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The objective of this trial, Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART), was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety. This randomized double-blind parallel-group study was conducted in three academic medical centers and a single private pediatric practice. Eighty children or adolescents (aged 6-17 yrs) with autistic disorder were enrolled, and 61 patients were randomized to the study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase. All patients were treated with 2 weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10 weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed U.S. Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4; patients were then maintained on a fixed dose for 6 additional weeks. Safety, physical, and psychological assessments were recorded weekly or every 2 weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist-Irritability subscale after 1 week and continued for the remaining 9 weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38 kg, p=0.033) and week 10 (1.61 vs 3.31 kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26). Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within 1 week and lasted at least 22 weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder., (© 2019 Pharmacotherapy Publications, Inc.)

Background: Recruitment to randomised controlled trials (RCTs) is challenging. Pre-trial qualitative research provides insights into the feasibility and acceptability of proposed trial designs and delivery; however, this is rarely conducted. This paper reports on work undertaken in advance of the Prepare for Kidney Care trial (formerly PrepareME), which compares preparing for dialysis with preparing for conservative care for patients with chronic kidney disease. The paper describes how the findings refined plans for the forthcoming trial., Methods: Semi-structured interviews were undertaken with health-care professionals involved in delivering or recruiting to the trial. Interview findings were considered in relation to observations of a patient advisory group workshop and introductory site visits, which were set up to present the trial to professionals involved in the internal pilot phase of the RCT. The use of findings and input from multiple sources was intended to support suggested refinements to the forthcoming trial. The findings were fed back to the trial management group and other expert stakeholders., Results: Sixteen health-care professionals were interviewed, and one patient advisory group workshop and six introductory visits to sites involved in the internal pilot were observed. The professionals interviewed included renal consultants, nurses and renal social workers. Key themes identified from the interviews, supported by the observations, were concerns around the eligibility criteria, the feasibility of the trial intervention, imbalances in the presentation of the trial arms, and anticipated recruitment issues arising from patients' and clinicians' preferences for one arm or the other. Changes to the design were made in response, including to the content of the intervention, the presentation of the trial arms and the name of the RCT., Conclusions: This study highlights the value of carrying out pre-trial work with health-care professionals to identify issues with delivering the proposed trial. This work can be particularly valuable in trials of new interventions, for which the barriers to their integration into routine care are unknown. This work has important implications for facilitating the identification of further obstacles in the main RCT. We suggest that pre-trial qualitative work is undertaken to address design issues early on, in addition to ongoing qualitative research to monitor the emergence of obstacles affecting recruitment.

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R 2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: -0.62; -1.03, -0.02; p = 0.004), pyruvate (β: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (β: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: -0.65; -1.04, -0.26; p = 0.001 and β: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Randomized controlled trials (RCTs) can provide high quality evidence about the comparative effectiveness of health care interventions, but many RCTs struggle with or fail to complete recruitment. RCTs are built on the principles of the experimental method, but their planning, conduct, and interpretation can depend on complex social, behavioral, and cultural factors that may be best understood through qualitative research. Most qualitative studies undertaken alongside RCTs involve interviews that produce data that are used in a supportive or supplicatory role, but there is potential for qualitative research to be more influential. In this article, we describe the research methods underpinning the "QuinteT" (Qualitative Research Integrated Within Trials) approach to understand and address RCT recruitment difficulties. The QuinteT Recruitment Intervention (QRI) brings together multiple qualitative strategies and quantitative data and uses triangulation to understand recruitment issues rapidly. These nuanced understandings are used to inform the implementation of collaborative actions to improve recruitment.

Qualitative researchers are increasingly reanalyzing and synthesizing data sets from different studies, and this method has now been used across trials to inform trial methodology and delivery. Despite this work, however, limited guidance exists about how this method should be employed. This article details an example in which interview data collected during three primary care depression trials were brought together to explore trial participants' study and treatment journeys. It details the process involved and the decisions made. It also presents findings from this synthesis to illustrate how this method can be used to inform the development of future trials and complex interventions, through raising questions about how researchers currently define and design treatment arms and indicating what factors may improve or hinder participants' engagement with their allocated treatment.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

Objective: To evaluate the impact of the QuinteT Recruitment Intervention (QRI) on recruitment in challenging randomized controlled trials (RCTs) that have applied the intervention. The QRI aims to understand recruitment difficulties and then implements "QRI actions" to address these as recruitment proceeds., Study Design and Setting: A mixed-methods study, comprising (1) before-and-after comparisons of recruitment rates and the numbers of patients approached and (2) qualitative case studies, including documentary analysis and interviews with RCT investigators., Results: Five UK-based publicly funded RCTs were included in the evaluation. All recruited to target. Randomized controlled trial 2 and RCT 5 both received up-front prerecruitment training before the intervention was applied. Randomized controlled trial 2 did not encounter recruitment issues and recruited above target from its outset. Recruitment difficulties, particularly communication issues, were identified and addressed through QRI actions in RCTs 1, 3, 4, and 5. Randomization rates significantly improved after QRI action in RCTs 1, 3, and 4. Quintet Recruitment Intervention actions addressed issues with approaching eligible patients in RCTs 3 and 5, which both saw significant increases in the number of patients approached. Trial investigators reported that the QRI had unearthed issues they had been unaware of and reportedly changed their practices after QRI action., Conclusion: There is promising evidence to suggest that the QRI can support recruitment to difficult RCTs. This needs to be substantiated with future controlled evaluations., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r g  = 0.57, p = 4.6 × 10 -8 ), breast and ovarian cancer (r g  = 0.24, p = 7 × 10 -5 ), breast and lung cancer (r g  = 0.18, p =1.5 × 10 -6 ) and breast and colorectal cancer (r g  = 0.15, p = 1.1 × 10 -4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH) 2 D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness ( P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH) 2 D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease., (©2018 American Association for Cancer Research.)

Objective: To describe how clinicians conceptualised equipoise in the PART (Partial prostate Ablation vs Radical prosTatectomy in intermediate-risk unilateral clinically localised prostate cancer) feasibility study and how this affected recruitment., Subjects and Methods: PART included a QuinteT Recruitment Intervention (QRI) to optimise recruitment. Phase I aimed to understand recruitment, and included: scrutinising recruitment data, interviewing the trial management group and recruiters (n = 13), and audio-recording recruitment consultations (n = 64). Data were analysed using qualitative content and thematic analysis methods. In Phase II, strategies to improve recruitment were developed and delivered., Results: Initially many recruiters found it difficult to maintain a position of equipoise and held preconceptions about which treatment was best for particular patients. They did not feel comfortable about approaching all eligible patients, and when the study was discussed, biases were conveyed through the use of terminology, poorly balanced information, and direct treatment recommendations. Individual and group feedback led to presentations to patients becoming clearer and enabled recruiters to reconsider their sense of equipoise. Although the precise impact of the QRI alone cannot be determined, recruitment increased (from a mean [range] of 1.4 [0-4] to 4.5 [0-12] patients/month) and the feasibility study reached its recruitment target., Conclusion: Although clinicians find it challenging to recruit patients to a trial comparing different contemporary treatments for prostate cancer, training and support can enable recruiters to become more comfortable with conveying equipoise and providing clearer information to patients., (© 2018 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

[This corrects the article DOI: 10.1186/s40814-018-0365-6.].

