Search

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 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.

BACKGROUND People with intellectual disability (ID) are more likely to experience chronic depression compared with the general population, which may be compounded by loneliness and lower levels of social support. Befriending aims to provide social support and promote engagement in community activities. No randomised controlled trials have examined whether befriending improves symptoms of depression and social outcomes in people with ID. The aim of this pilot trial was to assess the feasibility and acceptability of a future larger trial of one-to-one befriending by volunteers in people with ID and depressive symptoms. METHODS Participants were adults with mild or moderate ID with a score of 5 or more on the Glasgow Depression Scale for People with Learning Disabilities (GDS-LD). They were randomised to the intervention arm (matched to a volunteer befriender for 6 months) or the control arm (usual care). Volunteers received training and supervision provided by two community befriending schemes. The main outcomes were feasibility of recruitment (minimum target n = 35), retention rate of participants, adherence (minimum 10 meetings), acceptability of the intervention, changes in depressive symptoms (assessed at baseline and 6 months) and feasibility of collecting data for a health economic analysis. RESULTS Recruitment was challenging, and only 16 participants with ID and 10 volunteers were recruited. Six participants were matched with a volunteer and no participants dropped out (except for two volunteers). Four participants completed 10 meetings (mean 11.8). Befriending was thought to be acceptable, but modifications were suggested. An exploratory analysis suggested that GDS-LD score was lower in the intervention group compared with the control group after adjusting for baseline scores, but not significant (adjusted mean difference: -4.0; 95% confidence interval: -11.2 to 3.2). CONCLUSIONS A large trial would not be feasible based on the recruitment strategies employed in this study. A further feasibility study addressing these challenges or the use of other study designs should be considered.

Background Clustered data arise in research when patients are clustered within larger units. Generalised Estimating Equations (GEE) and Generalised Linear Models (GLMM) can be used to provide marginal and cluster-specific inference and predictions, respectively. Methods Confounding by Cluster (CBC) and Informative cluster size (ICS) are two complications that may arise when modelling clustered data. CBC can arise when the distribution of a predictor variable (termed ‘exposure’), varies between clusters causing confounding of the exposure-outcome relationship. ICS means that the cluster size conditional on covariates is not independent of the outcome. In both situations, standard GEE and GLMM may provide biased or misleading inference, and modifications have been proposed. However, both CBC and ICS are routinely overlooked in the context of risk prediction, and their impact on the predictive ability of the models has been little explored. We study the effect of CBC and ICS on the predictive ability of risk models for binary outcomes when GEE and GLMM are used. We examine whether two simple approaches to handle CBC and ICS, which involve adjusting for the cluster mean of the exposure and the cluster size, respectively, can improve the accuracy of predictions. Results Both CBC and ICS can be viewed as violations of the assumptions in the standard GLMM; the random effects are correlated with exposure for CBC and cluster size for ICS. Based on these principles, we simulated data subject to CBC/ICS. The simulation studies suggested that the predictive ability of models derived from using standard GLMM and GEE ignoring CBC/ICS was affected. Marginal predictions were found to be mis-calibrated. Adjusting for the cluster-mean of the exposure or the cluster size improved calibration, discrimination and the overall predictive accuracy of marginal predictions, by explaining part of the between cluster variability. The presence of CBC/ICS did not affect the accuracy of conditional predictions. We illustrate these concepts using real data from a multicentre study with potential CBC. Conclusion Ignoring CBC and ICS when developing prediction models for clustered data can affect the accuracy of marginal predictions. Adjusting for the cluster mean of the exposure or the cluster size can improve the predictive accuracy of marginal predictions.

Multiple primary outcomes are sometimes collected and analysed in randomised controlled trials (RCTs), and are used in favour of a single outcome. By collecting multiple primary outcomes, it is possible to fully evaluate the effect that an intervention has for a given disease process. A simple approach to analysing multiple outcomes is to consider each outcome separately, however, this approach does not account for any pairwise correlations between the outcomes. Any cases with missing values must be ignored, unless an additional imputation step is performed. Alternatively, multivariate methods that explicitly model the pairwise correlations between the outcomes may be more efficient when some of the outcomes have missing values. In this paper, we present an overview of relevant methods that can be used to analyse multiple outcome measures in RCTs, including methods based on multivariate multilevel (MM) models. We perform simulation studies to evaluate the bias in the estimates of the intervention effects and the power of detecting true intervention effects observed when using selected methods. Different simulation scenarios were constructed by varying the number of outcomes, the type of outcomes, the degree of correlations between the outcomes and the proportions and mechanisms of missing data. We compare multivariate methods to univariate methods with and without multiple imputation. When there are strong correlations between the outcome measures (ρ > .4), our simulation studies suggest that there are small power gains when using the MM model when compared to analysing the outcome measures separately. In contrast, when there are weak correlations (ρ < .4), the power is reduced when using univariate methods with multiple imputation when compared to analysing the outcome measures separately.

Aims Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. Methods and results A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1–16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48–2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52–0.97) and Uno’s C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81). Conclusions This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.

Background: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. Methods: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1–16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). Results: MLVWT Z score was Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3–9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. Conclusions: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

Objective:Nearly half of care home residents with advanced dementia have clinically significant agitation. Little is known about costs associated with these symptoms toward the end of life. We calculated monetary costs associated with agitation from UK National Health Service, personal social services, and societal perspectives.Design:Prospective cohort study.Setting:Thirteen nursing homes in London and the southeast of England.Participants:Seventy-nine people with advanced dementia (Functional Assessment Staging Tool grade 6e and above) residing in nursing homes, and thirty-five of their informal carers.Measurements:Data collected at study entry and monthly for up to 9 months, extrapolated for expression per annum. Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Health and social care costs of residing in care homes, and costs of contacts with health and social care services were calculated from national unit costs; for a societal perspective, costs of providing informal care were estimated using the resource utilization in dementia (RUD)-Lite scale.Results:After adjustment, health and social care costs, and costs of providing informal care varied significantly by level of agitation as death approached, from £23,000 over a 1-year period with no agitation symptoms (CMAI agitation score 0–10) to £45,000 at the most severe level (CMAI agitation score >100). On average, agitation accounted for 30% of health and social care costs. Informal care costs were substantial, constituting 29% of total costs.Conclusions:With the increasing prevalence of dementia, costs of care will impact on healthcare and social services systems, as well as informal carers. Agitation is a key driver of these costs in people with advanced dementia presenting complex challenges for symptom management, service planners, and providers.

Objectives\ud Globally, the number of people with dementia who have palliative care needs will increase fourfold over the next 40 years. The Empowering Better End‐of‐Life Dementia Care (EMBED‐Care) Programme aims to deliver a step change in care through a large sequential study, spanning multiple work streams.\ud \ud Methods\ud We will use mixed methods across settings where people with dementia live and die: their own homes, care homes, and hospitals. Beginning with policy syntheses and reviews of interventions, we will develop a conceptual framework and underpinning theory of change. We will use linked data sets to explore current service use, care transitions, and inequalities and predict future need for end‐of‐life dementia care. Longitudinal cohort studies of people with dementia (including young onset and prion dementias) and their carers will describe care transitions, quality of life, symptoms, formal and informal care provision, and costs. Data will be synthesised, underpinned by the Knowledge‐to‐Action Implementation Framework, to design a novel complex intervention to support assessment, decision making, and communication between patients, carers, and inter‐professional teams. This will be feasibility and pilot tested in UK settings. Patient and public involvement and engagement, innovative work with artists, policymakers, and third sector organisations are embedded to drive impact. We will build research capacity and develop an international network for excellence in dementia palliative care.\ud \ud Conclusions\ud EMBED‐Care will help us understand current and future need, develop novel cost‐effective care innovations, build research capacity, and promote international collaborations in research and practice to ensure people live and die well with dementia.

