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Objective: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. Materials and Methods: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55–69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55–59, 60–64 and 65–69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. Results: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55–59 years was 0.96 (95% confidence interval [CI] 0.75–1.24) in Finland, 0.70 (95% CI 0.44–1.12) in the Netherlands and 0.42 (95% CI 0.24–0.73) in Sweden. The HR for men aged 60–64 years was 1.03 (95% CI 0.77–1.37) in Finland, 0.76 (95% CI 0.50–1.16) in the Netherlands and 0.97 (95% CI 0.64–1.48) in Sweden. The HR for men aged 65–69 years was 0.80 (95% CI 0.62–1.03) in Finland and 0.57 (95% CI 0.38–0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56–0.82) in Finland, 0.28 (95% CI 0.18–0.44) in the Netherlands, and 0.48 (95% CI 0.30–0.78) in Sweden. Conclusion: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift. [ABSTRACT FROM AUTHOR]

Background: Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles. Objectives: To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials. Search strategy: The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Selection criteria: Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data. Data collection and analysis: An individual participant data meta‐analysis was carried out. Main results: Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low‐dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low‐dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low‐dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low‐dose vaginal misoprostol (aOR 0.80, 95% CI 0.65–0.98, P = 0.03, I2 = 0%). Conclusions: Low‐dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low‐dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone. This article includes Author Insights, a video abstract available at: https://vimeo.com/915799731. [ABSTRACT FROM AUTHOR]

Better data are fundamental to improving the effectiveness of policies. Drawing on examples from nutrition, education, criminal justice and income support, I discuss how data access has contributed to policy improvements. Data linkage across departments can also help ensure that policymakers are focussed on the right policy goals, rather than merely those that are easiest to measure. As governments increase the rigour of evaluation, quality data will be crucial. [ABSTRACT FROM AUTHOR]

Objective: To review the ongoing randomised trials of cytoreductive prostatectomy (CRP) in de novo hormone‐sensitive metastatic prostate cancer (HSPC) in order to identify their goals and assess their strengths and weaknesses. Methods: PubMed, MEDLINE and clinical trials websites searches were performed to identify currently ongoing trials of CRP in de novo HSPC. Results: Nine randomised clinical trials in CRP were identified and included: Southwest Oncology Group (SWOG) 1802, Surgery in Metastatic Carcinoma of Prostate (SIMCAP), Adjuvant Treatments to the Local Tumour for Metastatic Prostate Cancer: Assessment of Novel Treatment Algorithms (IP2‐ATLANTA), Testing Radical prostatectomy in men with prostate cancer and oligoMetastases to the bone (TRoMbone), Impact of Radical Prostatectomy as Primary Treatment in Patients with Prostate Cancer with Limited Bone Metastases (g‐RAMPP), Cytoreductive Prostatectomy vs Cytoreductive Prostate Irradiation as a Local Treatment Option for Metastatic Prostate Cancer: a Multicentric Feasibility Trial (LoMP II), Androgen‐Deprivation Therapy or Androgen‐Deprivation Therapy Plus Definitive Treatment (Radiation or Surgery) (FUSCC‐OMPCa), and the Testing Radical Prostatectomy in Chinese Men with Prostate Cancer and oligoMetastases to the Bone study. Each study was different; assessing various primary outcome measures including overall survival (OS), progression‐free survival and feasibility to randomise between standard therapy and CRP or between radiation therapy and CRP in the metastatic setting. In the oligometastatic setting, the trials assess OS, feasibility to randomise and time to castration resistance. Similarly, a number of secondary endpoints ranging from cancer‐specific outcomes to quality‐of‐life outcomes are being investigated. The inclusion criteria in these trials also varied in terms of volume of metastatic disease (oligometastatic to high‐volume metastatic disease), diagnosis of metastases (imaging based vs biopsy confirmed), imaging modalities used (conventional to newer modalities), as well as outcomes and follow‐up regimes. Conclusion: While there are differences in each protocol, each trial aims to address different aspects of CRP in de novo HSPC. Therefore, the specific goals of each study and the limitations have to be taken into consideration when interpreting the results of these trials. [ABSTRACT FROM AUTHOR]