Background: Job loss, austerity measures, financial difficulties and house repossession contribute to the risk of self-harm and suicide during recessions. Navigating the benefits system and accessing sources of welfare and debt advice is a difficult experience for vulnerable people, further contributing to their distress. Whilst there is some evidence that advice-type interventions can lead to financial gain, there is mixed evidence for their effectiveness in improving mental health in those experiencing financial difficulties. There have been no interventions targeting those who have self-harmed due to economic hardship., Methods: Our aim was to determine the feasibility and acceptability of a brief psychosocial intervention (the 'HOPE' service) for people presenting to hospital emergency departments (ED) following self-harm or in acute distress because of financial, employment or welfare (benefit) difficulties. Nineteen people consented to random allocation to the intervention or control arm on a 2:1 basis. Participants randomised to the intervention arm ( n  = 13) received up to six sessions of 1:1 support provided by community support staff trained in Motivational Interviewing (MI). Control participants ( n  = 6) received a one-off session signposting them to relevant support organisations. Fourteen participants were followed up after 3 months. Participants and mental health workers took part in qualitative interviews. The acceptability of outcome measures including the PHQ-9, GAD-7, repeat self-harm, EQ5D-5 L and questions about debt, employment and welfare benefits were explored., Results: Interviews indicated the main benefits of the service as the resolution of specific financial problems and receiving support when participants were feeling most vulnerable. Randomisation was acceptable to most participants although not always fully understood and control participants could be disappointed. Recruitment was slow (1-2 per month). The outcome measures were acceptable and appeared sensitive to change., Discussion: The HOPE intervention is feasible and acceptable. There was evidence of need and it is a relatively inexpensive intervention. Refining aspects of the intervention would be straightforward. A full-scale RCT would be feasible, if broadened eligibility criteria led to increased recruitment and improvements were made to staff training and support., Trial Registration: ISRCTN58531248., Competing Interests: The study received ethical approval from South West Central Bristol Research Ethics Committee (REC: 16/SW/0005). Individual written consent was taken for each participant including consent to report anonymised data.Written consent to publish anonymised data was given in the individual consent taken for each participant.The authors declare they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10 -15 ), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

We investigated the experience and perspectives of menopause among 48 UK mothers through qualitative in-depth interviews. Interviews were analyzed thematically then explored using social science theories. Three interdependent narratives emerged: menopause as a normal, biological process, distinct from self and social transitions; menopause as struggle, an "idiom of distress" expressing upset, identity loss, shame, and social upheaval; and menopause as transformative and liberating, arising from biopsychic and relational changes. Some women followed a predictable "rite of passage" trajectory with transformation emerging from distress, but not all: Menopause arises from a complex interplay of personal predicament, somatic change, and sociocultural context.

Epidemiologic studies suggest that diet can alter prostate cancer risk. This study aimed to establish the feasibility and acceptability of dietary modification in men at increased risk of prostate cancer. Men were invited with a PSA level of 2.0-2.95 ng/mL or 3.0-19.95 ng/mL with negative prostate biopsies. Randomization (3 × 3 factorial design) to daily green tea and lycopene: green tea drink (3 cups, unblinded) or capsules [blinded, 600 mg flavan-3-ol ()-epigallocatechin-3-gallate (EGCG) or placebo] and lycopene-rich foods (unblinded) or capsules (blinded, 15 mg lycopene or placebo) for 6 months. Primary endpoints were randomization rates and intervention adherence (blinded assessment of metabolites) at 6 months with secondary endpoints of acceptability (from interviews), safety, weight, blood pressure, and PSA. A total of 133 of 469 (28.4%) men approached agreed to be randomized and 132 were followed-up (99.2%). Mean lycopene was 1.28 [95% confidence intervals (CI), 1.09-1.50, P = 0.003] times higher in the lycopene capsule group and 1.42 (95% CI, 1.21-1.66; P < 0.001) times higher in the lycopene-enriched diet group compared with placebo capsules. Median EGCG was 10.7 nmol/L (95% CI, 7.0-32.0) higher in in the active capsule group and 20.0 nmol/L (95% CI, 0.0-19.0) higher in the green tea drink group compared with placebo capsules (both P < 0.001). All interventions were acceptable and well tolerated although men preferred the capsules. Dietary prevention is acceptable to men at risk of prostate cancer. This intervention trial demonstrates that a chemoprevention clinical trial is feasible. Cancer Prev Res; 11(11); 687-96. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Prostate cancer (PCa) is the most common cancer in men in the UK. Patients with intermediate-risk, clinically localised disease are offered radical treatments such as surgery or radiotherapy, which can result in severe side effects. A number of alternative partial ablation (PA) technologies that may reduce treatment burden are available; however the comparative effectiveness of these techniques has never been evaluated in a randomised controlled trial (RCT)., Objectives: To assess the feasibility of a RCT of PA using high-intensity focused ultrasound (HIFU) versus radical prostatectomy (RP) for intermediate-risk PCa and to test and optimise methods of data capture., Design: We carried out a prospective, multicentre, open-label feasibility study to inform the design and conduct of a future RCT, involving a QuinteT Recruitment Intervention (QRI) to understand barriers to participation., Setting: Five NHS hospitals in England., Participants: Men with unilateral, intermediate-risk, clinically localised PCa., Interventions: Radical prostatectomy compared with HIFU., Primary Outcome Measure: The randomisation of 80 men., Secondary Outcome Measures: Findings of the QRI and assessment of data capture methods., Results: Eighty-seven patients consented to participate by 31 March 2017 and 82 men were randomised by 4 May 2017 (41 men to the RP arm and 41 to the HIFU arm). The QRI was conducted in two iterative phases: phase I identified a number of barriers to recruitment, including organisational challenges, lack of recruiter equipoise and difficulties communicating with patients about the study, and phase II comprised the development and delivery of tailored strategies to optimise recruitment, including group training, individual feedback and 'tips' documents. At the time of data extraction, on 10 October 2017, treatment data were available for 71 patients. Patient characteristics were similar at baseline and the rate of return of all clinical case report forms (CRFs) was 95%; the return rate of the patient-reported outcome measures (PROMs) questionnaire pack was 90.5%. Centres with specific long-standing expertise in offering HIFU as a routine NHS treatment option had lower recruitment rates (Basingstoke and Southampton) - with University College Hospital failing to enrol any participants - than centres offering HIFU in the trial context only., Conclusions: Randomisation of men to a RCT comparing PA with radical treatments of the prostate is feasible. The QRI provided insights into the complexities of recruiting to this surgical trial and has highlighted a number of key lessons that are likely to be important if the study progresses to a main trial. A full RCT comparing clinical effectiveness, cost-effectiveness and quality-of-life outcomes between radical treatments and PA is now warranted., Future Work: Men recruited to the feasibility study will be followed up for 36 months in accordance with the protocol. We will design a full RCT, taking into account the lessons learnt from this study. CRFs will be streamlined, and the length and frequency of PROMs and resource use diaries will be reviewed to reduce the burden on patients and research nurses and to optimise data completeness., Trial Registration: Current Controlled Trials ISRCTN99760303., 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. 52. See the NIHR Journals Library website for further project information., Competing Interests: Ray Fitzpatrick is a member of the Health Technology Assessment Priority Research Advisory Methods Group. Richard Hindley has received payments for lecturing and proctoring for SonaCare Medical (Charlotte, NC, USA; high-intensity focused ultrasound treatment). Hashim U Ahmed reports grants and personal fees from SonaCare Medical and grants from Trod Medical (Heverlee, Belgium) and Sophiris Bio Inc. (La Jolla, CA, USA) outside the submitted work.