IntroductionSpecialist gender services for children and young people (CYP) worldwide have experienced a significant increase in referrals in recent years. As rates of referrals increase, it is important to understand the characteristics and profile of CYP attending these services in order to inform treatment pathways and to ensure optimal outcomes.Methods and analysisA retrospective observational study of clinical health records from specialist gender services for CYP in the UK and the Netherlands. The retrospective analysis will examine routinely collected clinical and outcome measures data including demographic, clinical, gender identity-related and healthcare resource use information. Data will be reported for each service and also compared between services. This study forms part of a wider programme of research investigating outcomes of gender identity in children (the Longitudinal Outcomes of Gender Identity in Children study).Ethics and disseminationThe proposed study has been approved by the Health Research Authority and London—Hampstead Research Ethics Committee as application 19/LO/0181. The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events.

IntroductionGender identity development services (GIDS) worldwide have seen a significant increase in referrals in recent years. Many of these referrals consist of children and young people (CYP) who experience gender-related distress. This study aims to improve understanding of outcomes of CYP referred to the UK GIDS, specifically regarding gender identity, mental health, physical health and quality of life. The impact of factors such as co-occurring autism and early social transition on outcomes over time will be explored.Methods and analysisThis is a prospective cohort study of CYP aged 3–14 years when referred to the UK GIDS. Eligible participants will be ≤14 years at the time their referral was accepted and will be on the waitlist for the service when baseline measures are completed. Children aged under 12 years will complete the measures in an interview format with a researcher, while young people aged 12 years and over and their parents/caregivers will complete online or paper-based questionnaires. Participants will complete follow-up measures 12 months and 24 months later. The final sample size is expected to be approximately 500. Logistic regression models will be used to explore associations between prespecified explanatory variables and gender dysphoria. Appropriate regression models will also be used to investigate explanatory variables for other outcomes. Subgroup analyses based on birth-assigned gender, age at referral and co-occurring autistic traits will be explored.Ethics and disseminationThe study has been approved by the Health Research Authority and London – Hampstead Research Ethics Committee (reference: 19/LO/0857). The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events. Findings will be used to inform clinical practice.

Introduction Sudden cardiac death is the most common cause of mortality in childhood onset hypertrophic cardiomyopathy. Identifying individuals at highest risk is therefore an essential part of clinical care but remains challenging. The 12 lead electrocardiogram (ECG) has been proposed as a useful tool for risk stratification and an ECG risk score has been proposed. However, this has not been independently validated and the ECG phenotype of childhood HCM has not been previously described. The aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods Participants with an available baseline resting 12-lead ECG were identified from a large, international, multi-centre, retrospective cohort of patients aged less than 16 years fulfilling the diagnostic criteria for HCM (n=1029). Resting baseline ECG was evaluated and ECG variables were extracted. In addition, the ECG risk score based on 8 parameters (deviation in QRS axis, pathological T-wave inversion in limb or precordial leads, ST-segment depression, dominant S-wave in V4, limb-lead amplitude sum, 12-lead amplitude duration product and QTc) was calculated as previously described. The primary study endpoint was a composite outcome of major cardiac events (MACE) defined as SCD, resuscitated cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia (VT) with haemodynamic compromise. The discriminatory performance of using an ECG risk score >5 to identify patients at increased risk of MACE at 5 years was determined using Harrell’s C-index. Results Of 356 patients with childhood HCM (68.9% male, mean age at presentation 10.1 ± 4.5 years), 347 (97.5%) had baseline ECG abnormalities such as: repolarization abnormalities (n=277, 77.8%), left ventricular hypertrophy (n=240. 67.6%), abnormal QRS axis (n=126, 35.4%) or QT prolongation (n=131, 36.8%). Over a median follow up of 3.9 years (IQR 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year MACE on univariable or multivariable Cox regression analysis. Of the 164 participants with an ECG score >5, 153 (93.3%) did not have a MACE within 5 years. Harrell’s C-index (the probability of correctly distinguishing between high and low risk patients using an ECG risk score threshold of >5) was 0.60 (95% CI 0.484-0.715) at 5 years. The corresponding positive and negative predictive values were 6.7% (95% CI 4.7 – 9.4%) and 96.9% (95% CI 94.2 – 98.4%). Conclusions In a large, international, multi-centre cohort of children with HCM, ECG abnormalities are common. No ECG characteristic, either in isolation or combined in the ECG risk score, was associated with 5-year MACE risk. This suggests that the role of the baseline ECG phenotype in improving risk stratification in childhood HCM is limited. Conflict of Interest None

BACKGROUND The aim was to pilot an adapted manualised weight management programme for persons with mild-moderate intellectual disabilities affected by overweight or obesity ('Shape Up-LD'). METHOD Adults with intellectual disabilities were enrolled in a 6-month trial (3-month active intervention and 3-month follow-up) and were individually randomised to Shape Up-LD or a usual care control. Feasibility outcomes included recruitment, retention, initial effectiveness and cost. RESULTS Fifty people were enrolled. Follow-up rates were 78% at 3 months and 74% at 6 months. At 3 and 6 months, controlling for baseline weight, no difference was observed between groups (3 months: β: -0.34, 95% confidence interval [CI]: -2.38, 1.69, 6 months: β: -0.55, 95%CI -4.34, 3.24). CONCLUSION It may be possible to carry out a trial of Shape Up-LD, although barriers to recruitment, carer engagement and questionnaire completion need to be addressed, alongside refinements to the intervention.

Background The Prognosis in Palliative care Study (PiPS) prognostic survival models predict survival in patients with incurable cancer. PiPS-A (Prognosis in Palliative care Study – All), which involved clinical observations only, and PiPS-B (Prognosis in Palliative care Study – Blood), which additionally required blood test results, consist of 14- and 56-day models that combine to create survival risk categories: ‘days’, ‘weeks’ and ‘months+’. Objectives The primary objectives were to compare PIPS-B risk categories against agreed multiprofessional estimates of survival and to validate PiPS-A and PiPS-B. The secondary objectives were to validate other prognostic models, to assess the acceptability of the models to patients, carers and health-care professionals and to identify barriers to and facilitators of clinical use. Design This was a national, multicentre, prospective, observational, cohort study with a nested qualitative substudy using interviews with patients, carers and health-care professionals. Setting Community, hospital and hospice palliative care services across England and Wales. Participants For the validation study, the participants were adults with incurable cancer, with or without capacity to consent, who had been recently referred to palliative care services and had sufficient English language. For the qualitative substudy, a subset of participants in the validation study took part, along with informal carers, patients who declined to participate in the main study and health-care professionals. Main outcome measures For the validation study, the primary outcomes were survival, clinical prediction of survival and PiPS-B risk category predictions. The secondary outcomes were predictions of PiPS-A and other prognostic models. For the qualitative substudy, the main outcomes were participants’ views about prognostication and the use of prognostic models. Results For the validation study, 1833 participants were recruited. PiPS-B risk categories were as accurate as agreed multiprofessional estimates of survival (61%; p = 0.851). Discrimination of the PiPS-B 14-day model (c-statistic 0.837, 95% confidence interval 0.810 to 0.863) and the PiPS-B 56-day model (c-statistic 0.810, 95% confidence interval 0.788 to 0.832) was excellent. The PiPS-B 14-day model showed some overfitting (calibration in the large –0.202, 95% confidence interval –0.364 to –0.039; calibration slope 0.840, 95% confidence interval 0.730 to 0.950). The PiPS-B 56-day model was well-calibrated (calibration in the large 0.152, 95% confidence interval 0.030 to 0.273; calibration slope 0.914, 95% confidence interval 0.808 to 1.02). PiPS-A risk categories were less accurate than agreed multiprofessional estimates of survival (p c-statistic 0.825, 95% confidence interval 0.803 to 0.848; calibration in the large –0.037, 95% confidence interval –0.168 to 0.095; calibration slope 0.981, 95% confidence interval 0.872 to 1.09) and the PiPS-A 56-day model (c-statistic 0.776, 95% confidence interval 0.755 to 0.797; calibration in the large 0.109, 95% confidence interval 0.002 to 0.215; calibration slope 0.946, 95% confidence interval 0.842 to 1.05) had excellent or reasonably good discrimination and calibration. Other prognostic models were also validated. Where comparisons were possible, the other prognostic models performed less well than PiPS-B. For the qualitative substudy, 32 health-care professionals, 29 patients and 20 carers were interviewed. The majority of patients and carers expressed a desire for prognostic information and said that PiPS could be helpful. Health-care professionals said that PiPS was user friendly and may be helpful for decision-making and care-planning. The need for a blood test for PiPS-B was considered a limitation. Limitations The results may not be generalisable to other populations. Conclusions PiPS-B risk categories are as accurate as agreed multiprofessional estimates of survival. PiPS-A categories are less accurate. Patients, carers and health-care professionals regard PiPS as potentially helpful in clinical practice. Future work A study to evaluate the impact of introducing PiPS into routine clinical practice is needed. Trial registration Current Controlled Trials ISRCTN13688211. 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. 28. See the NIHR Journals Library website for further project information.

