 1.12; p = 0.638) after adjustment for covariates. The adjusted difference in mean weekly normative adherence was 9.5% (95% confidence interval 8.6% to 10.4%) across 1 year, favouring the intervention. Adjusted mean difference in forced expiratory volume in 1 second (per cent) predicted at 12 months was 1.4% (95% confidence interval –0.2% to 3.0%). No adverse events were related to the intervention. Process evaluation – fidelity of intervention delivery was high, the intervention was acceptable to people with cystic fibrosis, participants engaged with the intervention [287/305 (94%) attended the first intervention visit], expected mechanisms of action were identified and contextual factors varied between randomised controlled trial sites. Qualitative interviews with 22 people with cystic fibrosis and 26 interventionists identified that people with cystic fibrosis welcomed the objective adherence data as proof of actions to self and others, and valued the relationship that they built with the interventionists. Economic modelling – the within-trial analysis suggests that the intervention generated 0.01 additional quality-adjusted life-years at an additional cost of £865.91 per patient, leading to an incremental cost-effectiveness ratio of £71,136 per quality-adjusted life-year gained. This should be interpreted with caution owing to the short time horizon. The health economic model suggests that the intervention is expected to generate 0.17 additional quality-adjusted life-years and cost savings of £1790 over a lifetime (70-year) horizon; hence, the intervention is expected to dominate usual care. Assuming a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained, the probability that the intervention generates more net benefit than usual care is 0.89. The model results are dependent on assumptions regarding the duration over which costs and effects of the intervention apply, the impact of the intervention on forced expiratory volume in 1 second (per cent) predicted and the relationship between increased adherence and drug-prescribing levels. Limitations Number of exacerbations is a sensitive and valid measure of clinical change used in many trials. However, data collection of this outcome in this context was challenging and could have been subject to bias. It was not possible to measure baseline adherence accurately. It was not possible to quantify the impact of the intervention on the number of packs of medicines prescribed. Conclusions We developed a feasible and acceptable intervention that was delivered to fidelity in the randomised controlled trial. We observed no statistically significant difference in the primary outcome of exacerbation rates over 12 months. We observed an increase in normative adherence levels in a disease where adherence levels are low. The magnitude of the increase in adherence may not have been large enough to affect exacerbations. Future work Given the non-significant difference in the primary outcome, further research is required to explore why an...
, , Elizabeth Biswell, , , , James Fuller, , Nigel Hewett, Alan Kilmister, et al.
Health Services and Delivery Research, Volume 9, pp 1-186; https://doi.org/10.3310/hsdr09170

Abstract:
Background In 2013, 70% of people who were homeless on admission to hospital were discharged back to the street without having their care and support needs addressed. In response, the UK government provided funding for 52 new specialist homeless hospital discharge schemes. This study employed RAMESES II (Realist And Meta-narrative Evidence Syntheses: Evolving Standards) guidelines between September 2015 and 2019 to undertake a realist evaluation to establish what worked, for whom, under what circumstances and why. It was hypothesised that delivering outcomes linked to consistently safe, timely care transfers for homeless patients would depend on hospital discharge schemes implementing a series of high-impact changes (resource mechanisms). These changes encompassed multidisciplinary discharge co-ordination (delivered through clinically led homeless teams) and ‘step-down’ intermediate care. These facilitated time-limited care and support and alternative pathways out of hospital for people who could not go straight home. Methods The realist hypothesis was tested empirically and refined through three work packages. Work package 1 generated seven qualitative case studies, comparing sites with different types of specialist homeless hospital discharge schemes (n = 5) and those with no specialist discharge scheme (standard care) (n = 2). Methods of data collection included interviews with 77 practitioners and stakeholders and 70 people who were homeless on admission to hospital. A ‘data linkage’ process (work package 2) and an economic evaluation (work package 3) were also undertaken. The data linkage process resulted in data being collected on > 3882 patients from 17 discharge schemes across England. The study involved people with lived experience of homelessness in all stages. Results There was strong evidence to support our realist hypothesis. Specialist homeless hospital discharge schemes employing multidisciplinary discharge co-ordination and ‘step-down’ intermediate care were more effective and cost-effective than standard care. Specialist care was shown to reduce delayed transfers of care. Accident and emergency visits were also 18% lower among homeless patients discharged at a site with a step-down service than at those without. However, there was an impact on the effectiveness of the schemes when they were underfunded or when there was a shortage of permanent supportive housing and longer-term care and support. In these contexts, it remained (tacitly) accepted practice (across both standard and specialist care sites) to discharge homeless patients to the streets, rather than delay their transfer. We found little evidence that discharge schemes fired a change in reasoning with regard to the cultural distance that positions ‘homeless patients’ as somehow less vulnerable than other groups of patients. We refined our hypothesis to reflect that high-impact changes need to be underpinned by robust adult safeguarding. Strengths and limitations To our knowledge, this is the largest study of the outcomes of homeless patients discharged from hospital in the UK. Owing to issues with the comparator group, the effectiveness analysis undertaken for the data linkage was limited to comparisons of different types of specialist discharge scheme (rather than specialist vs. standard care). Future work There is a need to consider approaches that align with those for value or alliance-based commissioning where the evaluative gaze is shifted from discrete interventions to understanding how the system is working as a whole to deliver outcomes for a defined patient population. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 17. See the NIHR Journals Library website for further project information.
Public Health Research, Volume 9, pp 1-116; https://doi.org/10.3310/phr09090

Abstract:
Background Family-based physical activity promotion presents a promising avenue for promoting whole-family physical activity, but high-quality research is lacking. Objectives To assess the feasibility, acceptability and preliminary effectiveness of FRESH (Families Reporting Every Step to Health), a child-led online family-based physical activity intervention; and to identify effective and resource-efficient family recruitment strategies. Design The project consisted of (1) a randomised feasibility trial, (2) a randomised controlled pilot trial and (3) a systematic review and Delphi study. Setting Norfolk/Suffolk counties, UK. Participants Families, recruited from schools, workplaces and community settings, were eligible to participate if one child aged 7–11 years and one adult responsible for their care provided written consent; all family members could participate. Interventions The FRESH intervention, guided by self-determination theory, targeted whole families and was delivered via an online platform. All family members received pedometers and were given website access to select family step challenges to ‘travel’ to target cities around the world, log steps, and track progress as they virtually globetrotted. Families were randomised to FRESH intervention, pedometer-only or control arm. Main outcome measures Physical (e.g. blood pressure), psychosocial (e.g. family functioning) and behavioural (e.g. device-measured family physical activity) measures were collected at baseline and at 8- and 52-week follow-up. A mixed-methods process evaluation assessed the acceptability of the intervention and evaluation. Data sources review Systematic search of four databases (Cochrane Library, PubMed, PsycINFO and SCOPUS). Review methods Articles were screened in duplicate, and data extraction was fully checked. Academic experts participated in the three-round Delphi study. Data were combined to identify effective and resource-efficient family recruitment strategies. Inclusion criteria Included generally healthy school-aged children and at least one adult; intervention attempted to change physical activity, sedentary behaviour, screen use, diet, or prevent overweight/obesity in multiple family members; presented relevant measure of effect in children and adults. Results The feasibility study (12 families, 32 participants; 100% retention at 8 weeks) demonstrated the feasibility and acceptability of FRESH, but highlighted that adaptations were required. Of 41 families recruited in the pilot study (149 participants), 98% and 88% were retained at the 8-week and 52-week follow-up, respectively. More children in the FRESH arm self-reported doing more family physical activity, and they thought that FRESH was fun. There were no notable between-group differences in children’s outcomes. Change in moderate to vigorous physical activity at 8 weeks favoured FRESH intervention adults [vs. control: 9.4 minutes/week (95% confidence interval 0.4 to 18.4) vs. pedometer only: 15.3 (95% confidence interval 6.0 to 24.5)], and was stronger in fathers, but this was not maintained. In 49 included studies, apart from recruitment settings and strategies used (reported in 84% and 73% of the studies, respectively), recruitment details were scarce. School-based recruitment was predominant. The Delphi study identified a wide range of recruitment settings and strategies. Limitations Recruitment was the main limitation of the FRESH studies; generalisability of the proposed recruitment strategies may be limited. Conclusions This study has demonstrated the feasibility and acceptability of the FRESH intervention. However, we failed to recruit the target sample size and were unable to demonstrate a signal of effectiveness. Future research should employ a multifaceted recruitment approach. Future work Further refinements to intervention delivery and recruitment methods should be investigated. Study registration Current Controlled Trials ISRCTN12789422 and PROSPERO CRD42019140042. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 9, No. 9. See the NIHR Journals Library website for further project information.
, Margaret Horne, Merel Bruijn, Helen White, , , , Lorna Aucott, , , et al.
Health Technology Assessment, Volume 25, pp 1-168; https://doi.org/10.3310/hta25520