Outcomes in a clinical trial can be affected by any underlying preferences that its participants have for the treatments under comparison and by whether they actually receive their preferred treatment. These effects cannot be evaluated in standard trial designs but are estimable in the alternative two-stage randomised trial design, in which some patients can choose their treatment, while the rest are randomly assigned. We have previously shown that, when all two-stage trial participants have a preferred treatment, the preference effects can be evaluated, in addition to the usual direct effect of treatment. We also determined criteria by which to optimise how many participants should be given a choice of treatment vs being randomised. More recently, we extended our methodology to allow for participants who are unable or unwilling to express a treatment preference if they are assigned to the choice group. In this paper, we show how to optimise the two-stage design when some participants are undecided about their treatment. We demonstrate that the undecided group should be regarded as distinct in the analysis, to obtain valid estimates of the preference effects. We derive the optimal proportion of participants who should be offered a choice of treatment, which in many cases will be close to 50%. More generally, the optima depend on the preference rates for treatments and the proportion of undecided participants, and the parameters of primary interest. We discuss some advantages and disadvantages of the two-stage trial design in this situation and describe a practical example. [ABSTRACT FROM AUTHOR]

Rich meta-epidemiological data sets have been collected to explore associations between intervention effect estimates and study-level characteristics. Welton et al proposed models for the analysis of meta-epidemiological data, but these models are restrictive because they force heterogeneity among studies with a particular characteristic to be at least as large as that among studies without the characteristic. In this paper we present alternative models that are invariant to the labels defining the 2 categories of studies. To exemplify the methods, we use a collection of meta-analyses in which the Cochrane Risk of Bias tool has been implemented. We first investigate the influence of small trial sample sizes (less than 100 participants), before investigating the influence of multiple methodological flaws (inadequate or unclear sequence generation, allocation concealment, and blinding). We fit both the Welton et al model and our proposed label-invariant model and compare the results. Estimates of mean bias associated with the trial characteristics and of between-trial variances are not very sensitive to the choice of model. Results from fitting a univariable model show that heterogeneity variance is, on average, 88% greater among trials with less than 100 participants. On the basis of a multivariable model, heterogeneity variance is, on average, 25% greater among trials with inadequate/unclear sequence generation, 51% greater among trials with inadequate/unclear blinding, and 23% lower among trials with inadequate/unclear allocation concealment, although the 95% intervals for these ratios are very wide. Our proposed label-invariant models for meta-epidemiological data analysis facilitate investigations of between-study heterogeneity attributable to certain study characteristics. [ABSTRACT FROM AUTHOR]

Randomised controlled trials ( RCTs) are typically viewed as the gold standard for causal inference. This is because effects of interest can be identified with the fewest assumptions, especially imbalance in background characteristics. Yet because conducting RCTs are expensive, time consuming and sometimes unethical, observational studies are frequently used to study causal associations. In these studies, imbalance, or confounding, is usually controlled with multiple regression, which entails strong assumptions. The purpose of this manuscript is to describe strengths and weaknesses of several methods to control for confounding in observational studies, and to demonstrate their use in cross-sectional dataset that use patient registration data from the Juan Pablo II Primary Care Clinic in La Pintana-Chile. The dataset contains responses from 5855 families who provided complete information on family socio-demographics, family functioning and health problems among their family members. We employ regression adjustment, stratification, restriction, matching, propensity score matching, standardisation and inverse probability weighting to illustrate the approaches to better causal inference in non-experimental data and compare results. By applying study design and data analysis techniques that control for confounding in different ways than regression adjustment, researchers may strengthen the scientific relevance of observational studies. [ABSTRACT FROM AUTHOR]

A key component of the Cochrane Collaboration's risk of bias tool for critically evaluating randomised trials is the consideration of whether baseline characteristics of the treatment groups being compared are systematically different. Considered under the domain of 'selection bias', this is currently evaluated by looking at the methods of randomisation and specifically at the generation of the randomised allocation sequence and the concealment of this sequence during the process of randomisation. Assessment of the actual similarity of baseline variables across groups in demographic and clinical characteristics is seldom performed. Even when performed, the link with selection bias is sometimes not considered. Methods of randomisation and allocation concealment are often poorly reported in published trials, yet baseline data tables are presented in a large majority of trial reports. In this article, we propose that assessment of trial baseline data should form a key and prominent part of selection bias judgements when using the risk of bias tool. We outline the possible benefits from using this approach, including reduced uncertainty in systematic review conclusions, reduced risk of chance findings being ascribed to treatment effects and better use of available evidence by a more considered approach to evaluating studies using imperfect randomisation and allocation methods. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Induction of labour (IOL) is an increasingly common obstetric intervention globally. There is a choice of mechanical or pharmacological methods for induction of labour when the cervix is unfavorable. Which approach is both effective and safe however is not clear due to how trials are designed and reported. A tradeoff between the common primary outcomes of vaginal birth or time to delivery and rare safety outcomes mean trials are underpowered to determine both. There is also a lack of reporting of the indications for the operative births (prolonged labour or fetal compromise) and their relationship to each IOL method. We recommend that future trials should be large enough to adequately assess both effectiveness and safety outcomes, and that the indications for operative birth are also reported. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