Risk-prediction models for health outcomes are used in practice as part of clinical decision-making, and it is essential that their performance be externally validated. An important aspect in the design of a validation study is choosing an adequate sample size. In this paper, we investigate the sample size requirements for validation studies with binary outcomes to estimate measures of predictive performance (C-statistic for discrimination and calibration slope and calibration in the large). We aim for sufficient precision in the estimated measures. In addition, we investigate the sample size to achieve sufficient power to detect a difference from a target value. Under normality assumptions on the distribution of the linear predictor, we obtain simple estimators for sample size calculations based on the measures above. Simulation studies show that the estimators perform well for common values of the C-statistic and outcome prevalence when the linear predictor is marginally Normal. Their performance deteriorates only slightly when the normality assumptions are violated. We also propose estimators which do not require normality assumptions but require specification of the marginal distribution of the linear predictor and require the use of numerical integration. These estimators were also seen to perform very well under marginal normality. Our sample size equations require a specified standard error (SE) and the anticipated C-statistic and outcome prevalence. The sample size requirement varies according to the prognostic strength of the model, outcome prevalence, choice of the performance measure and study objective. For example, to achieve an SE

Background Prognosis in Palliative care Study (PiPS) models predict survival probabilities in advanced cancer. PiPS-A (clinical observations only) and PiPS-B (additionally requiring blood results) consist of 14- and 56-day models (PiPS-A14; PiPS-A56; PiPS-B14; PiPS-B56) to create survival risk categories: days, weeks, months. The primary aim was to compare PIPS-B risk categories against agreed multi-professional estimates of survival (AMPES) and to validate PiPS-A and PiPS-B. Secondary aims were to assess acceptability of PiPS to patients, caregivers and health professionals (HPs). Methods and findings A national, multi-centre, prospective, observational, cohort study with nested qualitative sub-study using interviews with patients, caregivers and HPs. Validation study participants were adults with incurable cancer; with or without capacity; recently referred to community, hospital and hospice palliative care services across England and Wales. Sub-study participants were patients, caregivers and HPs. 1833 participants were recruited. PiPS-B risk categories were as accurate as AMPES [PiPS-B accuracy (910/1484; 61%); AMPES (914/1484; 61%); p = 0.851]. PiPS-B14 discrimination (C-statistic 0.837) and PiPS-B56 (0.810) were excellent. PiPS-B14 predictions were too high in the 57–74% risk group (Calibration-in-the-large [CiL] -0.202; Calibration slope [CS] 0.840). PiPS-B56 was well-calibrated (CiL 0.152; CS 0.914). PiPS-A risk categories were less accurate than AMPES (p Conclusions PiPS-B risk categories are as accurate as AMPES made by experienced doctors and nurses. PiPS-A categories are less accurate. Patients, carers and HPs regard PiPS as potentially helpful in clinical practice. Study registration ISRCTN13688211.

Background\ud Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis.\ud \ud Methods\ud CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045.\ud \ud Results\ud Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group.\ud \ud Conclusions\ud Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered.

AIM: Surgery for spinal metastases can improve symptoms, but sometimes complications can negate the benefits. Operations may have different indications, complexities and risks, and the choice for an individual is a tailor-made personalised decision. Previous prognostic scoring systems are becoming out of date and inaccurate. We designed a risk calculator to estimate survival after surgery, to inform clinicians and patients when making management decisions. METHODS: A prospective cohort study was performed, including 1430 patients with spinal metastases who underwent surgery. Of them, 1264 patients from 20 centres were used for model development using a Cox frailty model. Calibration slope, D-statistic and C-index were used for model validation based on 166 patients. Follow-up was to death or minimum of 2 years after surgery. Pre-operative indices (examination findings, pain, Karnofsky physical functioning score, and radiology) were assessed. RESULTS: An algorithm to predict survival was constructed including the tumour type, ambulatory status, analgesic use, American Society of Anesthesiologists score, number of spinal metastases, previous radiotherapy or chemotherapy, presence of visceral metastases, cervical or thoracic spine involvement, as predictors. An Internet-based risk calculator was developed based on this algorithm, with similar or improved accuracy compared to other validated prognostic scoring systems (C-index, 0.68; 95% confidence interval, 0.63--0.73, and calibration slope, 1.00; 95% confidence interval, 0.68--1.32). CONCLUSION: A large, prospective, surgical series of patients with symptomatic spinal metastases was used to create a validated risk calculator that can help clinicians to inform patients about the most appropriate treatment plan. The calculator is available at www.spinemet.com. ispartof: EUROPEAN JOURNAL OF CANCER vol:107 pages:28-36 ispartof: location:England status: published

OBJECTIVE: To understand the feasibility of recruiting people with advanced cancer into a randomised controlled trial of Acceptance and Commitment therapy (ACT) vs a standardised Talking Control (TC) and delivering ACT to this population; to explore the acceptability of outcome measures and generate normative data. METHODS: This was a feasibility two-arm randomised controlled trial. Participants were attendees with advanced cancer at one of three hospice-based day- therapy units in London, UK, who demonstrated low scores on the Functional Assessment of Cancer Therapies - General (FACT-G). The primary end point was three months. RESULTS: The recruitment target was 54 participants; 42 people were recruited and randomised to up to eight individual sessions of ACT (n=20) or TC (n=22). 18/42 (43%) of participants completed the primary outcome at three months, and at least one follow-up was available in 30/42 (71%) participants. An exploratory analysis revealed a non-significant adjusted mean difference after three months in the main outcome FACT-G of -3.41 (CI= -18.61, 11.79) with TC having better functioning. Over six months the adjusted mean difference between trial arms was 2.25 (CI= -6.03, 10.52) in favour of ACT. CONCLUSIONS: It is feasible to recruit people with advanced cancer in a trial of ACT versus TC. Future research should test the effectiveness of ACT in a fully powered trial.