Objectives: To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment., Study Design and Setting: Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties., Results: One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was "best for them". Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation., Conclusions: The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation., (Copyright © 2018 University of Bristol. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10 -8 ) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10 -9 ; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10 -9 ; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

International government guidance recommends patient and public involvement (PPI) to improve the relevance and quality of research.  PPI is defined as research being carried out 'with' or 'by' patients and members of the public rather than 'to', 'about' or 'for' them ( http://www.invo.org.uk/). Patient involvement is different from collecting data from patients as participants.  Ethical considerations also differ.  PPI is about patients actively contributing through discussion to decisions about research design, acceptability, relevance, conduct and governance from study conception to dissemination.  Occasionally patients lead or do research.  The research methods of PPI range from informal discussions to partnership research approaches such as action research, co-production and co-learning. This article discusses how researchers can involve patients when they are applying for research funding and considers some opportunities and pitfalls.  It reviews research funder requirements, draws on the literature and our collective experiences as clinicians, patients, academics and members of UK funding panels., Competing Interests: No competing interests were disclosed.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Background: Femoroacetabular impingement syndrome is an important cause of hip pain in young adults. It can be treated by arthroscopic hip surgery, including reshaping the hip, or with physiotherapist-led conservative care. We aimed to compare the clinical effectiveness of hip arthroscopy with best conservative care., Methods: UK FASHIoN is a pragmatic, multicentre, assessor-blinded randomised controlled trial, done at 23 National Health Service hospitals in the UK. We enrolled patients with femoroacetabular impingement syndrome who presented at these hospitals. Eligible patients were at least 16 years old, had hip pain with radiographic features of cam or pincer morphology but no osteoarthritis, and were believed to be likely to benefit from hip arthroscopy. Patients with bilateral femoroacetabular impingement syndrome were eligible; only the most symptomatic hip was randomly assigned to treatment and followed-up. Participants were randomly allocated (1:1) to receive hip arthroscopy or personalised hip therapy (an individualised, supervised, and progressive physiotherapist-led programme of conservative care). Randomisation was stratified by impingement type and recruiting centre and was done by research staff at each hospital, using a central telephone randomisation service. Patients and treating clinicians were not masked to treatment allocation, but researchers who collected the outcome assessments and analysed the results were masked. The primary outcome was hip-related quality of life, as measured by the patient-reported International Hip Outcome Tool (iHOT-33) 12 months after randomisation, and analysed in all eligible participants who were allocated to treatment (the intention-to-treat population). This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN64081839, and is closed to recruitment., Findings: Between July 20, 2012, and July 15, 2016, we identified 648 eligible patients and recruited 348 participants: 171 participants were allocated to receive hip arthroscopy and 177 to receive personalised hip therapy. Three further patients were excluded from the trial after randomisation because they did not meet the eligibility criteria. Follow-up at the primary outcome assessment was 92% (319 of 348 participants). At 12 months after randomisation, mean iHOT-33 scores had improved from 39·2 (SD 20·9) to 58·8 (27·2) for participants in the hip arthroscopy group, and from 35·6 (18·2) to 49·7 (25·5) in the personalised hip therapy group. In the primary analysis, the mean difference in iHOT-33 scores, adjusted for impingement type, sex, baseline iHOT-33 score, and centre, was 6·8 (95% CI 1·7-12·0) in favour of hip arthroscopy (p=0·0093). This estimate of treatment effect exceeded the minimum clinically important difference (6·1 points). There were 147 patient-reported adverse events (in 100 [72%] of 138 patients) in the hip arthroscopy group) versus 102 events (in 88 [60%] of 146 patients) in the personalised hip therapy group, with muscle soreness being the most common of these (58 [42%] vs 69 [47%]). There were seven serious adverse events reported by participating hospitals. Five (83%) of six serious adverse events in the hip arthroscopy group were related to treatment, and the one in the personalised hip therapy group was not. There were no treatment-related deaths, but one patient in the hip arthroscopy group developed a hip joint infection after surgery., Interpretation: Hip arthroscopy and personalised hip therapy both improved hip-related quality of life for patients with femoroacetabular impingement syndrome. Hip arthroscopy led to a greater improvement than did personalised hip therapy, and this difference was clinically significant. Further follow-up will reveal whether the clinical benefits of hip arthroscopy are maintained and whether it is cost effective in the long term., Funding: The Health Technology Assessment Programme of the National Institute of Health Research., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The 4 kallikrein panel, commercially available as the 4Kscore®, is a statistical model that has been shown to accurately predict Gleason Grade Group 2 or greater (high grade) cancer on biopsy and the long-term risk of distant prostate cancer metastases. The panel includes 2 novel markers, namely intact prostate specific antigen and hK2. It has been questioned whether these 2 additional markers add discrimination to the clinical predictors of patient age, digital rectal examination and prior biopsy, and the established molecular markers total and free prostate specific antigen., Materials and Methods: We performed an individual patient data meta-analysis of published studies in which the 4 kallikrein panel was measured in men undergoing prostate biopsy. We assess the improvement in discrimination associated with including intact prostate specific antigen and hK2 along with total and free prostate specific antigen in the statistical model., Results: Included in analysis were 14,510 men from a total of 10 studies. The fixed effects meta-analytical estimate of the discrimination of the model without intact prostate specific antigen and hK2 was 0.742 (95% CI 0.727-0.756) compared to 0.813 (95% CI 0.801-0.825) for the full kallikrein model. The 95% CIs did not overlap and the difference in discrimination was highly statistically significant (0.069, 95% CI 0.057-0.080, p <0.0001). Intact prostate specific antigen (increase in discrimination 0.059, 95% CI 0.050-0.069) and hK2 (increase in discrimination 0.024, 95% CI 0.020-0.029, each p <0.0001) added independently to the model., Conclusions: The clinical value of the panel could not be replicated using data readily available to urologists without measuring intact prostate specific antigen and hK2., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Addressing the prevalence of severe obesity and its concomitant morbidities is widely acknowledged as one of the most pressing global health priorities. Nevertheless, a paucity of effective interventions and universal pressure on health-care budgets means that access to obesity treatments is often limited. Although health-care rationing can be conceived as a socially constructed process, little is known about how decisions emerge within the context of face-to-face doctor-patient interactions., Methods: In this study, we used in-depth interviews and clinic observations to investigate clinicians' (n = 11) and patients' (n = 22) experiences of the rationing of obesity surgery and to examine how broader cultural assumptions around personal responsibility for health emerged in the context of clinical interactions., Results: Patients and clinicians worked within similar frameworks when it came to self-responsibility for health and the appropriateness of providing publicly-funded weight loss surgery. Issues around personal accountability dominated consultations, and patients were expected to provide narratives of the development of their obesity and to account for the failure of previous interventions. Clinicians faced the added pressure of having to prioritise a limited number of patients for surgery, which was predominantly managed through mandating pre-referral weight loss targets., Discussion: Although clinicians sought to maintain an empathic attitude towards individual patients, in practice they were conflicted by their responsibility to ration health-care resources and tended to rely on entrenched models of behaviour change to allocate treatment. As a result, the content of consultations was mostly focused on issues of personal responsibility, reflecting wider stigmatized attitudes towards extreme obesity., (© 2017 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Despite accelerating interest in the impact of the internet on suicidal behaviour, empirical work has not captured detailed narratives from those who engaged in suicide-related internet use. This study explored the suicide-related online behaviour of two contrasting samples of distressed users, focusing on their purpose, methods and the main content viewed. In-depth interviews were conducted in the UK between 2014-2016 with i) young people in the community; and ii) self-harm patients presenting to hospital emergency departments. Data were analysed using methods of constant comparison. Suicide-related internet use varied according to the severity of suicidal feelings. In the young people sample, where severity was lower, use was characterised by disorganised browsing without clear purpose. A range of content was 'stumbled upon' including information about suicide methods. They also pursued opportunities to interact with others and explore online help. Self-harm patients were a higher severity group with a history of suicidal behaviour. Their use was purposeful and strategic, focused around 'researching' suicide methods to maximise effectiveness. They made specific choices about content viewed; many consulting factual content in preference to user generated accounts, while help content and communication was avoided. Findings indicate further action is necessary to improve online safety. Also, novel online help approaches are needed to engage individuals experiencing suicidal crisis. Awareness of the nature of suicide-related internet use and how this may reflect the status of an individual's suicidal thinking could be beneficial to clinicians to promote safety and indicate risk., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To develop a core information set for informed consent to surgery for oral/oropharyngeal surgery. A core information set is baseline information rated important by patients and surgeons and is intended to improve patients' understanding of the intended procedure., Design: A mixed-methods study. Systematic reviews of scientific and written healthcare literature, qualitative interviews and observations, Delphi surveys, and group consensus meetings identified information domains of importance for consent., Setting: A regional head and neck clinic in the United Kingdom. Questionnaire participants were recruited from around the UK., Participants: Patients about to undergo, or who had previously undergone, surgery for oral/oropharyngeal cancer. Healthcare professionals involved in the management of head and neck cancer., Main Outcome Measures: The main outcome was a core information set., Results: Systematic reviews, interviews and consultation observations yielded 887 pieces of information that were categorised into 87 information domains. Survey response rates were 67% (n = 50) and 71% (n = 52) for patient and healthcare professional groups in round one. More than 90% responded in each group in the second round. Healthcare professionals were more likely to rate information about short-term or peri-operative events as important while patients rated longer term issues about survival and quality of life. The consensus-building process resulted in an agreed core information set of 13 domains plus two procedure-specific domains about tracheostomy and free-flap surgery., Conclusion: This study produced a core information set for surgeons and patients to discuss before surgery for oral/oropharyngeal cancer. Future work will optimise ways to integrate core information into routine consultations., (© 2017 John Wiley & Sons Ltd.)