Abstract:
Background The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. Objectives To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. Design The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. Data sources/setting The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Participants Pregnant women at 22+0–34+6 weeks’ gestation with signs and symptoms of preterm labour. Health technology being assessed Quantitative fetal fibronectin. Main outcome measures Spontaneous preterm birth within 7 days. Results The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. Limitations The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. Conclusions A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. Future work The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. Study registration This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.
, , , Anna Brockbank, Alice Cox, Carolyn Gill, , , , , et al.
Efficacy and Mechanism Evaluation, Volume 8, pp 1-28; https://doi.org/10.3310/eme08120

Abstract:
Background Women whose pregnancies are affected by hypertensive disorders of pregnancy, in particular preterm pre-eclampsia, are at increased risk of long-term cardiovascular morbidity and mortality. Objectives To investigate the hypothesis that prolongation of a pregnancy affected by preterm pre-eclampsia managed by expectant management compared with planned early delivery would result in worse cardiovascular function 6 months postpartum. Design A randomised controlled trial. Setting 28 maternity hospitals in England and Wales. Participants Women who were eligible for the Pre-eclampsia in HOspital: Early iNductIon or eXpectant management (PHOENIX) study were approached and recruited for the PHOEBE study. The PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) study was a parallel-group, non-masked, multicentre, randomised controlled trial that was carried out in 46 maternity units across England and Wales. This study compared planned early delivery with expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia who were 34 weeks’ gestation to less than 37 weeks’ gestation and having a singleton or dichorionic diamniotic twin pregnancy. Interventions Postpartum follow-up included medical history, blood pressure assessment and echocardiography. All women had blood sampling performed on at least two time points from recruitment to the 6-month follow-up for assessment of cardiac necrosis markers. Main outcome measures Primary outcome was a composite of systolic and/or diastolic dysfunction (originally by 2009 guidelines then updated by 2016 guidelines, with an amended definition of diastolic dysfunction). Analyses were by intention to treat, together with a per-protocol analysis for the primary and secondary outcomes. Results Between 27 April 2016 and 30 November 2018, 623 women were found to be eligible, of whom 420 (67%) were recruited across 28 maternity units in England and Wales. A total of 133 women were allocated to planned delivery, 137 women were allocated to expectant management and a further 150 received non-randomised expectant management within usual care. The mean time from enrolment to delivery was 2.5 (standard deviation 1.9) days in the planned delivery group compared with 6.8 (standard deviation 5.3) days in the expectant management group. There were no differences in the primary outcome between women in the planned delivery group and those in the expectant management group using either the 2009 (risk ratio 1.06, 95% confidence interval 0.80 to 1.40) or the 2016 definition (risk ratio 0.78, 95% confidence interval 0.33 to 1.86). Overall, 10% (31/321) of women had a left ventricular ejection fraction < 55% and 71% of the cohort remained hypertensive at 6 months postpartum. No differences were observed between groups in cardiorespiratory outcomes prior to discharge from hospital or in systolic or diastolic blood pressure measurements. Variables associated with the primary outcome (2009 definition) at 6 months postpartum were maternal body mass index (adjusted odds ratio 1.33 per 5 kg/m2, 95% confidence interval 1.12 to 1.59 per 5 kg/m2) and maternal age (adjusted odds ratio 2.16, 95% confidence interval 1.44 to 3.22 per 10 years). Limitations include changing definitions regarding systolic and/or diastolic dysfunction. Conclusions Preterm pre-eclampsia results in persistence of hypertension in the majority of women with late preterm pre-eclampsia at 6 months postpartum and systolic dysfunction in 10%. Pre-eclampsia should not be considered a self-limiting disease of pregnancy alone. Future work Interventions aimed at reducing cardiovascular dysfunction. Trial registration Current Controlled Trials ISRCTN01879376. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 12. See the NIHR Journals Library website for further project information.
Health Technology Assessment, Volume 25, pp 1-52; https://doi.org/10.3310/hta25530

Abstract:
Background The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. Objectives To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. Design To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. Setting A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. Results To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. Conclusions The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. Limitations Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. Future work Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. Funding Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme.
, Alexis Llewellyn, , , , , Claire Rothery,
Health Technology Assessment, Volume 25, pp 1-230; https://doi.org/10.3310/hta25560

Abstract:
Background QAngio® XA 3D/QFR® (three-dimensional/quantitative flow ratio) imaging software (Medis Medical Imaging Systems BV, Leiden, the Netherlands) and CAAS® vFFR® (vessel fractional flow reserve) imaging software (Pie Medical Imaging BV, Maastricht, the Netherlands) are non-invasive technologies to assess the functional significance of coronary stenoses, which can be alternatives to invasive fractional flow reserve assessment. Objectives The objectives were to determine the clinical effectiveness and cost-effectiveness of QAngio XA 3D/QFR and CAAS vFFR. Methods We performed a systematic review of all evidence on QAngio XA 3D/QFR and CAAS vFFR, including diagnostic accuracy, clinical effectiveness, implementation and economic analyses. We searched MEDLINE and other databases to January 2020 for studies where either technology was used and compared with fractional flow reserve in patients with intermediate stenosis. The risk of bias was assessed with quality assessment of diagnostic accuracy studies. Meta-analyses of diagnostic accuracy were performed. Clinical and implementation outcomes were synthesised narratively. A simulation study investigated the clinical impact of using QAngio XA 3D/QFR. We developed a de novo decision-analytic model to estimate the cost-effectiveness of QAngio XA 3D/QFR and CAAS vFFR relative to invasive fractional flow reserve or invasive coronary angiography alone. Scenario analyses were undertaken to explore the robustness of the results to variation in the sources of data used to populate the model and alternative assumptions. Results Thirty-nine studies (5440 patients) of QAngio XA 3D/QFR and three studies (500 patients) of CAAS vFFR were included. QAngio XA 3D/QFR had good diagnostic accuracy to predict functionally significant fractional flow reserve (≤ 0.80 cut-off point); contrast-flow quantitative flow ratio had a sensitivity of 85% (95% confidence interval 78% to 90%) and a specificity of 91% (95% confidence interval 85% to 95%). A total of 95% of quantitative flow ratio measurements were within 0.14 of the fractional flow reserve. Data on the diagnostic accuracy of CAAS vFFR were limited and a full meta-analysis was not feasible. There were very few data on clinical and implementation outcomes. The simulation found that quantitative flow ratio slightly increased the revascularisation rate when compared with fractional flow reserve, from 40.2% to 42.0%. Quantitative flow ratio and fractional flow reserve resulted in similar numbers of subsequent coronary events. The base-case cost-effectiveness results showed that the test strategy with the highest net benefit was invasive coronary angiography with confirmatory fractional flow reserve. The next best strategies were QAngio XA 3D/QFR and CAAS vFFR (without fractional flow reserve). However, the difference in net benefit between this best strategy and the next best was small, ranging from 0.007 to 0.012 quality-adjusted life-years (or equivalently £140–240) per patient diagnosed at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. Limitations Diagnostic accuracy evidence on CAAS vFFR, and evidence on the clinical impact of QAngio XA 3D/QFR, were limited. Conclusions Quantitative flow ratio as measured by QAngio XA 3D/QFR has good agreement and diagnostic accuracy compared with fractional flow reserve and is preferable to standard invasive coronary angiography alone. It appears to have very similar cost-effectiveness to fractional flow reserve and, therefore, pending further evidence on general clinical benefits and specific subgroups, could be a reasonable alternative. The clinical effectiveness and cost-effectiveness of CAAS vFFR are uncertain. Randomised controlled trial evidence evaluating the effect of quantitative flow ratio on clinical and patient-centred outcomes is needed. Future work Studies are required to assess the diagnostic accuracy and clinical feasibility of CAAS vFFR. Large ongoing randomised trials will hopefully inform the clinical value of QAngio XA 3D/QFR. Study registration This study is registered as PROSPERO CRD42019154575. Funding This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 56. See the NIHR Journals Library website for further project information.
Health Technology Assessment, Volume 25, pp 1-72; https://doi.org/10.3310/hta25550