Background We aimed to estimate the clinical effectiveness of Community Occupational Therapy for people with dementia and family carers–UK version (Community Occupational Therapy in Dementia–UK version [COTiD-UK]) relative to treatment as usual (TAU). We hypothesised that COTiD-UK would improve the ability of people with dementia to perform activities of daily living (ADL), and family carers’ sense of competence, compared with TAU. Methods and findings The study design was a multicentre, 2-arm, parallel-group, assessor-masked, individually randomised controlled trial (RCT) with internal pilot. It was conducted in 15 sites across England from September 2014 to January 2018. People with a diagnosis of mild to moderate dementia living in their own home were recruited in pairs with a family carer who provided domestic or personal support for at least 4 hours per week. Pairs were randomised to either receive COTiD-UK, which comprised 10 hours of occupational therapy delivered over 10 weeks in the person with dementia’s home or TAU, which comprised the usual local service provision that may or may not include standard occupational therapy. The primary outcome was the Bristol Activities of Daily Living Scale (BADLS) score at 26 weeks. Secondary outcomes for the person with dementia included the following: the BADLS scores at 52 and 78 weeks, cognition, quality of life, and mood; and for the family carer: sense of competence and mood; plus the number of social contacts and leisure activities for both partners. Participants were analysed by treatment allocated. A total of 468 pairs were recruited: people with dementia ranged from 55 to 97 years with a mean age of 78.6 and family carers ranged from 29 to 94 with a mean of 69.1 years. Of the people with dementia, 74.8% were married and 19.2% lived alone. Of the family carers, 72.6% were spouses, and 22.2% were adult children. On randomisation, 249 pairs were assigned to COTiD-UK (62% people with dementia and 23% carers were male) and 219 to TAU (52% people with dementia and 32% carers were male). At the 26 weeks follow-up, data were available for 364 pairs (77.8%). The BADLS score at 26 weeks did not differ significantly between groups (adjusted mean difference estimate 0.35, 95% CI −0.81 to 1.51; p = 0.55). Secondary outcomes did not differ between the groups. In total, 91% of the activity-based goals set by the pairs taking part in the COTiD-UK intervention were fully or partially achieved by the final COTiD-UK session. Study limitations include the following: Intervention fidelity was moderate but varied across and within sites, and the reliance on primarily proxy data focused on measuring the level of functional or cognitive impairment which may not truly reflect the actual performance and views of the person living with dementia. Conclusions Providing community occupational therapy as delivered in this study did not improve ADL performance, cognition, quality of life, or mood in people with dementia nor sense of competence or mood in family carers. Future research should consider measuring person-centred outcomes that are more meaningful and closely aligned to participants’ priorities, such as goal achievement or the quantity and quality of activity engagement and participation. Trial Registration Current Controlled Trials ISRCTN10748953., Jennifer Wenborn and colleagues investigate the effectiveness of community occupational therapy program in improving activities of daily living, cognition, and mood for people with dementia., Author summary Why was this study done? Maintaining everyday and pleasurable activities can be difficult for a person with dementia, as well as their family carer who often feels increasingly stressed as they need to give more and more support. Occupational therapists assist people to improve their health and well-being through carrying on with the activities they need and want to do. It is therefore important to develop effective strategies to deliver occupational therapy to people with dementia and their family carers who support them. What did the researchers do and find? We tested the effectiveness of the Community Occupational Therapy in Dementia–UK version (COTiD-UK) programme compared to the care that people with mild to moderate dementia and their family carers usually receive, through a clinical trial. We recruited 468 pairs comprising a person with dementia and a family carer across England who were randomly allocated to either take part in the COTiD-UK programme or to continue with their usual care. We found no statistical evidence that COTiD-UK gave more benefit to people with dementia or their carers than the usual care provided in terms of the people with dementia being able to carry out activities or their mood or quality of life nor their family carers’ sense of competence or mood. The pairs who took part in the COTiD-UK intervention set an average of 4.09 goals each, of which 91% were fully or partially achieved by the final COTiD-UK session. What do these findings mean? We did not find evidence to support commissioning the COTiD-UK intervention for people with mild to moderate dementia and their family carers. Future studies need to develop more realistic methods of measuring the effectiveness of programmes such as this, particularly to focus on the outcomes that most matter to the individuals taking part and to truly reflect the actual performance, experience, and views of the person living with dementia.

Supplemental material, sj-pdf-1-smm-10.1177_09622802211007522 for Estimation of required sample size for external validation of risk models for binary outcomes by Menelaos Pavlou, Chen Qu, Rumana Z Omar, Shaun R Seaman, Ewout W Steyerberg, Ian R White and Gareth Ambler in Statistical Methods in Medical Research

Supplemental material, sj-pdf-2-smm-10.1177_09622802211007522 for Estimation of required sample size for external validation of risk models for binary outcomes by Menelaos Pavlou, Chen Qu, Rumana Z Omar, Shaun R Seaman, Ewout W Steyerberg, Ian R White and Gareth Ambler in Statistical Methods in Medical Research

Purpose The Palliative Prognostic (PaP) score; Palliative Prognostic Index (PPI); Feliu Prognostic Nomogram (FPN) and Palliative Performance Scale (PPS) have all been proposed as prognostic tools for palliative cancer care. However, clinical judgement remains the principal way by which palliative care professionals determine prognoses and it is important that the performance of prognostic tools is compared against clinical predictions of survival (CPS). Methods This was a multi-centre, cohort validation study of prognostic tools. Study participants were adults with advanced cancer receiving palliative care, with or without capacity to consent. Key prognostic data were collected at baseline, shortly after referral to palliative care services. CPS were obtained independently from a doctor and a nurse. Results Prognostic data were collected on 1833 participants. All prognostic tools showed acceptable discrimination and calibration, but none showed superiority to CPS. Both PaP and CPS were equally able to accurately categorise patients according to their risk of dying within 30 days. There was no difference in performance between CPS and FPN at stratifying patients according to their risk of dying at 15, 30 or 60 days. PPI was significantly (p Conclusions Although four commonly used prognostic algorithms for palliative care generally showed good discrimination and calibration, none of them demonstrated superiority to CPS. Prognostic tools which are less accurate than CPS are of no clinical use. However, prognostic tools which perform similarly to CPS may have other advantages to recommend them for use in clinical practice (e.g. being more objective, more reproducible, acting as a second opinion or as an educational tool). Future studies should therefore assess the impact of prognostic tools on clinical practice and decision-making.

Aims The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods and results Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7% Conclusion In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

Background Loss of smell and taste are commonly reported symptoms associated with coronavirus disease 2019 (COVID-19); however, the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in people with acute loss of smell and/or taste is unknown. The study aimed to determine the seroprevalence of SARS-CoV-2 antibodies in a community-based population with acute loss of smell and/or taste and to compare the frequency of COVID-19 associated symptoms in participants with and without SARS-CoV-2 antibodies. It also evaluated whether smell or taste loss are indicative of COVID-19 infection. Methods and findings Text messages, sent via primary care centers in London, United Kingdom, invited people with loss of smell and/or taste in the preceding month, to participate. Recruitment took place between 23 April 2020 and 14 May 2020. A total of 590 participants enrolled via a web-based platform and responded to questions about loss of smell and taste and other COVID-19–related symptoms. Mean age was 39.4 years (SD ± 12.0) and 69.1% (n = 392) of participants were female. A total of 567 (96.1%) had a telemedicine consultation during which their COVID-19–related symptoms were verified and a lateral flow immunoassay test that detected SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies was undertaken under medical supervision. A total of 77.6% of 567 participants with acute smell and/or taste loss had SARS-CoV-2 antibodies; of these, 39.8% (n = 175) had neither cough nor fever. New loss of smell was more prevalent in participants with SARS-CoV-2 antibodies, compared with those without antibodies (93.4% versus 78.7%, p < 0.001), whereas taste loss was equally prevalent (90.2% versus 89.0%, p = 0.738). Seropositivity for SARS-CoV-2 was 3 times more likely in participants with smell loss (OR 2.86; 95% CI 1.27–6.36; p < 0.001) compared with those with taste loss. The limitations of this study are the lack of a general population control group, the self-reported nature of the smell and taste changes, and the fact our methodology does not take into account the possibility that a population subset may not seroconvert to develop SARS-CoV-2 antibodies post-COVID-19. Conclusions Our findings suggest that recent loss of smell is a highly specific COVID-19 symptom and should be considered more generally in guiding case isolation, testing, and treatment of COVID-19. Trials registration ClinicalTrials.gov NCT04377815, In a UK-based cohort, Janine Makaronidis and colleagues investigate COVID-19 seropositivity in individuals with loss of smell and/or taste., Author summary Why was this study done? Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, was declared a pandemic in March 2020. COVID-19 can cause loss or reduced ability to smell (anosmia) or taste, without cough or fever, but few countries recommend self-isolation and testing on the basis of smell or taste changes alone. This study aimed to find out the proportion of people who have developed SARS-CoV-2 antibodies in a community-based population with a newly developed loss in their sense of smell and/or taste in London, UK. What did the researchers do and find? Text messages were sent out to people registered with a number of primary care centers in London inviting people with a new loss in their sense of smell and/or taste to participate. Recruited participants completed online questionnaires regarding demographics, their loss of smell and/or taste, and other COVID-19 symptoms, before they had a telemedicine consultation with a healthcare professional who confirmed the history of their symptoms and supervised a test to find out if they had SARS-CoV-2 antibodies. A total of 78% of 567 people with smell and/or taste loss had SARS-CoV-2 antibodies; of these, 40% had neither cough nor fever, and participants with loss of smell were 3 times more to have SARS-CoV-2 antibodies, compared with those with loss of taste. What do these findings mean? Loss of smell is a highly specific symptom of COVID-19. COVID-19 can present with loss of smell and/or taste without cough or fever. Loss of smell should be take into consideration in case isolation, testing, and treatment strategies for COVID-19.