Background Cataract surgery is the most frequently undertaken NHS surgical procedure. Visual acuity (VA) provides a poor indication of visual difficulty in a complex visual world. In the absence of a suitable outcome metric, recent efforts have been directed towards the development of a cataract patient-reported outcome measure (PROM) of sufficient brevity, precision, and responsiveness to be implementable in routine high volume clinical services.Aim To compare and contrast the two most promising candidate PROMs for routine cataract surgery.Method The psychometric performance and patient acceptability of the recently UK developed five-item Cat-PROM5 questionnaire was compared with the English translation of the Swedish nine-item Catquest-9SF using Rasch-based performance metrics and qualitative semistructured interviews.Results Rasch-based performance was assessed in 822 typical NHS cataract surgery patients across four centres in England. Both questionnaires demonstrated good to excellent performance for all metrics assessed, including Person Reliability Indices of 0.90 (Cat-PROM5) and 0.88 (Catquest-9SF), responsiveness to surgery (Cohen's standardized effect size) of 1.45 SD (Cat-PROM5) and 1.47 SD (Catquest-9SF) and they were highly correlated with each other (R=0.85). Qualitative assessments confirmed that both questionnaires were acceptable to patients, including in the presence of ocular comorbidities. Preferences were expressed for the shorter Cat-PROM5, which allowed patients to map their own issues to the questions as opposed to the more restrictive specific scenarios of Catquest-9SF.Conclusion The recently UK developed Cat-PROM5 cataract surgery questionnaire is shorter, with performance and patient acceptability at least as good or better than the previous 'best of class' Catquest-9SF instrument.

PurposeTo develop a short, psychometrically robust and responsive cataract patient reported outcome measure suitable for use in high-volume surgical environments.MethodsA prospective study in which participants completed development versions of questionnaires exploring the quality of their eyesight using items harvested from two existing United Kingdom developed parent questionnaires. Participants were 822 patients awaiting cataract surgery recruited from 4 cataract surgical centres based in the UK. Exclusion criteria were other visually significant comorbidities and age <50 years. An iterative multi-stage process of evaluation using Rasch and factor analyses with sequential item reduction was undertaken.ResultsA definitive item set of just five items delivered performance in accordance with the requirements of the Rasch model: no threshold disordering, no misfitting items, Rasch-based reliability 0.90, person separation 2.98, Cronbach's α 0.89, good targeting of questions to patients with cataract with pre-operative item mean -0.41 logits and absence of significant floor or ceiling effects, minor deviations of item invariance, and confirmed unidimensionality. The test-re-test repeatability intra-class correlation coefficient was 0.89 with excellent responsiveness to surgery, Cohen's d -1.45 SD. Rasch calibration values are provided for Cat-PROM5 users.ConclusionsA psychometrically robust and highly responsive five-item cataract surgery patient reported outcome measure has been developed, which is suitable for use in high-volume cataract surgical services.