Abstract:
Background Measurement can affect the people being measured; for example, asking people to complete a questionnaire can result in changes in behaviour (the ‘question–behaviour effect’). The usual methods of conduct and analysis of randomised controlled trials implicitly assume that the taking of measurements has no effect on research participants. Changes in measured behaviour and other outcomes due to measurement reactivity may therefore introduce bias in otherwise well-conducted randomised controlled trials, yielding incorrect estimates of intervention effects, including underestimates. Objectives The main objectives were (1) to promote awareness of how and where taking measurements can lead to bias and (2) to provide recommendations on how best to avoid or minimise bias due to measurement reactivity in randomised controlled trials of interventions to improve health. Methods We conducted (1) a series of systematic and rapid reviews, (2) a Delphi study and (3) an expert workshop. A protocol paper was published [Miles LM, Elbourne D, Farmer A, Gulliford M, Locock L, McCambridge J, et al. Bias due to MEasurement Reactions In Trials to improve health (MERIT): protocol for research to develop MRC guidance. Trials 2018;19:653]. An updated systematic review examined whether or not measuring participants had an effect on participants’ health-related behaviours relative to no-measurement controls. Three new rapid systematic reviews were conducted to identify (1) existing guidance on measurement reactivity, (2) existing systematic reviews of studies that have quantified the effects of measurement on outcomes relating to behaviour and affective outcomes and (3) experimental studies that have investigated the effects of exposure to objective measurements of behaviour on health-related behaviour. The views of 40 experts defined the scope of the recommendations in two waves of data collection during the Delphi procedure. A workshop aimed to produce a set of recommendations that were formed in discussion in groups. Results Systematic reviews – we identified a total of 43 studies that compared interview or questionnaire measurement with no measurement and these had an overall small effect (standardised mean difference 0.06, 95% confidence interval 0.02 to 0.09; n = 104,096, I 2 = 54%). The three rapid systematic reviews identified no existing guidance on measurement reactivity, but we did identify five systematic reviews that quantified the effects of measurement on outcomes (all focused on the question–behaviour effect, with all standardised mean differences in the range of 0.09—0.28) and 16 studies that examined reactive effects of objective measurement of behaviour, with most evidence of reactivity of small effect and short duration. Delphi procedure – substantial agreement was reached on the scope of the present recommendations. Workshop – 14 recommendations and three main aims were produced. The aims were to identify whether or not bias is likely to be a problem for a trial, to decide whether or not to collect further quantitative or qualitative data to inform decisions about if bias is likely to be a problem, and to identify how to design trials to minimise the likelihood of this bias. Limitation The main limitation was the shortage of high-quality evidence regarding the extent of measurement reactivity, with some notable exceptions, and the circumstances that are likely to bring it about. Conclusion We hope that these recommendations will be used to develop new trials that are less likely to be at risk of bias. Future work The greatest need is to increase the number of high-quality primary studies regarding the extent of measurement reactivity. Study registration The first systematic review in this study is registered as PROSPERO CRD42018102511. Funding Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research Programme.
, Julie Loebach Wetherell, , Kate Kimona, , Rebecca Jones, , Philip Wilkinson, , Marie Le Novere, et al.
Health Technology Assessment, Volume 25, pp 1-150; https://doi.org/10.3310/hta25540

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Background Generalised anxiety disorder, characterised by excessive anxiety and worry, is the most common anxiety disorder among older people. It is a condition that may persist for decades and is associated with numerous negative outcomes. Front-line treatments include pharmacological and psychological therapy, but many older people do not find these treatments effective. Guidance on managing treatment-resistant generalised anxiety disorder in older people is lacking. Objectives To assess whether or not a study to examine the clinical effectiveness and cost-effectiveness of acceptance and commitment therapy for older people with treatment-resistant generalised anxiety disorder is feasible, we developed an intervention based on acceptance and commitment therapy for this population, assessed its acceptability and feasibility in an uncontrolled feasibility study and clarified key study design parameters. Design Phase 1 involved qualitative interviews to develop and optimise an intervention as well as a survey of service users and clinicians to clarify usual care. Phase 2 involved an uncontrolled feasibility study and qualitative interviews to refine the intervention. Setting Participants were recruited from general practices, Improving Access to Psychological Therapies services, Community Mental Health Teams and the community. Participants Participants were people aged ≥ 65 years with treatment-resistant generalised anxiety disorder. Intervention Participants received up to 16 one-to-one sessions of acceptance and commitment therapy, adapted for older people with treatment-resistant generalised anxiety disorder, in addition to usual care. Sessions were delivered by therapists based in primary and secondary care services, either in the clinic or at participants’ homes. Sessions were weekly for the first 14 sessions and fortnightly thereafter. Main outcome measures The co-primary outcome measures for phase 2 were acceptability (session attendance and satisfaction with therapy) and feasibility (recruitment and retention). Secondary outcome measures included additional measures of acceptability and feasibility and self-reported measures of anxiety, worry, depression and psychological flexibility. Self-reported outcomes were assessed at 0 weeks (baseline) and 20 weeks (follow-up). Health economic outcomes included intervention and resource use costs and health-related quality of life. Results Fifteen older people with treatment-resistant generalised anxiety disorder participated in phase 1 and 37 participated in phase 2. A high level of feasibility was demonstrated by a recruitment rate of 93% and a retention rate of 81%. A high level of acceptability was found with respect to session attendance (70% of participants attended ≥ 10 sessions) and satisfaction with therapy was adequate (60% of participants scored ≥ 21 out of 30 points on the Satisfaction with Therapy subscale of the Satisfaction with Therapy and Therapist Scale-Revised, although 80% of participants had not finished receiving therapy at the time of rating). Secondary outcome measures and qualitative data further supported the feasibility and acceptability of the intervention. Health economic data supported the feasibility of examining cost-effectiveness in a future randomised controlled trial. Although the study was not powered to examine clinical effectiveness, there was indicative evidence of improvements in scores for anxiety, depression and psychological flexibility. Limitations Non-specific therapeutic factors were not controlled for, and recruitment in phase 2 was limited to London. Conclusions There was evidence of high levels of feasibility and acceptability and indicative evidence of improvements in symptoms of anxiety, depression and psychological flexibility. The results of this study suggest that a larger-scale randomised controlled trial would be feasible to conduct and is warranted. Trial registration Current Controlled Trials ISRCTN12268776. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 54. See the NIHR Journals Library website for further project information.
, , Beth Hall, , , Lynne Williams, , , Candida Lovell-Smith, John Gallanders, et al.
Health Services and Delivery Research, Volume 9, pp 1-104; https://doi.org/10.3310/hsdr09160

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Background As people age and accumulate long-term conditions, their physical activity and physical function declines, resulting in disability and loss of independence. Primary care is well placed to empower individuals and communities to reduce this decline; however, the best approach is uncertain. Objectives To develop a programme theory to explain the mechanisms through which interventions improve physical activity and physical function in people with long-term conditions in different primary care contexts, and to co-design a prototype intervention. Data sources Systematic literature searches of relevant databases with forwards and backwards citation tracking, grey literature searches and further purposive searches were conducted. Qualitative data were collected through workshops and interviews. Design Realist evidence synthesis and co-design for primary care service innovation. Setting Primary care in Wales and England. Participants Stakeholders included people with long-term conditions, primary care professionals, people working in relevant community roles and researchers. Methods The realist evidence synthesis combined evidence from varied sources of literature with the views, experiences and ideas of stakeholders. The resulting context, mechanism and outcome statements informed three co-design workshops and a knowledge mobilisation workshop for primary care service innovation. Results Five context, mechanism and outcome statements were developed. (1) Improving physical activity and function is not prioritised in primary care (context). If the practice team culture is aligned to the elements of physical literacy (mechanism), then physical activity promotion will become routine and embedded in usual care (outcome). (2) Physical activity promotion is inconsistent and unco-ordinated (context). If specific resources are allocated to physical activity promotion (in combination with a supportive practice culture) (mechanism), then this will improve opportunities to change behaviour (outcome). (3) People with long-term conditions have varying levels of physical function and physical activity, varying attitudes to physical activity and differing access to local resources that enable physical activity (context). If physical activity promotion is adapted to individual needs, preferences and local resources (mechanism), then this will facilitate a sustained improvement in physical activity (outcome). (4) Many primary care practice staff lack the knowledge and confidence to promote physical activity (context). If staff develop an improved sense of capability through education and training (mechanism), then they will increase their engagement with physical activity promotion (outcome). (5) If a programme is credible with patients and professionals (context), then trust and confidence in the programme will develop (mechanism) and more patients and professionals will engage with the programme (outcome). A prototype multicomponent intervention was developed. This consisted of resources to nurture a culture of physical literacy, materials to develop the role of a credible professional who can promote physical activity using a directory of local opportunities and resources to assist with individual behaviour change. Limitations Realist synthesis and co-design is about what works in which contexts, so these resources and practice implications will need to be modified for different primary care contexts. Conclusions We developed a programme theory to explain how physical activity could be promoted in primary care in people with long-term conditions, which informed a prototype intervention. Future work A future research programme could further develop the prototype multicomponent intervention and assess its acceptability in practice alongside existing schemes before it is tested in a feasibility study to inform a future randomised controlled trial. Study registration This study is registered as PROSPERO CRD42018103027. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 16. See the NIHR Journals Library website for further project information.
Efficacy and Mechanism Evaluation, Volume 8, pp 1-36; https://doi.org/10.3310/eme08130