IntroductionPeople with intellectual disability (ID) are more likely to experience loneliness and have smaller social networks, which increases vulnerability to depression. Befriending may reduce depressive symptoms in other populations, but randomised controlled trials (RCTs) have not been carried out in this population. This pilot study aims to assess the acceptability and feasibility of carrying out a full RCT of one-to-one befriending by volunteers for people with ID, compared with an active control group.Methods and analysisThe trial aims to recruit 40 participants with ID. Participants in the intervention arm will receive weekly visits from a volunteer over 6 months. Community befriending schemes will recruit, train, supervise volunteers and match them to individuals with ID. Both groups will receive a booklet about local activities and have access to usual care. Health and social outcomes will be measured at the end of the intervention and 6 months’ follow-up. The following outcomes will be assessed: (1) recruitment and retention of individuals with ID and volunteers in the trial, (2) adverse events related to the intervention, (3) the acceptability of the intervention, (4) whether the intervention is delivered as intended, (5) changes in health and social outcomes and (6) the feasibility of carrying out a cost-effectiveness analysis in a full trial. Qualitative data from participants, volunteers, staff and carers will identify barriers and facilitators of a future full trial.Ethics and disseminationThe study has been approved by the London City and East Research Ethics Committee (reference 18/LO/2188). The findings will be presented at conferences and published in a peer-reviewed journal and in the National Institute of Health Research journals library. A public engagement seminar will be held at the end of the study aimed at key stakeholders.Trial registration numberNCT63779614.

Background Behaviour that challenges in people with intellectual disability is associated with higher healthcare, social care and societal costs. Although behavioural therapies are widely used, there is limited evidence regarding the cost and quality-adjusted life-years (QALYs). Aims We aimed to assess the incremental cost per QALY gained of therapist training in positive behaviour support (PBS) and treatment as usual (TAU) compared with TAU using data from a cluster randomised controlled trial (Clinical Trials.gov registration: NCT01680276). Method We conducted a cost-utility analysis (cost per QALY gained) of 23 teams randomised to PBS or TAU, with a total of 246 participants followed up over 36 months. The primary analysis was from a healthcare cost perspective with a secondary analysis from a societal cost perspective. Results Over 36 months the intervention resulted in an additional 0.175 QALYs (discounted and adjusted 95% CI −0.068 to 0.418). The total cost of training in and delivery of PBS is £1598 per participant plus an additional cost of healthcare of £399 (discounted and adjusted 95% CI −603 to 1724). From a healthcare cost perspective there is an 85% probability that the intervention is cost-effective compared with TAU at a £30 000 willingness to pay for a QALY threshold. Conclusions There was a high probability that training in PBS is cost-effective as the cost of training and delivery of PBS is balanced out by modest improvements in quality of life. However, staff training in PBS is not supported given we found no evidence for clinical effectiveness.

Background Preliminary studies have indicated that training staff in Positive Behaviour Support (PBS) may help to reduce challenging behaviour among people with intellectual disability (ID). Objective To evaluate whether or not such training is clinically effective in reducing challenging behaviour in routine care. The study also included longer-term follow-up (approximately 36 months). Design A multicentre, single-blind, two-arm, parallel-cluster randomised controlled trial. The unit of randomisation was the community ID service using an independent web-based randomisation system and random permuted blocks on a 1 : 1 allocation stratified by a staff-to-patient ratio for each cluster. Setting Community ID services in England. Participants Adults (aged > 18 years) across the range of ID with challenging behaviour [≥ 15 Aberrant Behaviour Checklist – Community total score (ABC-CT)]. Interventions Manual-assisted face-to-face PBS training to therapists and treatment as usual (TAU) compared with TAU only in the control arm. Main outcome measures Carer-reported changes in challenging behaviour as measured by the ABC-CT over 12 months. Secondary outcomes included psychopathology, community participation, family and paid carer burden, family carer psychopathology, costs of care and quality-adjusted life-years (QALYs). Data on main outcome, service use and health-related quality of life were collected for the 36-month follow-up. Results A total of 246 participants were recruited from 23 teams, of whom 109 were in the intervention arm (11 teams) and 137 were in the control arm (12 teams). The difference in ABC-CT between the intervention and control arms [mean difference –2.14, 95% confidence interval (CI) –8.79 to 4.51; p = 0.528] was not statistically significant. No treatment effects were found for any of the secondary outcomes. The mean cost per participant in the intervention arm was £1201. Over 12 months, there was a difference in QALYs of 0.076 in favour of the intervention (95% CI 0.011 to 0.140 QALYs) and a 60% chance that the intervention is cost-effective compared with TAU from a health and social care cost perspective at the threshold of £20,000 per QALY gained. Twenty-nine participants experienced 45 serious adverse events (intervention arm, n = 19; control arm, n = 26). PBS plans were available for 33 participants. An independent assessment of the quality of these plans found that all were less than optimal. Forty-six qualitative interviews were conducted with service users, family carers, paid carers and service managers as part of the process evaluation. Service users reported that they had learned to manage difficult situations and had gained new skills, and carers reported a positive relationship with therapists. At 36 months’ follow-up (n = 184), the mean ABC-CT difference between arms was not significant (–3.70, 95% CI –9.25 to 1.85; p = 0.191). The initial cost-effectiveness of the intervention dissipated over time. Limitations The main limitations were low treatment fidelity and reach of the intervention. Conclusions Findings from the main study and the naturalistic follow-up suggest that staff training in PBS as delivered in this study is insufficient to achieve significant clinical gains beyond TAU in community ID services. Although there is an indication that training in PBS is potentially cost-effective, this is not maintained in the longer term. There is increased scope to develop new approaches to challenging behaviour as well as optimising the delivery of PBS in routine clinical practice. Trial registration This study is registered as NCT01680276. 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. 22, No. 15. See the NIHR Journals Library website for further project information.