Objectives: Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability., Study Design and Setting: Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct., Results: The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa., Conclusion: The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

This corrects the article DOI: 10.1038/bjc.2017.231.

Importance: Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment., Objective: To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality., Design, Setting, and Participants: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016., Intervention: An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice., Main Outcomes and Measures: Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic., Results: Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95% CI, -0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66)., Conclusions and Relevance: Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening., Trial Registration: ISRCTN Identifier: ISRCTN92187251.

Objectives: The objective of this study was to describe and evaluate a training intervention for recruiting patients to randomized controlled trials (RCTs), particularly for those anticipated to be difficult for recruitment., Study Design and Setting: One of three training workshops was offered to surgeons and one to research nurses. Self-confidence in recruitment was measured through questionnaires before and up to 3 months after training; perceived impact of training on practice was assessed after. Data were analyzed using two-sample t-tests and supplemented with findings from the content analysis of free-text comments., Results: Sixty-seven surgeons and 32 nurses attended. Self-confidence scores for all 10 questions increased after training [range of mean scores before 5.1-6.9 and after 6.9-8.2 (scale 0-10, all 95% confidence intervals are above 0 and all P-values <0.05)]. Awareness of hidden challenges of recruitment following training was high-surgeons' mean score 8.8 [standard deviation (SD), 1.2] and nurses' 8.4 (SD, 1.3) (scale 0-10); 50% (19/38) of surgeons and 40% (10/25) of nurses reported on a 4-point Likert scale that training had made "a lot" of difference to their RCT discussions. Analysis of free text revealed this was mostly in relation to how to convey equipoise, explain randomization, and manage treatment preferences., Conclusion: Surgeons and research nurses reported increased self-confidence in discussing RCTs with patients, a raised awareness of hidden challenges and a positive impact on recruitment practice following QuinteT RCT Recruitment Training. Training will be made more available and evaluated in relation to recruitment rates and informed consent., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine whether age-related reference ranges for "normal" prostate-specific antigen (PSA) change (determined in men without prostate cancer) can be used to identify men at high risk of having prostate cancer., Methods: Subjects were men aged 50-69 years with PSA < 10 ng/mL from the UK-based Prostate Testing for cancer and Treatment (ProtecT) study. Men with prostate cancer were categorized as high or low risk of progression (Low risk: Gleason score ≤ 6 and stage T1-T2a; High risk: Gleason score 7-10 or stage T2C). Men without prostate cancer were those with no histological confirmation of prostate cancer. Previously developed longitudinal reference ranges for normal age-related PSA change were used to calculate an age-specific PSA threshold. We compared the ability of our age-specific PSA threshold to discriminate between high- and no/low-risk prostate cancer with that of two existing thresholds: (i) threshold of PSA = 3 ng/ml for all ages; (ii) National Institute of Clinical Excellence (NICE) guidelines dependent on age-group thresholds (age 50-59: PSA = 3 ng/mL; age 60-70: PSA = 4 ng/mL; age ≥ 70: PSA = 5 ng/mL)., Results: We included 823 men with high-risk prostate cancer and 80,721 men with no/low-risk prostate cancer. A threshold of PSA = 3 ng/ml for all ages identified more high-risk prostate cancers, recommending biopsy in 9.8% of men, of which 10.3% (n = 823) had high-risk prostate cancer. Using the NICE guidelines as the threshold for biopsy, 6.9% men were recommended for biopsy, of which 11.9% (n = 668) had high-risk prostate cancer. Using the new age-specific threshold for biopsy, 2.3% men were recommended for biopsy, of which 15.2% (n = 290) had high-risk prostate cancer. The age-specific threshold identified fewer high-risk prostate cancers, but fewer men received unnecessary biopsy., Conclusion: There is no benefit to using reference ranges for "normal" PSA that change with age nor the age-specific thresholds suggested by the NICE guidelines. While the age-varying thresholds are more discriminatory, too many high-risk cancers are missed.

Background: Arthroscopic sub-acromial decompression (decompressing the sub-acromial space by removing bone spurs and soft tissue arthroscopically) is a common surgery for subacromial shoulder pain, but its effectiveness is uncertain. We did a study to assess its effectiveness and to investigate the mechanism for surgical decompression., Methods: We did a multicentre, randomised, pragmatic, parallel group, placebo-controlled, three-group trial at 32 hospitals in the UK with 51 surgeons. Participants were patients who had subacromial pain for at least 3 months with intact rotator cuff tendons, were eligible for arthroscopic surgery, and had previously completed a non-operative management programme that included exercise therapy and at least one steroid injection. Exclusion criteria included a full-thickness torn rotator cuff. We randomly assigned participants (1:1:1) to arthroscopic subacromial decompression, investigational arthroscopy only, or no treatment (attendance of one reassessment appointment with a specialist shoulder clinician 3 months after study entry, but no intervention). Arthroscopy only was a placebo as the essential surgical element (bone and soft tissue removal) was omitted. We did the randomisation with a computer-generated minimisation system. In the surgical intervention groups, patients were not told which type of surgery they were receiving (to ensure masking). Patients were followed up at 6 months and 1 year after randomisation; surgeons coordinated their waiting lists to schedule surgeries as close as possible to randomisation. The primary outcome was the Oxford Shoulder Score (0 [worst] to 48 [best]) at 6 months, analysed by intention to treat. The sample size calculation was based upon a target difference of 4·5 points (SD 9·0). This trial has been registered at ClinicalTrials.gov, number NCT01623011., Findings: Between Sept 14, 2012, and June 16, 2015, we randomly assigned 313 patients to treatment groups (106 to decompression surgery, 103 to arthroscopy only, and 104 to no treatment). 24 [23%], 43 [42%], and 12 [12%] of the decompression, arthroscopy only, and no treatment groups, respectively, did not receive their assigned treatment by 6 months. At 6 months, data for the Oxford Shoulder Score were available for 90 patients assigned to decompression, 94 to arthroscopy, and 90 to no treatment. Mean Oxford Shoulder Score did not differ between the two surgical groups at 6 months (decompression mean 32·7 points [SD 11·6] vs arthroscopy mean 34·2 points [9·2]; mean difference -1·3 points (95% CI -3·9 to 1·3, p=0·3141). Both surgical groups showed a small benefit over no treatment (mean 29·4 points [SD 11·9], mean difference vs decompression 2·8 points [95% CI 0·5-5·2], p=0·0186; mean difference vs arthroscopy 4·2 [1·8-6·6], p=0·0014) but these differences were not clinically important. There were six study-related complications that were all frozen shoulders (in two patients in each group)., Interpretation: Surgical groups had better outcomes for shoulder pain and function compared with no treatment but this difference was not clinically important. Additionally, surgical decompression appeared to offer no extra benefit over arthroscopy only. The difference between the surgical groups and no treatment might be the result of, for instance, a placebo effect or postoperative physiotherapy. The findings question the value of this operation for these indications, and this should be communicated to patients during the shared treatment decision-making process., Funding: Arthritis Research UK, the National Institute for Health Research Biomedical Research Centre, and the Royal College of Surgeons (England)., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Research has shown that recruitment to trials is a process that stretches from identifying potentially eligible patients, through eligibility assessment, to obtaining informed consent. The length and complexity of this pathway means that many patients do not have the opportunity to consider participation. This article presents the development of a simple framework to document, understand and improve the process of trial recruitment., Methods: Eight RCTs integrated a QuinteT Recruitment Intervention (QRI) into the main trial, feasibility or pilot study. Part of the QRI required mapping the patient recruitment pathway using trial-specific screening and recruitment logs. A content analysis compared the logs to identify aspects of the recruitment pathway and process that were useful in monitoring and improving recruitment. Findings were synthesised to develop an optimised simple framework that can be used in a wide range of RCTs., Results: The eight trials recorded basic information about patients screened for trial participation and randomisation outcome. Three trials systematically recorded reasons why an individual was not enrolled in the trial, and further details why they were not eligible or approached, or declined randomisation. A framework to facilitate clearer recording of the recruitment process and reasons for non-participation was developed: SEAR - Screening, to identify potentially eligible trial participants; Eligibility, assessed against the trial protocol inclusion/exclusion criteria; Approach, the provision of oral and written information and invitation to participate in the trial, and Randomised or not, with the outcome of randomisation or treatment received., Conclusions: The SEAR framework encourages the collection of information to identify recruitment obstacles and facilitate improvements to the recruitment process. SEAR can be adapted to monitor recruitment to most RCTs, but is likely to add most value in trials where recruitment problems are anticipated or evident. Further work to test it more widely is recommended.