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Background Reliable vascular access is essential for patients receiving haemodialysis. An arteriovenous fistula is the preferred option; however, these are prone to developing stenotic segments. These lesions are treated with angioplasty, but there is a high rate of recurrence. When the PAVE (Paclitaxel-assisted balloon Angioplasty of Venous stenosis in haEmodialysis access) trial was conceived, a number of small studies suggested that restenosis may be reduced by paclitaxel-coated balloons. Objective To test the efficacy of paclitaxel-coated balloons in arteriovenous fistulas. Design A randomised controlled trial. Setting Twenty UK centres. Participants Patients (aged ≥ 18 years) referred with a clinical indication for angioplasty of an arteriovenous fistula (212 patients in total, 106 per group). Interventions High-pressure plain balloon fistuloplasty was performed in all patients. In the intervention arm, the second component was insertion of a paclitaxel-coated balloon. In the control arm, an identical procedure was followed, but using a standard balloon. Main outcome measures The primary end point was time (days) to loss of target lesion primary patency. Secondary patency end points were time to loss of access circuit primary patency and time to loss of access circuit cumulative patency. Other secondary end points included angiographically determined late lumen loss, rate of binary angiographic restenosis, procedural success, number of thrombosis events, fistula interventions, adverse events during follow-up and patient quality of life. Results Primary analysis showed no evidence for a difference in time to end of target lesion primary patency between groups (hazard ratio 1.18, 95% confidence interval 0.78 to 1.79; p = 0.440). An adjusted secondary analysis with prespecified clinical covariates gave similar results (hazard ratio 1.11, 95% confidence interval 0.69 to 1.78; p = 0.664). Prespecified secondary outcomes included the time to intervention anywhere in the access circuit or the time until the fistula was abandoned. There were no differences in these patency-related secondary outcomes or in any other secondary outcomes, such as adverse events. Limitations The PAVE trial was not a fully blinded trial. It was impossible to ensure that treating radiologists were blinded to treatment allocation because of the appearance of the paclitaxel-coated balloon. The extent to which our findings can be generalised to patients with multiple lesions could be questioned, given the proportion randomised. However, if paclitaxel-coated balloons had been effective at a single lesion segment, then there is no plausible reason why they could not be effective in patients with multiple lesions. Conclusions There were no differences in primary or secondary outcomes. Following a plain balloon angioplasty, additional treatment with a paclitaxel-coated balloon does not provide benefit. Future work The reasons for differences between the results of the PAVE trial and of other studies deserve further analysis and consideration. Other interventions to prevent restenosis following a fistuloplasty are needed. Trial registration Current Controlled Trials ISRCTN14284759. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 13. See the NIHR Journals Library website for further project information.
Health Technology Assessment, Volume 25, pp 1-132; https://doi.org/10.3310/hta25570

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Background The Medical Research Council published the second edition of its framework in 2006 on developing and evaluating complex interventions. Since then, there have been considerable developments in the field of complex intervention research. The objective of this project was to update the framework in the light of these developments. The framework aims to help research teams prioritise research questions and design, and conduct research with an appropriate choice of methods, rather than to provide detailed guidance on the use of specific methods. Methods There were four stages to the update: (1) gap analysis to identify developments in the methods and practice since the previous framework was published; (2) an expert workshop of 36 participants to discuss the topics identified in the gap analysis; (3) an open consultation process to seek comments on a first draft of the new framework; and (4) findings from the previous stages were used to redraft the framework, and final expert review was obtained. The process was overseen by a Scientific Advisory Group representing the range of relevant National Institute for Health Research and Medical Research Council research investments. Results Key changes to the previous framework include (1) an updated definition of complex interventions, highlighting the dynamic relationship between the intervention and its context; (2) an emphasis on the use of diverse research perspectives: efficacy, effectiveness, theory-based and systems perspectives; (3) a focus on the usefulness of evidence as the basis for determining research perspective and questions; (4) an increased focus on interventions developed outside research teams, for example changes in policy or health services delivery; and (5) the identification of six ‘core elements’ that should guide all phases of complex intervention research: consider context; develop, refine and test programme theory; engage stakeholders; identify key uncertainties; refine the intervention; and economic considerations. We divide the research process into four phases: development, feasibility, evaluation and implementation. For each phase we provide a concise summary of recent developments, key points to address and signposts to further reading. We also present case studies to illustrate the points being made throughout. Limitations The framework aims to help research teams prioritise research questions and design and conduct research with an appropriate choice of methods, rather than to provide detailed guidance on the use of specific methods. In many of the areas of innovation that we highlight, such as the use of systems approaches, there are still only a few practical examples. We refer to more specific and detailed guidance where available and note where promising approaches require further development. Conclusions This new framework incorporates developments in complex intervention research published since the previous edition was written in 2006. As well as taking account of established practice and recent refinements, we draw attention to new approaches and place greater emphasis on economic considerations in complex intervention research. We have introduced a new emphasis on the importance of context and the value of understanding interventions as ‘events in systems’ that produce effects through interactions with features of the contexts in which they are implemented. The framework adopts a pluralist approach, encouraging researchers and research funders to adopt diverse research perspectives and to select research questions and methods pragmatically, with the aim of providing evidence that is useful to decision-makers. Future work We call for further work to develop relevant methods and provide examples in practice. The use of this framework should be monitored and the move should be made to a more fluid resource in the future, for example a web-based format that can be frequently updated to incorporate new material and links to emerging resources. Funding This project was jointly funded by the Medical Research Council (MRC) and the National Institute for Health Research (Department of Health and Social Care 73514).
, , , Michael Davidson, Graziella Favarato, , Terry Harper, , Hameed Khan, , et al.
Health Services and Delivery Research, Volume 9, pp 1-122; https://doi.org/10.3310/hsdr09180