5008 Background: Multiparametric MRI (mpMRI) of the prostate followed by targeted biopsy is recommended in men at risk of prostate cancer. Dissemination of this pathway may be limited by cost, variable scan and reporting quality, and contraindicated in the presence of metallic implants and claustrophobia. Multi-parametric ultrasound (mpUSS) is a point of care test with low cost that combines b-mode, colour Doppler, elastography and contrast enhancement. CADMUS compared the diagnostic performance of mpUSS to mpMRI. Methods: CADMUS recruited 370 patients from seven sites to a prospective, multicentre, paired-cohort trial (ISRCTN 38541912). Ethics committee approval was obtained. Patients underwent both mpUSS and mpMRI independently, each with a positive test defined as a Likert score of >3. Those with either a positive mpUSS or mpMRI, or both, were advised to undergo targeted biopsies. Reporting of each scan was carried out blind to the other and prior to biopsy; patients advised for biopsy were blinded to which test was positive. The order of mpUSS and mpMRI targeting was randomised. Primary outcomes were proportion of positive tests and detection of clinically significant cancer (csPCa) defined as Gleason >4+3 of any length and/or maximum cancer core length of >6mm of any grade [PROMIS definition1]. Results: 306 completed both mpUSS and mpMRI. Agreement in lesion detection between mpUSS and mpMRI was 73.2% (kappa 0.06, p = 0.14). 257 with positive results on mpUSS, mpMRI or both had targeted biopsies. Agreement on detection of csPCa was 91.1% (expected 59.8%, kappa 0.78, p < 0.01). Overall, mpUSS detected 4.3% fewer csPCa than mpMRI (95% CI = [-8.3%, -1.5%]; p = 0.042 [Bonferroni correction]). mpUSS detected 7.2% (6/83) csPCa missed by mpMRI; mpMRI detected 20.5% (17/83) csPCa that mpUSS missed. At a less stringent definition of significant cancer, Gleason grade >3+4 of any length (definition 3), agreement was 89.1% (expected 55.6%, kappa 0.75, p < 0.01) mpUSS detected 5.4% fewer definition 3 cancers than mpMRI overall. mpUSS detected 7% (7/99) definition 3 cancers that mpMRI missed; mpMRI detected 21% (21/99) definition 3 cancers that mpUSS missed. Conclusions: The CADMUS trial shows mpUSS has a diagnostic performance approaching that of mpMRI and significant cancer detection is improved by the use of both scans over mpMRI alone. Clinical trial information: 38541912. [Table: see text]

ObjectivesThe Prognosis in Palliative care Study II (PiPS2) was a large multicentre observational study validating prognostic tools in patients with advanced cancer. Many palliative care studies fail to reach their recruitment target. To inform future studies, PiPS2 rigorously monitored and identified any potential recruitment barriers.MethodsKey recruitment stages (ie, whether patients were eligible for the study, approached by the researchers and whether consent was obtained for enrolment) were monitored via comprehensive screening logs at participating sites (inpatient hospices, hospitals and community palliative care teams). The reasons for patients’ ineligibility, inaccessibility or decision not to consent were documented.Results17 014 patients were screened across 27 participating sites over a 20-month recruitment period. Of those, 4642 (27%) were ineligible for participation in the study primarily due to non-cancer diagnoses. Of 12 372 eligible patients, 9073 (73%) were not approached, the most common reason being a clinical decision not to do so. Other reasons included patients’ death or discharge before they were approached by the researchers. Of the 3299 approached patients, 1458 (44%) declined participation mainly because of feeling too unwell, experiencing severe distress or having other competing priorities. 11% (n=1841/17 014) of patients screened were enrolled in the study, representing 15% (n=1841/12 372) of eligible patients. Different recruitment patterns were observed across inpatient hospice, hospital and community palliative care teams.ConclusionsThe main barrier to recruitment was ‘accessing’ potentially eligible patients. Monitoring key recruitment stages may help to identify barriers and facilitators to enrolment and allow results to be put into better context.Trial registration numberISRCTN13688211.

Background: Increasing number of people are dying with advanced dementia. Comfort and quality of life are key goals of care. Aims: To describe (1) physical and psychological symptoms, (2) health and social care service utilisation and (3) care at end of life in people with advanced dementia. Design: 9-month prospective cohort study. Setting and participants: Greater London, England, people with advanced dementia (Functional Assessment Staging Scale 6e and above) from 14 nursing homes or their own homes. Main outcome measures: At study entry and monthly: prescriptions, Charlson Comorbidity Index, pressure sore risk/severity (Waterlow Scale/Stirling Scale, respectively), acute medical events, pain (Pain Assessment in Advanced Dementia), neuropsychiatric symptoms (Neuropsychiatric Inventory), quality of life (Quality of Life in Late-Stage Dementia Scale), resource use (Resource Utilization in Dementia Questionnaire and Client Services Receipt Inventory), presence/type of advance care plans, interventions, mortality, place of death and comfort (Symptom Management at End of Life in Dementia Scale). Results: Of 159 potential participants, 85 were recruited (62% alive at end of follow-up). Pain (11% at rest, 61% on movement) and significant agitation (54%) were common and persistent. Aspiration, dyspnoea, septicaemia and pneumonia were more frequent in those who died. In total, 76% had ‘do not resuscitate’ statements, less than 40% advance care plans. Most received primary care visits, there was little input from geriatrics or mental health but contact with emergency paramedics was common. Conclusion: People with advanced dementia lived with distressing symptoms. Service provision was not tailored to their needs. Longitudinal multidisciplinary input could optimise symptom control and quality of life.

BackgroundThe REAL (Rehabilitation Effectiveness for Activities for Life) research programme, funded by the National Institute for Heath Research (NIHR) from 2009 to 2015, investigated NHS mental health rehabiliation services across England. The users of these services are people with longer-term, complex mental health problems, such as schizophrenia, who have additional problems that complicate recovery. Although only around 10% of people with severe mental illness require inpatient rehabilitation, because of the severity and complexity of their problems they cost 25–50% of the total mental health budget. Despite this, there has been little research to help clinicians and commissioners to plan and deliver effective treatments and services. This research aimed to address this gap.MethodsThe programme had four phases. (1) A national survey, using quantitative and qualitative methods, was used to provide a detailed understanding of the scope and quality of NHS mental health rehabilitation services in England and the characteristics of those who use them. (2) We developed a training intervention for staff of NHS inpatient mental health rehabilitation units to facilitate service users’ activities. (3) The clinical effectiveness and cost-effectiveness of the staff training programme was evaluated through a cluster randomised controlled trial involving 40 units that scored below average on our quality assessment tool in the national survey. A qualitative process evaluation and a realistic evaluation were carried out to inform our findings further. (4) A naturalistic cohort study was carried out involving 349 service users of 50 units that scored above average on our quality assessment tool in the national survey, who were followed up over 12 months. Factors associated with better clinical outcomes were investigated through exploratory analyses.ResultsMost NHS trusts provided inpatient mental health rehabilitation services. The quality of care provided was higher than that in similar facilities across Europe and was positively associated with service users’ autonomy. Our cluster trial did not find our staff training intervention to be clinically effective [coefficient 1.44, 95% confidence interval (CI) –1.35 to 4.24]; staff appeared to revert to previous practices once the training team left the unit. Our realistic review suggested that greater supervision and senior staff support could help to address this. Over half of the service users in our cohort study were successfully discharged from hospital over 12 months. Factors associated with this were service users’ activity levels [odds ratio (OR) 1.03, 95% CI 1.01 to 1.05] and social skills (OR 1.13, 95% CI 1.04 to 1.24), and the ‘recovery’ orientation of the unit (OR 1.04, 95% CI 1.00 to 1.08), which includes collaborative care planning with service users and holding hope for their progress. Quality of care was not associated with costs of care. A relatively small investment (£67 per service user per month) was required to achieve the improvement in everyday functioning that we found in our cohort study.ConclusionsPeople who require inpatient mental health rehabilitation are a ‘low-volume, high-needs’ group. Despite this, these services are able to successfully discharge most to the community within 18 months. Our results suggest that this may be facilitated by recovery-orientated practice that promotes service users’ activities and social skills. Further research is needed to identify effective interventions that enhance such practice to deliver these outcomes. Our research provides evidence that NHS inpatient mental health rehabilitation services deliver high-quality care that successfully supports service users with complex needs in their recovery.Main limitationOur programme included only NHS, non-secure, inpatient mental health rehabilitation services.Trial registrationCurrent Controlled Trials ISRCTN25898179.FundingThe NIHR Programme Grants for Applied Research programme.