Background: There is ongoing debate about the harms and benefits of a national prostate cancer screening programme. Several model-based cost-effectiveness analyses have been developed to determine whether the benefits of prostate cancer screening outweigh the costs and harms caused by over-detection and over-treatment, and the different approaches may impact results., Methods: To identify models of prostate cancer used to assess the cost-effectiveness of prostate cancer screening strategies, a systematic review of articles published since 2006 was conducted using the NHS Economic Evaluation Database, Medline, EMBASE and HTA databases. The NICE website, UK National Screening website, reference lists from relevant studies were also searched and experts contacted. Key model features, inputs, and cost-effectiveness recommendations were extracted., Results: Ten studies were included. Four of the studies identified some screening strategies to be potentially cost-effective at a PSA threshold of 3.0 ng/ml, including single screen at 55 years, annual or two yearly screens starting at 55 years old, and delayed radical treatment. Prostate cancer screening was modelled using both individual and cohort level models. Model pathways to reflect cancer progression varied widely, Gleason grade was not always considered and clinical verification was rarely outlined. Where quality of life was considered, the methods used did not follow recommended practice and key issues of overdiagnosis and overtreatment were not addressed by all studies., Conclusion: The cost-effectiveness of prostate cancer screening is unclear. There was no consensus on the optimal model type or approach to model prostate cancer progression. Due to limited data availability, individual patient-level modelling is unlikely to increase the accuracy of cost-effectiveness results compared with cohort-level modelling, but is more suitable when assessing adaptive screening strategies. Modelling prostate cancer is challenging and the justification for the data used and the approach to modelling natural disease progression was lacking. Country-specific data are required and recommended methods used to incorporate quality of life. Influence of data inputs on cost-effectiveness results need to be comprehensively assessed and the model structure and assumptions verified by clinical experts.

The American College of Chest Physicians guidelines recommend unfractionated heparin (UFH), low molecular weight heparins (LMWHs) or fondaparinux for prevention of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in medically-ill patients. Direct oral anticoagulants (DOACs) have been evaluated relative to enoxaparin for VTE prophylaxis though head-to-head comparisons of these agents are lacking. Therefore, we conducted a mixed treatment comparisons meta-analysis to evaluate the safety and efficacy of established treatments and DOACs for VTE prophylaxis in medically-ill patients. A comprehensive literature search was conducted to identify randomized trials evaluating UFH, LMWHs or DOACS for the prevention of VTE in medically ill patients. Articles were retrieved and cross-referenced for additional trials, evaluated and entered into ADDIS (version 1.16.6) to generate direct and indirect treatment comparisons for VTE, DVT, PE, death from any cause, and bleeding. Ten articles were included and eight anticoagulants were evaluated in a treatment network representing data on 28,382 patients. We found each treatment had similar efficacy in preventing VTE, DVT, PE, death from any cause and each had similar risk of minor and major bleeding. Overall, placebo was associated with more VTE and DVT events compared to LMWHs and DOACs. We found that UFH, LMWHs and DOACs are comparable in preventing VTE, DVT, PE, and death from any cause and in association with minor and major bleeding. Anticoagulant selection for VTE prophylaxis in medically-ill patients should be individualized by patient characteristics, risks and preferences along with specific pharmacokinetic and pharmacodynamic considerations.

Context: The importance of evidence from randomised trials is now widely recognised, although recruitment is often difficult. Qualitative research has shown promise in identifying the key barriers to recruitment, and interventions have been developed to reduce organisational difficulties and support clinicians undertaking recruitment., Objective: This article provides an introduction to qualitative research techniques and explains how this approach can be used to understand-and subsequently improve-recruitment and informed consent within a range of clinical trials., Evidence Acquisition: A literature search was performed using Medline, Embase, and CINAHL. All studies with qualitative research methods that focused on the recruitment activity of clinicians were included in the review., Evidence Synthesis: The majority of studies reported that organisational difficulties and lack of time for clinical staff were key barriers to recruitment. However, a synthesis of qualitative studies highlighted the intellectual and emotional challenges that arise when combining research with clinical roles, particularly in relation to equipoise and patient eligibility. To support recruiters to become more comfortable with the design and principles of randomised controlled trials, interventions have been developed, including the QuinteT Recruitment Intervention, which comprises in-depth investigation of recruitment obstacles in real time, followed by implementation of tailored strategies to address these challenges as the trial proceeds., Conclusions: Qualitative research can provide important insights into the complexities of recruitment to trials and inform the development of interventions, and provide support and training initiatives as required. Investigators should consider implementing such methods in trials expected to be challenging or recruiting below target., Patient Summary: Qualitative research is a term used to describe a range of methods that can be implemented to understand participants' perspectives and behaviours. Data are gathered from interviews, focus groups, or observations. In this review, we demonstrate how this approach can be used to understand-and improve-recruitment to clinical trials. Taken together, our review suggests that healthcare professionals can find recruiting to trials challenging and require support with this process., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Randomized controlled trials (RCTs) involving surgical procedures are challenging for recruitment and infrequent in the specialty of bariatrics. The pilot phase of the By-Band-Sleeve study (gastric bypass versus gastric band versus sleeve gastrectomy) provided the opportunity for an investigation of recruitment using a qualitative research integrated in trials (QuinteT) recruitment intervention (QRI)., Patients/methods: The QRI investigated recruitment in two centers in the pilot phase comparing bypass and banding, through the analysis of 12 in-depth staff interviews, 84 audio recordings of patient consultations, 19 non-participant observations of consultations and patient screening data. QRI findings were developed into a plan of action and fed back to centers to improve information provision and recruitment organization., Results: Recruitment proved to be extremely difficult with only two patients recruited during the first 2 months. The pivotal issue in Center A was that an effective and established clinical service could not easily adapt to the needs of the RCT. There was little scope to present RCT details or ensure efficient eligibility assessment, and recruiters struggled to convey equipoise. Following presentation of QRI findings, recruitment in Center A increased from 9% in the first 2 months (2/22) to 40% (26/65) in the 4 months thereafter. Center B, commencing recruitment 3 months after Center A, learnt from the emerging issues in Center A and set up a special clinic for trial recruitment. The trial successfully completed pilot recruitment and progressed to the main phase across 11 centers., Conclusions: The QRI identified key issues that enabled the integration of the trial into the clinical setting. This contributed to successful recruitment in the By-Band-Sleeve trial-currently the largest in bariatric practice-and offers opportunities to optimize recruitment in other trials in bariatrics.