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Background For people in mental health crisis, acute day units provide daily structured sessions and peer support in non-residential settings as an alternative to crisis resolution teams. Objectives To investigate the provision, effectiveness, intervention acceptability and re-admission rates of acute day units. Design Work package 1 – mapping and national questionnaire survey of acute day units. Work package 2.1 – cohort study comparing outcomes during a 6-month period between acute day unit and crisis resolution team participants. Work package 2.2 – qualitative interviews with staff and service users of acute day units. Work package 3 – a cohort study within the Mental Health Minimum Data Set exploring re-admissions to acute care over 6 months. A patient and public involvement group supported the study throughout. Setting and participants Work package 1 – all non-residential acute day units (NHS and voluntary sector) in England. Work packages 2.1 and 2.2 – four NHS trusts with staff, service users and carers in acute day units and crisis resolution teams. Work package 3 – all individuals using mental health NHS trusts in England. Results Work package 1 – we identified 27 acute day units in 17 out of 58 trusts. Acute day units are typically available on weekdays from 10 a.m. to 4 p.m., providing a wide range of interventions and a multidisciplinary team, including clinicians, and having an average attendance of 5 weeks. Work package 2.1 – we recruited 744 participants (acute day units, n = 431; crisis resolution teams, n = 312). In the primary analysis, 21% of acute day unit participants (vs. 23% of crisis resolution team participants) were re-admitted to acute mental health services over 6 months. There was no statistically significant difference in the fully adjusted model (acute day unit hazard ratio 0.78, 95% confidence interval 0.54 to 1.14; p = 0.20), with highly heterogeneous results between trusts. Acute day unit participants had higher satisfaction and well-being scores and lower depression scores than crisis resolution team participants. The health economics analysis found no difference in resource use or cost between the acute day unit and crisis resolution team groups in the fully adjusted analysis. Work package 2.2 – 36 people were interviewed (acute day unit staff, n = 12; service users, n = 21; carers, n = 3). There was an overwhelming consensus that acute day units are highly valued. Service users found the high amount of contact time and staff continuity, peer support and structure provided by acute day units particularly beneficial. Staff also valued providing continuity, building strong therapeutic relationships and providing a variety of flexible, personalised support. Work package 3 – of 231,998 individuals discharged from acute care (crisis resolution team, acute day unit or inpatient ward), 21.4% were re-admitted for acute treatment within 6 months, with women, single people, people of mixed or black ethnicity, those living in more deprived areas and those in the severe psychosis care cluster being more likely to be re-admitted. Little variation in re-admissions was explained at the trust level, or between trusts with and trusts without acute day units (adjusted odds ratio 0.96, 95% confidence interval 0.80 to 1.15). Limitations In work package 1, some of the information is likely to be incomplete as a result of trusts’ self-reporting. There may have been recruitment bias in work packages 2.1 and 2.2. Part of the health economics analysis relied on clinical Health of the Nations Outcome Scale ratings. The Mental Health Minimum Data Set did not contain a variable identifying acute day units, and some covariates had a considerable number of missing data. Conclusions Acute day units are not provided routinely in the NHS but are highly valued by staff and service users, giving better outcomes in terms of satisfaction, well-being and depression than, and no significant differences in risk of re-admission or increased costs from, crisis resolution teams. Future work should investigate wider health and care system structures and the place of acute day units within them; the development of a model of best practice for acute day units; and staff turnover and well-being (including the impacts of these on care). Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 18. See the NIHR Journals Library website for further project information.
Stuart Haylock, National Institute for Health Research
Early identification and treatment of young people at high risk of recurrent mood disorders: a feasibility study, Volume 1; https://doi.org/10.3310/nihropenres.1115163.1

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PB-PG-0609-16166 – NIHR Research for Patient Benefit Programme – Final report Project title: Early identification and treatment of young people at high risk of recurrent mood disorders: a feasibility study Authors: Professor Jan Scott - Newcastle University Dr Paul McArdle - Northumberland, Tyne and Wear NHS Foundation Trust Dr Thomas Meyer - University of Newcastle upon Tyne Dr Aditya Sharma - Northumberland, Tyne and Wear NHS Foundation Trust Dr Iain Macmillan - Northumberland, Tyne and Wear NHS Foundation Trust Plain language summary Despite 15-25 years being the peak age of onset for recurrent depression or bipolar disorders (BD), recognition of mood disorders (and differentiating them from transient distress) and/or the introduction of appropriate treatment are frequently delayed. This study examined ways to identify young people at high risk of repeated episodes of mood disorder and to work out whether they would get recurrent depression or BD. Also, we developed a therapy that could be offered to young people with ‘emerging mood disorders’ and we talked to those who are at 'above average' risk of getting these problems, to ask their views about future services or interventions. As well as working on our study, we collaborated with teams doing similar research in Australia, the USA, France, Norway and Germany. Interestingly, it appears that there are many common findings internationally. For example, even at a very early stage in the development of recurrent mood disorders, young people are already significantly impaired in their day to day functioning. Furthermore this problem is worsened if the young person tries to cope with their mood problems by using harmful amounts of alcohol or illicit drugs. We found that 20-30% of mood disorders developed into BD and this was most likely to occur in those with a family history of BD, with cyclothymia (a personality style characterised by fluctuating cycles of up and down moods), who had experienced depressions at an earlier age, and/or if they had recently experienced some milder symptoms of mania (that were similar to those seen in mania, but that did not add up to the full diagnosis). Young people who were at risk of BD because they had a parent with BD wanted both help to cope with the times when their parent was unwell, as well as help to learn how to cope better with any stress they experienced themselves. The young people were also clear that if they were ‘at risk’ of BD (but did not actually have BD), they were more likely to accept a psychological therapy rather than the medications used to treat those people who definitely have a BD diagnosis. We reviewed the types of therapies available for young people at risk of BD or with an emerging mood disorder and have adapted the approaches to include sleep hygiene, emotional coping, physical health and reduction of harmful use of drugs and alcohol. Overall, the study has delivered a screening tool for BD and a therapy acceptable to these young people. Keywords bipolar, at risk, early intervention, screening, mood disorders, CBT, identification, prospective Summary of research findings Study Aim 1: Retrospectively assess the number of and presentation of clinically diagnosed cases of mood disorders across a range of NHS settings over the preceding 2 years. We were unable to answer the first goal exactly as initially planned (see next section for details),but we agreed with the RfPB manager on the following approach- 1. We would ask the NHS data managers to give ‘ball park’ figures on the prevalence of key symptoms related to bipolar disorders across 16-25 year olds. We would then try to construct clinical histories for a range of levels of symptoms e.g. individuals with single reports of depression, individuals with persistent recordings of depression, individuals identified as having depressive episodes, etc. 2. We would undertake a systematic review of the literature to address the original question we had posed. With regard to item 1, we found that 70% of 16-25 year olds report depressive symptoms on at least one occasion, about 48% have persistent reports of depression and about 39% probably meet criteria for depression. Over one year, about 50% of these individuals were discharged, and about 30% dropped out of the services. Crude estimates suggested transition to BD was as frequent in those who were discharged as those who were in continuous treatment (we do not have enough data to know about dropouts). However, the reliability and validity of these data were insufficient to allow publication at this stage. Also, the data managers have not been able to give more detailed prior histories due to time issues and pressure of other work (please note we offered to pay for out of hours work, but this was deemed inappropriate, as the managers felt this work did fit within the terms of reference of department work. As such, it was listed as work to be done when time was available- but there have been many issues with the ‘roll out’ of RIO across the Trust and at the time of writing the work is incomplete. The data managers have stated they will still try to hep to do this work and McCardle is liaising about the options). With regard to item 2, the systematic review showed that alcohol and substance use may be associated with early onset of mood symptoms and the presence of subthreshold bipolar symptoms increases the risk of developing harmful substance use (i.e. the problems are bi-directional). This suggests screening in youth drug and alcohol services should be considered. The review also showed that the best predictors of transition to BD in young people are: cyclothymia with a family history of BD and/or a prior history of one or more depressive episodes and evidence of subthreshold manic symptoms. (These findings are now confirmed by the data from the current study). Importantly, a childhood history of ADHD or of...
Laura Tornatore, National Institute for Health Research
Determination of the ideal medication characteristics for the safe and effective administration of medications via enteral feeding tubes, Volume 1; https://doi.org/10.3310/nihropenres.1115162.1