Background Cannabis is the most prevalent illicit substance among people with psychosis, and its use is associated with poorer clinical and social outcomes. However, so far, there has been limited evidence that any treatment is effective for reducing use. Contingency management (CM) is an incentive-based intervention for substance misuse that has a substantial evidence base across a range of substances and cohorts. However, to date there have been no randomised controlled trials (RCTs) of CM as a treatment for cannabis use specifically in psychosis. Objective To conduct a RCT investigating the clinical effectiveness and cost-effectiveness of CM in reducing cannabis use among Early Intervention in Psychosis (EIP) service users. Design The CIRCLE (Contingency Intervention for Reduction of Cannabis in Early Psychosis) trial was a rater-blinded, multicentre RCT with two arms. Participants were randomised 1 : 1 to either an CM arm, in which participants received CM for cannabis use alongside an optimised treatment-as-usual programme including structured psychoeducation, or a control arm in which participants received the treatment as usual only. Setting EIP services across the Midlands and the south-east of England. Participants The main eligibility criteria were EIP service users with a history of psychosis, aged 18–36 years, and having used cannabis at least once per week during 12 of the previous 24 weeks. Intervention The CM intervention offered financial incentives (i.e. shopping vouchers) for cannabis abstinence over 12 once-weekly sessions, confirmed using urinalysis. The maximum value in vouchers that participants could receive was £240. Main outcome measures The main outcome was time to relapse, operationalised as admission to an acute mental health service or hospital. The primary outcome was assessed at 18 months post inclusion using electronic patient records. Secondary outcomes assessed the clinical effectiveness and cost-effectiveness of the intervention, for which data were collected at 3 and 18 months. Results A total of 278 participants were randomised to the CM arm and 273 were randomised to the control arm. In total, 530 (96%) participants were followed up for the primary outcome. There was no significant difference in time to admission between trial arms by 18 months following consent (hazard ratio 1.03, 95% confidence interval 0.76 to 1.40). There were no statistically significant differences in most secondary outcomes, including cannabis use, at either follow-up assessment. There were 58 serious adverse events, comprising 52 inpatient episodes, five deaths and one arrest. Limitations Participant retention was low at 18 months, limiting the assessment of secondary outcomes. A different CM intervention design or reward level may have been effective. Conclusions The CM intervention did not appear to be effective in reducing cannabis use and acute relapse among people with early psychosis and problematic cannabis use. Future work Cannabis use is still a significant clinical concern in this population. A pressing need remains to identify suitable treatments. A wider perspective on the social circumstances of young people with psychosis may be needed for a successful intervention to be found. Trial registration Current Controlled Trials ISRCTN33576045. 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. 23, No. 45. See the NIHR Journals Library website for further project information.

Background Multiple primary outcomes may be specified in randomised controlled trials (RCTs). When analysing multiple outcomes it’s important to control the family wise error rate (FWER). A popular approach to do this is to adjust the p-values corresponding to each statistical test used to investigate the intervention effects by using the Bonferroni correction. It’s also important to consider the power of the trial to detect true intervention effects. In the context of multiple outcomes, depending on the clinical objective, the power can be defined as: ‘disjunctive power’, the probability of detecting at least one true intervention effect across all the outcomes or ‘marginal power’ the probability of finding a true intervention effect on a nominated outcome. We provide practical recommendations on which method may be used to adjust for multiple comparisons in the sample size calculation and the analysis of RCTs with multiple primary outcomes. We also discuss the implications on the sample size for obtaining 90% disjunctive power and 90% marginal power. Methods We use simulation studies to investigate the disjunctive power, marginal power and FWER obtained after applying Bonferroni, Holm, Hochberg, Dubey/Armitage-Parmar and Stepdown-minP adjustment methods. Different simulation scenarios were constructed by varying the number of outcomes, degree of correlation between the outcomes, intervention effect sizes and proportion of missing data. Results The Bonferroni and Holm methods provide the same disjunctive power. The Hochberg and Hommel methods provide power gains for the analysis, albeit small, in comparison to the Bonferroni method. The Stepdown-minP procedure performs well for complete data. However, it removes participants with missing values prior to the analysis resulting in a loss of power when there are missing data. The sample size requirement to achieve the desired disjunctive power may be smaller than that required to achieve the desired marginal power. The choice between whether to specify a disjunctive or marginal power should depend on the clincial objective. Electronic supplementary material The online version of this article (10.1186/s12874-019-0754-4) contains supplementary material, which is available to authorized users.

Background Effective interventions are needed to prevent cardiovascular disease (CVD) in people with severe mental illnesses (SMI) because their risk of CVD is higher than that of the general population. Objectives (1) Develop and validate risk models for predicting CVD events in people with SMI and evaluate their cost-effectiveness, (2) develop an intervention to reduce levels of cholesterol and CVD risk in SMI and (3) test the clinical effectiveness and cost-effectiveness of this new intervention in primary care. Design Mixed methods with patient and public involvement throughout. The mixed methods were (1) a prospective cohort and risk score validation study and cost-effectiveness modelling, (2) development work (focus groups, updated systematic review of interventions, primary care database studies investigating statin prescribing and effectiveness) and (3) cluster randomised controlled trial (RCT) assessing the clinical effectiveness and cost-effectiveness of a new practitioner-led intervention, and fidelity assessment of audio-recorded appointments. Setting General practices across England. Participants All studies included adults with SMI (schizophrenia, bipolar disorder or other non-organic psychosis). The RCT included adults with SMI and two or more CVD risk factors. Interventions The intervention consisted of 8–12 appointments with a practice nurse/health-care assistant over 6 months, involving collaborative behavioural approaches to CVD risk factors. The intervention was compared with routine practice with a general practitioner (GP). Main outcome measures The primary outcome for the risk score work was CVD events, in the cost-effectiveness modelling it was quality-adjusted life-years (QALYs) and in the RCT it was level of total cholesterol. Data sources Databases studies used The Health Improvement Network (THIN). Intervention development work included focus groups and systematic reviews. The RCT collected patient self-reported and routine NHS GP data. Intervention appointments were audio-recorded. Results Two CVD risk score models were developed and validated in 38,824 people with SMI in THIN: the Primrose lipid model requiring cholesterol levels, and the Primrose body mass index (BMI) model with no blood test. These models performed better than published Cox Framingham models. In health economic modelling, the Primrose BMI model was most cost-effective when used as an algorithm to drive statin prescriptions. Focus groups identified barriers to, and facilitators of, reducing CVD risk in SMI including patient engagement and motivation, staff confidence, involving supportive others, goal-setting and continuity of care. Findings were synthesised with evidence from updated systematic reviews to create the Primrose intervention and training programme. THIN cohort studies in 16,854 people with SMI demonstrated that statins effectively reduced levels of cholesterol, with similar effect sizes to those in general population studies over 12–24 months (mean decrease 1.2 mmol/l). Cluster RCT: 76 GP practices were randomised to the Primrose intervention (n = 38) or treatment as usual (TAU) (n = 38). The primary outcome (level of cholesterol) was analysed for 137 out of 155 participants in Primrose and 152 out of 172 in TAU. There was no difference in levels of cholesterol at 12 months [5.4 mmol/l Primrose vs. 5.5 mmol/l TAU; coefficient 0.03; 95% confidence interval (CI) –0.22 to 0.29], nor in secondary outcomes related to cardiometabolic parameters, well-being or medication adherence. Mean cholesterol levels decreased over 12 months in both arms (–0.22 mmol/l Primrose vs. –0.39 mmol/l TAU). There was a significant reduction in the cost of inpatient mental health attendances (–£799, 95% CI –£1480 to –£117) and total health-care costs (–£895, 95% CI –£1631 to –£160; p = 0.012) in the intervention group, but no significant difference in QALYs (–0.011, 95% CI –0.034 to 0.011). A total of 69% of patients attended two or more Primrose appointments. Audiotapes revealed moderate fidelity to intervention delivery (67.7%). Statin prescribing and adherence was rarely addressed. Limitations RCT participants and practices may not represent all UK practices. CVD care in the TAU arm may have been enhanced by trial procedures involving CVD risk screening and feedback. Conclusions SMI-specific CVD risk scores better predict new CVD if used to guide statin prescribing in SMI. Statins are effective in reducing levels of cholesterol in people with SMI in UK clinical practice. This primary care RCT evaluated an evidence-based practitioner-led intervention that was well attended by patients and intervention components were delivered. No superiority was shown for the new intervention over TAU for level of cholesterol, but cholesterol levels decreased over 12 months in both arms and the intervention showed fewer inpatient admissions. There was no difference in cholesterol levels between the intervention and TAU arms, which might reflect better than standard general practice care in TAU, heterogeneity in intervention delivery or suboptimal emphasis on statins. Future work The new risk score should be updated, deployed and tested in different settings and compared with the latest versions of CVD risk scores in different countries. Future research on CVD risk interventions should emphasise statin prescriptions more. The mechanism behind lower costs with the Primrose intervention needs exploring, including SMI-related training and offering frequent support to people with SMI in primary care. Trial registration Current Controlled Trials ISRCTN13762819. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 2. See the NIHR Journals Library website for further project information. Professor David Osborn is supported by the University College London Hospital NIHR Biomedical Research Centre and he was also in part supported by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) North Thames at Barts Health NHS Trust.