Objectives: Cross-sectional studies suggest that around 6% of men undergo prostate-specific antigen (PSA) testing each year in UK general practice (GP). This longitudinal study aims to determine the cumulative testing pattern of men over a 10-year period and whether this testing can be considered equivalent to screening for prostate cancer (PCa)., Setting, Participants and Outcome Measures: Patient-level data on PSA tests, biopsies and PCa diagnoses were obtained from the UK Clinical Practice Research Datalink (CPRD) for the years 2002 to 2011. The cumulative risks of PSA testing and of being diagnosed with PCa were estimated for the 10-year study period. Associations of a man's age, region and index of multiple deprivation with the cumulative risk of PSA testing and PCa diagnosis were investigated. Rates of biopsy and diagnosis, following a high test result, were compared with those from the programme of PSA testing in the Prostate Testing for Cancer and Treatment (ProtecT) study., Results: The 10-year risk of exposure to at least one PSA test in men aged 45 to 69 years in UK GP was 39.2% (95% CI 39.0 to 39.4%). The age-specific risks ranged from 25.2% for men aged 45-49 years to 53.0% for men aged 65-69 years (p for trend <0.001). For those with a PSA level ≥3, a test in UK GP was less likely to result in a biopsy (6%) and/or diagnosis of PCa (15%) compared with ProtecT study participants (85% and 34%, respectively)., Conclusion: A high proportion of men aged 45-69 years undergo PSA tests in UK GP: 39% over a 10-year period. A high proportion of these tests appear to be for the investigation of lower urinary tract symptoms and not screening for PCa., Trial Registration Number: ISRCTN20141297,NCT02044172., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Self-harm and suicide increase in times of economic recession. Factors including job loss, austerity measures, financial difficulties and house repossession contribute to the risk. Vulnerable individuals commonly experience difficulties in navigating the benefits system and in accessing the available sources of welfare and debt advice, and this contributes to their distress. Our aim is to determine the feasibility and acceptability of a brief psychosocial intervention (the "HOPE" service) for people presenting to hospital emergency departments (ED) following self-harm or in acute distress because of financial, employment, or welfare (benefit) difficulties., Method: A pilot study including randomisation will be employed to determine whether it is possible to undertake a full-scale trial. Twenty people presenting to the ED who have self-harmed, have suicidal thoughts and depression and/or are in crisis and where financial, employment or benefit problems are cited as contributory factors will be asked to consent to random allocation to the intervention or control arm on a 2:1 basis. People who require secondary mental health follow-up will be excluded. Those randomised to the intervention arm will receive up to six sessions with a mental health worker who will provide practical help with financial and other problems. The mental health worker will use the motivational interviewing method in their interactions with participants. Control participants will receive one session signposting them to existing relevant support organisations. Participants will be followed up after 3 months. Participants and the mental health workers will take part in qualitative interviews to enable refinement of the intervention. The acceptability of outcome measures including the PHQ-9, GAD-7, repeat self-harm, EQ5D-5L and questions about debt, employment and welfare benefits will be explored., Discussion: This study will assess whether a full-scale randomised trial of this novel intervention to prevent self-harm among those distressed because of financial difficulties is feasible, including the acceptability of randomisation, potential rate of recruitment and the acceptability of outcome measures., Trial Registration: ISRCTN58531248.

Background and Purpose: To describe the incorporation of the American Pharmacists Association (APhA) Delivering Medication Therapy Management (MTM) Services program into a PharmD curriculum and to describe student perceptions of the program., Educational Activity and Setting: The program was delivered over 12 months to students on two campuses via two didactic courses in the second professional year and during the first two advanced pharmacy practice experiences in the third professional year of an accelerated school of pharmacy program., Findings: Student perceptions were assessed by review of responses to the APhA MTM program evaluation survey., Discussion and Summary: Incorporation of the APhA MTM program into an accelerated PharmD program required careful planning and coordination amongst faculty and course coordinators. Students perceived that the program was valuable, met their educational needs, and incorporated effective learning experiences and cases. These perceptions were reinforced by the high percentage of students who completed the program., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Surgical site infections (SSIs) are common, occurring in up to 25% of > 4 million operations performed in England each year. Previous trials of the effect of wound dressings on the risk of developing a SSI are of poor quality and underpowered., Methods/design: This study is a feasibility and pilot trial to examine the feasibility of a full trial that will compare simple dressings, no dressing and tissue-glue as a dressing. It is examining the overall acceptability of trial participation, identifying opportunities for refinement, testing the feasibility of and validating new outcome tools to assess SSI, wound management issues and patients' wound symptom experiences. It is also exploring methods for avoiding performance bias and blinding outcome assessors by testing the feasibility of collecting wound photographs taken in theatre immediately after wound closure and, at 4-8 weeks after surgery, taken by participants themselves or their carers. Finally, it is identifying the main cost drivers for an economic evaluation of dressing types. Integrated qualitative research is exploring acceptability and reasons for non-adherence to allocation. Adults undergoing primary elective or unplanned abdominal general surgery or Caesarean section are eligible. The main exclusion criteria are abdominal or other major surgery less than three months before the index operation or contraindication to dressing allocation. The trial is scheduled to recruit for nine months. The findings will be used to inform the design of a main trial., Discussion: This pilot trial is the first pragmatic study to randomise participants to no dressing or tissue-glue as a dressing versus a simple dressing. Early evidence from the ongoing pilot shows that recruitment is proceeding well and that the interventions are acceptable to participants. Combined with the qualitative findings, the findings will inform whether a main, large trial is feasible and, if so, how it should be designed., Trial Registration: ISRCTN49328913 . Registered on 20 October 2015.

Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer., Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions., Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group., Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.