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PB-PG-0101-12240 - NIHR Research for Patient Benefit Programme - Final Report Project title: Determination of the ideal medication characteristics for the safe and effective administration of medications via enteral feeding tubes Authors: Miss Rebecca White - Oxford Radcliffe Hospitals NHS Trust Professor Duncan Craig - University of East Anglia Mr John Wood - University of East Anglia Professor David Wright - University of East Anglia Plain language summary Background Many patients are unable to take nutrition by mouth and therefore enteral feeding tubes (EFTs) have to be inserted directly into the stomach either via the nose or straight through the abdomen. Over 37,000 patients in the UK use these tubes long term. Medicines given by this route are unlicensed and therefore patients and carers have no guidance available to them to decide how best to prepare and administer medicines for delivery via this route. GPs prescribing for these patients in the community are unsupported as technical information on this route of administration in primary care is limited. A survey of practice amongst nutrition nurses, dietitians, nursing homes and patients was undertaken to determine what methods were used for medication administration and which medication were associated with problems. Laboratory work was undertaken to find out if the liquid medicines associated with problems had similar properties and if the methods used for tablet administration, dispersion or crushing, delivered an accurate dose. Findings The methods and flushing volumes used to administer medication via EFTs are varied. Tablet crushing is common and obtaining a liquid formulation can be difficult. Administration practices advocated by nutrition nurses and dietitians are not routinely applied by healthcare staff and patients in primary care. Tablet dispersion did not affect the dose delivered however, the crushing methods used lead to a significant reduction in the dose Liquid medications are associated with administration problems if they have a high viscosity or granular properties. Non-granular viscous liquids can be diluted to make administration easier. Conclusions Clearer guidance on enteral tube drug administration is required for patients and carers. Not all liquid formulations are suitable for EFT administration however tablet crushing should be strongly discouraged. Benefit to patients Freely accessible information for General Practitioners and nursing homes on safe administration of medication via enteral feeding tubes for the most commonly prescribed medication and improved signposting for further information should improve the quality and safety of prescribing for patients with enteral feeding tubes. Publicising this information via patient support groups should also empower patients to encourage their GPs to seek further information. Keywords Enteral tube, Medication, Administration, Tablet crushing Summary of research findings Background The increase in awareness of the importance of adequate nutritional intake has increased the use of enteral feeding tubes (EFT) in all areas of healthcare. An EFT provides a means of maintaining nutritional intake when there is limited access to the gastrointestinal tract. The British Artificial Nutrition Survey published data indicating that there are currently more than 37,000 patients in the community on home enteral feeding. Identifying a suitable drug formulation for administration to a patient with limited GI access or dysphagia is difficult. In these patients the enteral feeding tube is often the only means of enteral access and increasingly is being used as a route for drug administration. Administering drugs via an enteral feeding tube usually falls outside of the terms of the drugs product license, this has implications for the professionals responsible for prescribing, supplying and administering the drug as they become liable for any adverse event that the patient may experience. The pharmaceutical companies can provide very limited information on medication use outside of product license. The quality of data published relating to medication administration via EFTs is largely anecdotal and individual case report based. A robust method for assessing new medicine formulations for appropriateness for this route of administration is lacking and hence licensing for this route is exceptionally rare. The NPSA safety alert number 19, ‘promoting safer measurement and administration of liquid medicines via oral and other enteral routes’, further highlights the common use of this method of drug administration and mandates the inclusion of guidance in medicines policy for this route of administration. However, robust evidence to inform such policies and protocols is lacking. Tube blockage due to medication remains a significant problem. Marcuard and Stegall (1990) found that medication administered via narrow bore feeding tubes was the cause of tube occlusions in 63% of cases. A study by Benson et al (1990) found that even following an irrigation protocol, a significant relationship was observed between the number of medications administered through the tube and tube blockage, with the likelihood of tube blockage increasing in proportion to the number of medications administered. In two studies investigating administration by nurses through EFTs (seifert et al, 1995;belknap et al, 1997), those nurses who received assistance from the pharmacy were significantly more likely to administer liquid forms than those nurse who reported no pharmacy assistance and less likely to experience tube occlusion due to medications. Despite this evidence, the automatic selection of a liquid formulation may not be appropriate. Edes et al (1990) estimated the incidence of osmotic diarrhoea in tube fed patients directly due to the osmolality of the liquid medicines to be about 48%. Furthermore some liquid formulations are too thick or sticky to administer via EFTs. Although it is...
Health Technology Assessment, Volume 25, pp 1-158; https://doi.org/10.3310/hta25480

Abstract:
Background Rotator cuff-related shoulder pain is very common, but there is uncertainty regarding which modes of exercise delivery are optimal and the long-term benefits of corticosteroid injections. Objectives To assess the clinical effectiveness and cost-effectiveness of progressive exercise compared with best-practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. Design This was a pragmatic multicentre superiority randomised controlled trial (with a 2 × 2 factorial design). Setting Twenty NHS primary care-based musculoskeletal and related physiotherapy services. Participants Adults aged ≥ 18 years with a new episode of rotator cuff-related shoulder pain in the previous 6 months. Interventions A total of 708 participants were randomised (March 2017–May 2019) by a centralised computer-generated 1 : 1 : 1 : 1 allocation ratio to one of four interventions: (1) progressive exercise (n = 174) (six or fewer physiotherapy sessions), (2) best-practice advice (n = 174) (one physiotherapy session), (3) corticosteroid injection then progressive exercise (n = 182) (six or fewer physiotherapy sessions) or (4) corticosteroid injection then best-practice advice (n = 178) (one physiotherapy session). Main outcome measures The primary outcome was Shoulder Pain and Disability Index (SPADI) score over 12 months. Secondary outcomes included SPADI subdomains, the EuroQol 5 Dimensions, five-level version, sleep disturbance, fear avoidance, pain self-efficacy, return to activity, Global Impression of Treatment and health resource use. Outcomes were collected by postal questionnaires at 8 weeks and at 6 and 12 months. A within-trial economic evaluation was also conducted. The primary analysis was intention to treat. Results Participants had a mean age of 55.5 (standard deviation 13.1) years and 49.3% were female. The mean baseline SPADI score was 54.1 (standard deviation 18.5). Follow-up rates were 91% at 8 weeks and 87% at 6 and 12 months. There was an overall improvement in SPADI score from baseline in each group over time. Over 12 months, there was no evidence of a difference in the SPADI scores between the progressive exercise intervention and the best-practice advice intervention in shoulder pain and function (adjusted mean difference between groups over 12 months –0.66, 99% confidence interval –4.52 to 3.20). There was also no difference in SPADI scores between the progressive exercise intervention and best-practice advice intervention when analysed at the 8-week and 6- and 12-month time points. Injection resulted in improvement in shoulder pain and function at 8 weeks compared with no injection (adjusted mean difference –5.64, 99% confidence interval –9.93 to –1.35), but not when analysed over 12 months (adjusted mean difference –1.11, 99% confidence interval –4.47 to 2.26), or at 6 and 12 months. There were no serious adverse events. In the base-case analysis, adding injection to best-practice advice gained 0.021 quality-adjusted life-years (p = 0.184) and increased the cost by £10 per participant (p = 0.747). Progressive exercise alone was £52 (p = 0.247) more expensive per participant than best-practice advice, and gained 0.019 QALYs (p = 0.220). At a ceiling ratio of £20,000 per quality-adjusted life-year, injection plus best-practice advice had a 54.93% probability of being the most cost-effective treatment. Limitations Participants and physiotherapists were not blinded to group allocation. Twelve-month follow-up may be insufficient for identifying all safety concerns. Conclusions Progressive exercise was not superior to a best-practice advice session with a physiotherapist. Subacromial corticosteroid injection improved shoulder pain and function, but provided only modest short-term benefit. Best-practice advice in combination with corticosteroid injection was expected to be most cost-effective, although there was substantial uncertainty. Future work Longer-term follow-up, including any serious adverse effects of corticosteroid injection. Trial registration Current Controlled Trials ISRCTN16539266 and EudraCT 2016-002991-28. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 48. See the NIHR Journals Library website for further project information.
Health Technology Assessment, Volume 25, pp 1-124; https://doi.org/10.3310/hta25500

Abstract:
Background The NHS Health Check is a national cardiovascular disease prevention programme. There is a lack of evidence on how health checks are conducted, how cardiovascular disease risk is communicated to foster risk-reducing intentions or behaviour, and the impact on communication of using different cardiovascular disease risk calculators. Objectives RIsk COmmunication in Health Check (RICO) study aimed to explore practitioner and patient understanding of cardiovascular disease risk, the associated advice or treatment offered by the practitioner, and the response of the patients in health checks supported by either the QRISK®2 or the JBS3 lifetime risk calculator. Design This was a qualitative study with quantitative process evaluation. Setting Twelve general practices in the West Midlands of England, stratified on deprivation of the local area (bottom 50% vs. top 50%), and with matched pairs randomly allocated to use QRISK2 or JBS3 during health checks. Participants A total of 173 patients eligible for NHS Health Check and 15 practitioners. Interventions The health check was delivered using either the QRISK2 10-year risk calculator (usual practice) or the JBS3 lifetime risk calculator, with heart age, event-free survival age and risk score manipulation (intervention). Results Video-recorded health checks were analysed quantitatively (n = 173; JBS3, n = 100; QRISK2, n = 73) and qualitatively (n = 128; n = 64 per group), and video-stimulated recall interviews were undertaken with 40 patients and 15 practitioners, with 10 in-depth case studies. The duration of the health check varied (6.8–38 minutes), but most health checks were short (60% lasting < 20 minutes), with little cardiovascular disease risk discussion (average < 2 minutes). The use of JBS3 was associated with more cardiovascular disease risk discussion and fewer practitioner-dominated consultations than the use of QRISK2. Heart age and visual representations of risk, as used in JBS3, appeared to be better understood by patients than 10-year risk (QRISK2) and, as a result, the use of JBS3 was more likely to lead to discussion of risk factors and their management. Event-free survival age was not well understood by practitioners or patients. However, a lack of effective cardiovascular disease risk discussion in both groups increased the likelihood of a maladaptive coping response (i.e. no risk-reducing behaviour change). In both groups, practitioners often missed opportunities to check patient understanding and to tailor information on cardiovascular disease risk and its management during health checks, confirming apparent practitioner verbal dominance. Limitations The main limitations were under-recruitment in some general practices and the resulting imbalance between groups. Conclusions Communication of cardiovascular disease risk during health checks was brief, particularly when using QRISK2. Patient understanding of and responses to cardiovascular disease risk information were limited. Practitioners need to better engage patients in discussion of and action-planning for their cardiovascular disease risk to reduce misunderstandings. The use of heart age, visual representation of risk and risk score manipulation was generally seen to be a useful way of doing this. Future work could focus on more fundamental issues of practitioner training and time allocation within health check consultations. Trial registration Current Controlled Trials ISRCTN10443908. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 50. See the NIHR Journals Library website for further project information.
Programme Grants for Applied Research, Volume 9, pp 1-218; https://doi.org/10.3310/pgfar09100