Sample size calculation methodology. Varying the effect size across outcomes. Skewed data. (DOCX 1675 kb)

Aims Sudden cardiac death (SCD) is the most common cause of death in children with hypertrophic cardiomyopathy (HCM). The European Society of Cardiology (ESC) recommends consideration of an implantable cardioverter-defibrillator (ICD) if two or more clinical risk factors (RFs) are present, but this approach to risk stratification has not been formally validated. Methods and results Four hundred and eleven paediatric HCM patients were assessed for four clinical RFs in accordance with current ESC recommendations: severe left ventricular hypertrophy, unexplained syncope, non-sustained ventricular tachycardia, and family history of SCD. The primary endpoint was a composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate ICD therapy, or sustained ventricular tachycardia), defined as a major arrhythmic cardiac event (MACE). Over a follow-up period of 2890 patient years (median 5.5 years), MACE occurred in 21 patients (7.5%) with 0 RFs, 19 (16.8%) with 1 RFs, and 3 (18.8%) with 2 or more RFs. Corresponding incidence rates were 1.13 [95% confidence interval (CI) 0.7–1.73], 2.07 (95% CI 1.25–3.23), and 2.52 (95% CI 0.53–7.35) per 100 patient years at risk. Patients with two or more RFs did not have a higher incidence of MACE (log-rank test P = 0.34), with a positive and negative predictive value of 19% and 90%, respectively. The C-statistic was 0.62 (95% CI 0.52–0.72) at 5 years. Conclusions The incidence of MACE is higher for patients with increasing numbers of clinical RFs. However, the current ESC guidelines have a low ability to discriminate between high- and low-risk individuals.

Risk prediction models are used to predict a clinical outcome for patients using a set of predictors. We focus on predicting low‐dimensional binary outcomes typically arising in epidemiology, health services and public health research where logistic regression is commonly used. When the number of events is small compared with the number of regression coefficients, model overfitting can be a serious problem. An overfitted model tends to demonstrate poor predictive accuracy when applied to new data. We review frequentist and Bayesian shrinkage methods that may alleviate overfitting by shrinking the regression coefficients towards zero (some methods can also provide more parsimonious models by omitting some predictors). We evaluated their predictive performance in comparison with maximum likelihood estimation using real and simulated data. The simulation study showed that maximum likelihood estimation tends to produce overfitted models with poor predictive performance in scenarios with few events, and penalised methods can offer improvement. Ridge regression performed well, except in scenarios with many noise predictors. Lasso performed better than ridge in scenarios with many noise predictors and worse in the presence of correlated predictors. Elastic net, a hybrid of the two, performed well in all scenarios. Adaptive lasso and smoothly clipped absolute deviation performed best in scenarios with many noise predictors; in other scenarios, their performance was inferior to that of ridge and lasso. Bayesian approaches performed well when the hyperparameters for the priors were chosen carefully. Their use may aid variable selection, and they can be easily extended to clustered‐data settings and to incorporate external information. © 2015 The Authors. Statistics in Medicine Published by JohnWiley & Sons Ltd.

Summary Multiple-imputation (MI) methods for imputing missing data in observational health studies with repeated measurements were evaluated with particular focus on incomplete time varying explanatory variables. Standard and random-effects imputation by chained equations, multivariate normal imputation and Bayesian MI were compared regarding bias and efficiency of regression coefficient estimates by using simulation studies. Flexibility of the methods in handling different types of variables (binary, categorical, skewed and normally distributed) and correlations between the repeated measurements of the incomplete variables were also compared. Multivariate normal imputation produced the least bias in most situations, is theoretically well justified and allows flexible correlation for the repeated measurements. It can be recommended for imputing continuous variables. Bayesian MI is efficient and may be preferable in the presence of categorical and non-normally distributed continuous variables. Imputation by chained equations approaches were sensitive to the correlation between the repeated measurements. The moving time window approach may be used for normally distributed continuous variables with auto-regressive correlation.

Objective Diabetic retinopathy (DR) is the leading cause of blindness in patients with type 1 or type 2 diabetes. The gold standard for the detection of DR requires expensive equipment. This study was undertaken to develop a simple and practical scoring system to predict the probability of DR. Methods A total of 1782 patients who had first-degree relatives with type II diabetes were selected. Eye examinations were performed by an expert ophthalmologist. Biochemical and anthropometric predictors of DR were measured. Logistic regression was used to develop a statistical model that can be used to predict DR. Goodness of fit was examined using the Hosmer-Lemeshow test and the area under the receiver operating characteristic (ROC) curve. Results The risk model demonstrated good calibration and discrimination (ROC area=0.76) in the validation sample. Factors associated with DR in our model were duration of diabetes (odds ratio [OR]=2.14, confidence interval [CI] 95%=1.87 to 2.45); glycated hemoglobin (A1C) (OR=1.21, CI 95%=1.13 to 1.30); fasting plasma glucose (OR=1.83, CI 95%=1.28 to 2.62); systolic blood pressure (OR=1.01, CI 95%= 1.00 to 1.02); and proteinuria (OR=1.37, CI 95%=1.01 to 1.85). The only factor that had a protective effect against DR were body mass index and education level (OR=0.95, CI 95%=0.92 to 0.98). Conclusions The good performance of our risk model suggests that it may be a useful risk-prediction tool for DR. It consisted of the positive predictors like A1C, diabetes duration, sex (male), fasting plasma glucose, systolic blood pressure and proteinuria, as well as negative risk factors like body mass index and education level.

BackgroundStaff training in positive behaviour support (PBS) is a widespread treatment approach for challenging behaviour in adults with intellectual disability.AimsTo evaluate whether such training is clinically effective in reducing challenging behaviour during routine care (trial registration: NCT01680276).MethodWe carried out a multicentre, cluster randomised controlled trial involving 23 community intellectual disability services in England, randomly allocated to manual-assisted staff training in PBS (n = 11) or treatment as usual (TAU, n = 12). Data were collected from 246 adult participants.ResultsNo treatment effects were found for the primary outcome (challenging behaviour over 12 months, adjusted mean difference = −2.14, 95% CI: −8.79, 4.51) or secondary outcomes.ConclusionsStaff training in PBS, as applied in this study, did not reduce challenging behaviour. Further research should tackle implementation issues and endeavour to identify other interventions that can reduce challenging behaviour.Declaration of interestNone.