Objectives: To determine the effects of low-to-moderate levels of maternal alcohol consumption in pregnancy on pregnancy and longer-term offspring outcomes., Search Strategy: Medline, Embase, Web of Science and Psychinfo from inception to 11 July 2016., Selection Criteria: Prospective observational studies, negative control and quasiexperimental studies of pregnant women estimating effects of light drinking in pregnancy (≤32 g/week) versus abstaining. Pregnancy outcomes such as birth weight and features of fetal alcohol syndrome were examined., Data Collection and Analysis: One reviewer extracted data and another checked extracted data. Random effects meta-analyses were performed where applicable, and a narrative summary of findings was carried out otherwise., Main Results: 24 cohort and two quasiexperimental studies were included. With the exception of birth size and gestational age, there was insufficient data to meta-analyse or make robust conclusions. Odds of small for gestational age (SGA) and preterm birth were higher for babies whose mothers consumed up to 32 g/week versus none, but estimates for preterm birth were also compatible with no association: summary OR 1.08, 95% CI (1.02 to 1.14), I 2 0%, (seven studies, all estimates were adjusted) OR 1.10, 95% CI (0.95 to 1.28), I 2 60%, (nine studies, includes one unadjusted estimates), respectively. The earliest time points of exposure were used in the analysis., Conclusion: Evidence of the effects of drinking ≤32 g/week in pregnancy is sparse. As there was some evidence that even light prenatal alcohol consumption is associated with being SGA and preterm delivery, guidance could advise abstention as a precautionary principle but should explain the paucity of evidence., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention., Methods: The By-Band study was designed in the UK in 2009-2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux-en-Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation., Results: The pilot phase recruited over 13 months in 2013-2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder., Conclusion: Adaptation of a two-group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (http://www.isrctn.com/)., (© 2017 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Purpose: The insulin-like growth factor (IGF) system is modifiable by diet and lifestyle, and has been linked to prostate cancer development and progression., Methods: We conducted a prospective cohort study of 621 men diagnosed with localized prostate cancer to investigate the associations of dietary and lifestyle changes with post-diagnosis circulating levels of IGF-I and IGFBP-3. We used analysis of covariance to estimate the associations, controlling for baseline IGF-I or IGFBP-3, respectively., Results: Mean IGF-I levels were 6.5% (95% CI -12.8, -0.3%, p = 0.04) lower in men who decreased their protein intake after diagnosis compared to men who did not change. Men who changed their fruit and vegetable intake had lower IGF-I levels compared to non-changers [Decreased intake: -10.1%, 95% CI -18.4, -1.8%, p = 0.02; Increased intake: -12.0%, 95% CI -18.4, -1.8%, p = 0.002]. IGFBP-3 was 14.6% (95% CI -24.5, -4.8%, p = 0.004) lower in men who achieved a healthy body mass index after diagnosis. Men who became inactive had 9.5% higher average IGF-I levels (95% CI 0.1, 18.9%, p = 0.05)., Conclusions: Decreased protein intake and body mass index, and increased physical activity and fruit and vegetable intake, following a prostate cancer diagnosis were associated with reduced post-diagnosis serum IGF-I and IGFBP-3. Counterintuitively, reduced fruit and vegetable intake was also associated with reduced IGF-I, but with weak statistical support, possibly implicating chance. If confirmed in other studies, our findings may inform potential lifestyle interventions in prostate cancer. ProtecT was registered at International Standard Randomised Controlled Trial Registry, http://isrctn.org as ISRCTN20141297.

Background: Informed consent (IC) is an ethical and legal prerequisite for trial participation, yet current approaches evaluating participant understanding for IC during recruitment lack consistency. No validated measure has been identified that evaluates participant understanding for IC based on their contributions during consent interactions. This paper outlines the development and formative evaluation of the Participatory and Informed Consent (PIC) measure for application to recorded recruitment appointments. The PIC allows the evaluation of recruiter information provision and evidence of participant understanding., Methods: Published guidelines for IC were reviewed to identify potential items for inclusion. Seventeen purposively sampled trial recruitment appointments from three diverse trials were reviewed to identify the presence of items relevant to IC. A developmental version of the measure (DevPICv1) was drafted and applied to six further recruitment appointments from three further diverse trials to evaluate feasibility, validity, stability and inter-rater reliability. Findings guided revision of the measure (DevPICv2) which was applied to six further recruitment appointments as above., Results: DevPICv1 assessed recruiter information provision (detail and clarity assessed separately) and participant talk (detail and understanding assessed separately) over 20 parameters (or 23 parameters for three-arm trials). Initial application of the measure to six diverse recruitment appointments demonstrated promising stability and inter-rater reliability but a need to simplify the measure to shorten time for completion. The revised measure (DevPICv2) combined assessment of detail and clarity of recruiter information and detail and evidence of participant understanding into two single scales for application to 22 parameters or 25 parameters for three-arm trials. Application of DevPICv2 to six further diverse recruitment appointments showed considerable improvements in feasibility (e.g. time to complete) with good levels of stability (i.e. test-retest reliability) and inter-rater reliability maintained., Conclusions: The DevPICv2 provides a measure for application to trial recruitment appointments to evaluate quality of recruiter information provision and evidence of patient understanding and participation during IC discussions. Initial evaluation shows promising feasibility, validity, reliability and ability to discriminate across a range of recruiter practice and evidence of participant understanding. More validation work is needed in new clinical trials to evaluate and refine the measure further.

Background: A research register (Reach West) has been established to facilitate recruitment of people and patients to health-related research. We conducted a prospective feasibility study to investigate the practicality of recruiting through outpatient clinics., Methods: Patients over 18 years of age attending dental, eye or oncology outpatient clinics in an acute hospital in the West of England were provided with the opportunity to participate in Reach West. In Phase I, recruitment packs were handed to clinic attendees who could place completed consent forms in secure drop-box or return them later on-line or by post. In Phase II, recruitment packs were posted directly to patients with consent forms to be returned by post or on-line. Response rates by age, sex, postcode (for level of deprivation), and clinic type were recorded for those agreeing to participate on paper or on-line., Results: In Phase I, 2,314 of 4,500 (51.4%) of recruitment packs were handed out to clinic attendees, and 114 (5%) consented to join Reach West. In Phase II, 7,173 of 9000 packs were posted (79.7%), and 387 (5.4%) consented to participate. The overall consent rate was 6% (580), with the majority doing so on paper (87%) rather than on-line. The sample was balanced by sex, but mostly comprised people over 50 years located in less deprived postcodes. Non-staff costs for postal recruitment were lower than hand-outs in clinic (£6.84 compared with £8.05 per participant)., Conclusions: Recruiting participants to the Reach West register was feasible among those with oncology, dental or eye outpatient appointments by post or with packs given out in the clinic. Response rates were similar to those achieved for other registers. Recruitment of participants can be achieved through outpatient clinics but other strategies will also be required to attract large numbers of participants and more diverse populations.