Abstract:
Background Long-term monitoring is important in chronic condition management. Despite considerable costs of monitoring, there is no or poor evidence on how, what and when to monitor. The aim of this study was to improve understanding, methods, evidence base and practice of clinical monitoring in primary care, focusing on two areas: chronic kidney disease and chronic heart failure. Objectives The research questions were as follows: does the choice of test affect better care while being affordable to the NHS? Can the number of tests used to manage individuals with early-stage kidney disease, and hence the costs, be reduced? Is it possible to monitor heart failure using a simple blood test? Can this be done using a rapid test in a general practitioner consultation? Would changes in the management of these conditions be acceptable to patients and carers? Design Various study designs were employed, including cohort, feasibility study, Clinical Practice Research Datalink analysis, seven systematic reviews, two qualitative studies, one cost-effectiveness analysis and one cost recommendation. Setting This study was set in UK primary care. Data sources Data were collected from study participants and sourced from UK general practice and hospital electronic health records, and worldwide literature. Participants The participants were NHS patients (Clinical Practice Research Datalink: 4.5 million patients), chronic kidney disease and chronic heart failure patients managed in primary care (including 750 participants in the cohort study) and primary care health professionals. Interventions The interventions were monitoring with blood and urine tests (for chronic kidney disease) and monitoring with blood tests and weight measurement (for chronic heart failure). Main outcome measures The main outcomes were the frequency, accuracy, utility, acceptability, costs and cost-effectiveness of monitoring. Results Chronic kidney disease: serum creatinine testing has increased steadily since 1997, with most results being normal (83% in 2013). Increases in tests of creatinine and proteinuria correspond to their introduction as indicators in the Quality and Outcomes Framework. The Chronic Kidney Disease Epidemiology Collaboration equation had 2.7% greater accuracy (95% confidence interval 1.6% to 3.8%) than the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate. Estimated annual transition rates to the next chronic kidney disease stage are ≈ 2% for people with normal urine albumin, 3–5% for people with microalbuminuria (3–30 mg/mmol) and 3–12% for people with macroalbuminuria (> 30 mg/mmol). Variability in estimated glomerular filtration rate-creatinine leads to misclassification of chronic kidney disease stage in 12–15% of tests in primary care. Glycaemic-control and lipid-modifying drugs are associated with a 6% (95% confidence interval 2% to 10%) and 4% (95% confidence interval 0% to 8%) improvement in renal function, respectively. Neither estimated glomerular filtration rate-creatinine nor estimated glomerular filtration rate-Cystatin C have utility in predicting rate of kidney function change. Patients viewed phrases such as ‘kidney damage’ or ‘kidney failure’ as frightening, and the term ‘chronic’ was misinterpreted as serious. Diagnosis of asymptomatic conditions (chronic kidney disease) was difficult to understand, and primary care professionals often did not use ‘chronic kidney disease’ when managing patients at early stages. General practitioners relied on Clinical Commissioning Group or Quality and Outcomes Framework alerts rather than National Institute for Health and Care Excellence guidance for information. Cost-effectiveness modelling did not demonstrate a tangible benefit of monitoring kidney function to guide preventative treatments, except for individuals with an estimated glomerular filtration rate of 60–90 ml/minute/1.73 m2, aged < 70 years and without cardiovascular disease, where monitoring every 3–4 years to guide cardiovascular prevention may be cost-effective. Chronic heart failure: natriuretic peptide-guided treatment could reduce all-cause mortality by 13% and heart failure admission by 20%. Implementing natriuretic peptide-guided treatment is likely to require predefined protocols, stringent natriuretic peptide targets, relative targets and being located in a specialist heart failure setting. Remote monitoring can reduce all-cause mortality and heart failure hospitalisation, and could improve quality of life. Diagnostic accuracy of point-of-care N-terminal prohormone of B-type natriuretic peptide (sensitivity, 0.99; specificity, 0.60) was better than point-of-care B-type natriuretic peptide (sensitivity, 0.95; specificity, 0.57). Within-person variation estimates for B-type natriuretic peptide and weight were as follows: coefficient of variation, 46% and coefficient of variation, 1.2%, respectively. Point-of-care N-terminal prohormone of B-type natriuretic peptide within-person variability over 12 months was 881 pg/ml (95% confidence interval 380 to 1382 pg/ml), whereas between-person variability was 1972 pg/ml (95% confidence interval 1525 to 2791 pg/ml). For individuals, monitoring provided reassurance; future changes, such as increased testing, would be acceptable. Point-of-care testing in general practice surgeries was perceived positively, reducing waiting time and anxiety. Community heart failure nurses had greater knowledge of National Institute for Health and Care Excellence guidance than general practitioners and practice nurses. Health-care professionals believed that the cost of natriuretic peptide tests in routine monitoring would outweigh potential benefits. The review of cost-effectiveness studies suggests that natriuretic peptide-guided treatment is cost-effective in specialist settings, but with no evidence for its value in primary care...
, , , , , Rhiannon R Baggott, Ailsa Bosworth, , Sofia Georgopoulou, Naomi Martin, et al.
Programme Grants for Applied Research, Volume 9, pp 1-186; https://doi.org/10.3310/pgfar09080

Abstract:
Background Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management. Objectives To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials. Design Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis. Setting Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions). Participants Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs. Interventions Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care. Main outcome measures Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments. Results Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p < 0.001]. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management n = 15 vs. standard care n = 11) and other adverse events (intensive management n = 114 vs. standard care n = 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial. Limitations The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’. Conclusion The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who...
Health Services and Delivery Research, Volume 9, pp 1-162; https://doi.org/10.3310/hsdr09140

Abstract:
Background More effective ways of managing symptoms of chronic and terminal illness enable patients to be cared for, and to die, at home. This requires patients and family caregivers to manage complex medicines regimens, including powerful painkillers that can have serious side effects. Little is known about how patients and family caregivers manage the physical and emotional work of managing medicines in the home or the support that they receive from health-care professionals and services. Objective To investigate how patients with serious and terminal illness, their family caregivers and the health-care professionals manage complex medication regimens and routines of care in the domestic setting. Design A qualitative study involving (1) semistructured interviews and group discussions with 40 health-care professionals and 21 bereaved family caregivers, (2) 20 patient case studies with up to 4 months’ follow-up and (3) two end-of-project stakeholder workshops. Setting This took place in Nottinghamshire and Leicestershire, UK. Results As patients’ health deteriorated, family caregivers assumed the role of a care co-ordinator, undertaking the everyday work of organising and collecting prescriptions and storing and administering medicines around other care tasks and daily routines. Participants described the difficulties of navigating a complex and fragmented system and the need to remain vigilant about medicines prescribed, especially when changes were made by different professionals. Access to support, resilience and coping capacity are mediated through the resources available to patients, through the relationships that they have with people in their personal and professional networks, and, beyond that, through the wider connections – or disconnections – that these links have with others. Health-care professionals often lacked understanding of the practical and emotional challenges involved. All participants experienced difficulties in communication and organisation within a health-care system that they felt was complicated and poorly co-ordinated. Having a key health professional to support and guide patients and family caregivers through the system was important to a good experience of care. Limitations The study achieved diversity in the recruitment of patients, with different characteristics relating to the type of illness and socioeconomic circumstances. However, recruitment of participants from ethnically diverse and disadvantaged or hard-to-reach populations was particularly challenging, and we were unable to include as many participants from these groups as had been originally planned. Conclusions The study identified two key and inter-related areas in which patient and family caregiver experience of managing medicines at home in end-of-life care could be improved: (1) reducing work and responsibility for medicines management and (2) improving co-ordination and communication in health care. It is important to be mindful of the need for transparency and open discussion about the extent to which patients and family caregivers can and should be co-opted as proto-professionals in the technically and emotionally demanding tasks of managing medicines at the end of life. Future work Priorities for future research include investigating how allocated key professionals could integrate and co-ordinate care and optimise medicines management; the role of domiciliary home care workers in supporting medicines management in end-of-life care; patient and family perspectives and understanding of anticipatory prescribing and their preferences for involvement in decision-making; the experience of medicines management in terminal illness among minority, disadvantaged and hard-to-reach patient groups; and barriers to and facilitators of increased involvement of community pharmacists in palliative and end-of-life care. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 14. See the NIHR Journals Library website for further project information.
, , Natalie Ives, , Sarah Tearne, Sheila M Greenfield, , , , Hannah Bensoussane, et al.
Health Technology Assessment, Volume 25, pp 1-130; https://doi.org/10.3310/hta25490

Abstract:
Background Pregnancy is a high-risk time for excessive weight gain. The rising prevalence of obesity in women, combined with excess weight gain during pregnancy, means that there are more women with obesity in the postnatal period. This can have adverse health consequences for women in later life and increases the health risks during subsequent pregnancies. Objective The primary aim was to produce evidence of whether or not a Phase III trial of a brief weight management intervention, in which postnatal women are encouraged by practice nurses as part of the national child immunisation programme to self-monitor their weight and use an online weight management programme, is feasible and acceptable. Design The research involved a cluster randomised controlled feasibility trial and two semistructured interview studies with intervention participants and practice nurses who delivered the intervention. Trial data were collected at baseline and 3 months later. The interview studies took place after trial follow-up. Setting The trial took place in Birmingham, UK. Participants Twenty-eight postnatal women who were overweight/obese were recruited via Birmingham Women’s Hospital or general practices. Nine intervention participants and seven nurses were interviewed. Interventions The intervention was delivered in the context of the national child immunisation programme. The intervention group were offered brief support that encouraged self-management of weight when they attended their practice to have their child immunised at 2, 3 and 4 months of age. The intervention involved the provision of motivation and support by nurses to encourage participants to make healthier lifestyle choices through self-monitoring of weight and signposting to an online weight management programme. The role of the nurse was to provide regular external accountability for weight loss. Women were asked to weigh themselves weekly and record this on a record card in their child’s health record (‘red book’) or using the online programme. The behavioural goal was for women to lose 0.5–1 kg per week. The usual-care group received a healthy lifestyle leaflet. Main outcome measures The primary outcome was the feasibility of a Phase III trial to test the effectiveness of the intervention, as assessed against three traffic-light stop–go criteria (recruitment, adherence to regular self-weighing and registration with an online weight management programme). Results The traffic-light criteria results were red for recruitment (28/80, 35% of target), amber for registration with the online weight loss programme (9/16, 56%) and green for adherence to weekly self-weighing (10/16, 63%). Nurses delivered the intervention with high fidelity. In the qualitative studies, participants indicated that the intervention was acceptable to them and they welcomed receiving support to lose weight at their child immunisation appointments. Although nurses raised some caveats to implementation, they felt that the intervention was easy to deliver and that it would motivate postnatal women to lose weight. Limitations Fewer participants were recruited than planned. Conclusions Although women and practice nurses responded well to the intervention and adherence to self-weighing was high, recruitment was challenging and there is scope to improve engagement with the intervention. Future work Future research should focus on investigating other methods of recruitment and, thereafter, testing the effectiveness of the intervention. Trial registration Current Controlled Trials ISRCTN12209332. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 49. See the NIHR Journals Library website for further project information.
Efficacy and Mechanism Evaluation, Volume 8, pp 1-90; https://doi.org/10.3310/eme08110

Abstract:
Background Reasoning may play a causal role in paranoid delusions in psychosis. SlowMo, a new digitally supported cognitive–behavioural therapy, targets reasoning to reduce paranoia. Objectives To examine the effectiveness of SlowMo therapy in reducing paranoia and in improving reasoning, quality of life and well-being, and to examine its mechanisms of action, moderators of effects and acceptability. Design A parallel-arm, assessor-blind, randomised controlled trial comparing SlowMo plus treatment as usual with treatment as usual alone. An online independent system randomised eligible participants (1 : 1) using randomly varying permuted blocks, stratified by site and paranoia severity. Setting Community mental health services in three NHS mental health trusts in England, plus patient identification centres. Participants A total of 362 participants with schizophrenia-spectrum psychosis. Eligibility criteria comprised distressing and persistent (≥ 3 months) paranoia. Interventions Eight face-to-face SlowMo sessions over 12 weeks plus treatment as usual, or treatment as usual alone (control group). Main outcome measures The primary outcome measure was paranoia measured by the Green Paranoid Thoughts Scale and its revised version, together with observer-rated measures of persecutory delusions (The Psychotic Symptom Rating Scales delusion scale and delusion items from the Scale for the Assessment of Positive Symptoms). The secondary outcome measures were reasoning (measures of belief flexibility, jumping to conclusions, and fast and slow thinking), well-being, quality of life, schemas, service use and worry. Results A total of 362 participants were recruited between 1 May 2017 and 14 May 2019: 181 in the SlowMo intervention group and 181 in the treatment-as-usual (control) group. One control participant subsequently withdrew. In total, 325 (90%) participants provided primary Green Paranoid Thoughts Scale outcome data at 12 weeks (SlowMo, n = 162; treatment as usual, n = 163). A total of 145 (80%) participants in the SlowMo group completed all eight therapy sessions. SlowMo was superior to treatment as usual in reducing paranoia on all three measures used: Green Paranoid Thoughts Scale total at 12 weeks (Cohen’s d = 0.30, 95% confidence interval 0.09 to 0.51; p = 0.005) and 24 weeks (Cohen’s d = 0.20, 95% confidence interval –0.02 to 0.40; p = 0.063); Psychotic Symptom Rating Scales delusions at 12 weeks (Cohen’s d = 0.47, 95% confidence interval 0.17 to 0.78; p = 0.002) and 24 weeks (Cohen’s d = 0.50, 95% confidence interval 0.20 to 0.80; p = 0.001); and Scale for the Assessment of Positive Symptoms persecutory delusions at 12 weeks (Cohen’s d = 0.43, 95% confidence interval 0.03 to 0.84; p = 0.035) and 24 weeks (Cohen’s d = 0.54, 95% confidence interval 0.14 to 0.94; p = 0.009). Reasoning (belief flexibility, possibility of being mistaken and Fast and Slow Thinking Questionnaire measure) improved, but jumping to conclusions did not improve. Worry, quality of life, well-being and self-concept also improved, improving most strongly at 24 weeks. Baseline characteristics did not moderate treatment effects. Changes in belief flexibility and worry mediated changes in paranoia. Peer researcher-led qualitative interviews confirmed positive experiences of the therapy and technology. Nineteen participants in the SlowMo group and 21 participants in the treatment-as-usual group reported 54 adverse events (51 serious events, no deaths). Limitations The trial included treatment as usual as the comparator and, thus, the trial design did not control for the effects of time with a therapist. Conclusions To the best of our knowledge, this is the largest trial of a psychological therapy for paranoia in people with psychosis and the first trial using a brief targeted digitally supported therapy. High rates of therapy uptake demonstrated acceptability. It was effective for paranoia, comparable to longer therapy, and equally effective for people with different levels of negative symptoms and working memory. Mediators were improvements in belief flexibility and worry. Our results suggest that targeting reasoning helps paranoia. Future work Further examination of SlowMo mechanisms of action and implementation. Trial registration Current Controlled Trials ISRCTN32448671. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 11. See the NIHR Journals Library website for further project information.
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