Outcomes in clinical trials may be affected by the choice of treatment that participants might make, if they were indeed allowed to choose (a so-called selection effect), and by whether they actually receive their preferred treatment (a preference effect). Selection and preference effects can be important, but they cannot be estimated in the conventional trial design. An alternative approach is the two-stage randomised trial, in which participants are first randomly divided into two subgroups. In one subgroup, participants are randomly assigned to treatments, while in the other, participants are allowed to choose their own treatment. This approach yields estimates of the direct treatment effect, and of the preference and selection effects. The latter two provide insight that goes considerably beyond what is possible in the standard randomised trial. In this paper, we determine the optimal proportion of participants who should be allocated to the choice subgroup. The precision of the estimated selection, preference and treatment effects are functions of: the total sample size; the proportion of participants allocated to choose their treatment; the variances of the outcome; the proportions of participants who select each treatment in the choice group; and the selection, preference and treatment effects themselves. We develop general expressions for the optimum proportion of participants in the choice group, depending on which effects are of primary interest. We illustrate the results with trial data comparing alternative clinical management strategies for women with abnormal results on cervical screening. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2weeks, with an intervening washout period of 2–4weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p =0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size. [Copyright &y& Elsevier]

Abstract: In psychological health treatment studies it has been shown that differences between therapists account for some of the non-specific effect of treatment but this phenomenon has not so far systematically been investigated in musculoskeletal disorders. In this study we evaluated and compared the size and potential influence of the ‘practitioner effect’ (or ‘therapist effect’) in three randomised treatment trials of low back pain and neck pain patients in primary care. We calculated the proportion of variance in outcomes attributable to differences across practitioners, i.e. the practitioner–variance partition coefficient (p–vpc). As measures of outcome, we focused on self-reported disability as the primary outcome, but we also investigated assessed psychological outcomes. The p–vpc for the disability measures ranged from 2.6% to 7.1% across trials and time points (post treatment and follow up). Estimates differed between treatment subgroups within trials; being highest in treatment subgroups assigned to psychosocial-based interventions. A ‘practitioner effect’ does exist and is more pronounced in treatments involving greater psychosocial emphasis. This has implications for both practice and research in this clinical area. It highlights the importance of patient–practitioner interactions, and the need to address practitioner effects in designing and analysing outcome studies in low back pain and neck pain in primary care. [Copyright &y& Elsevier]

Background Numerous randomised studies have reported pregnancy outcome in women who received acupuncture during their in vitro fertilisation (IVF) treatment cycle. Objective The objective of this study was to conduct a systematic review with meta-analysis of the trials of acupuncture during IVF treatment on the outcomes of clinical pregnancy and live birth rates. Search strategy Searches were conducted in MEDLINE, EMBASE, Cochrane Library, ISI Proceedings and SCISEARCH. Selection criteria All randomised controlled trials that evaluated the effects of acupuncture compared with no treatment or sham acupuncture in women undergoing IVF–intracytoplasmic sperm injection treatment were included. Data collection and analysis Study selection, quality appraisal and data extraction were performed independently and in duplicate. A sensitivity analysis was conducted where the meta-analysis was restricted to trials in which sham acupuncture was used in the control group. Meta-regression analysis was used to explore the association between study characteristics and pregnancy rates. Main results Thirteen relevant trials, including a total of 2500 women randomised to either acupuncture or control group, were identified. No evidence of publication bias was found (Begg’s test, P = 0.50). Five trials ( n = 877) evaluated IVF outcome when acupuncture was performed around the time of transvaginal oocyte retrieval, while eight trials ( n = 1623) reported IVF outcome when acupuncture was performed around the time of embryo transfer (ET). Meta-analysis of the five studies of acupuncture around the time of egg collection did not show a significant difference in clinical pregnancy (relative risks [RR] = 1.06, 95% CI 0.82–1.37, P = 0.65). Meta-analysis of the eight studies of acupuncture around the time of ET showed no difference in the clinical pregnancy rate (RR = 1.23, 95% CI 0.96–1.58, P = 0.1). Live birth data were available from five of the eight studies of acupuncture around the time of ET. Meta-analysis of these studies did not show a significant increase in live birth rate with acupuncture (RR = 1.34, 95% CI 0.85–2.11). Using meta-regression, no significant association between any of the studied covariates and clinical pregnancy rate was found ( P > 0.05 for all covariates). Conclusion Currently available literature does not provide sufficient evidence that adjuvant acupuncture improves IVF clinical pregnancy rate. [ABSTRACT FROM AUTHOR]

Objective  To analyse the ongoing process of recruiting patients into a multicenter randomized trial on follow-up after curative surgery for colorectal cancer. The trial is registered in Clinical Trials Registration. Method  Prospective registration of all operated patients as well as inclusions (curative resection, stage II or III disease, ≤ 75 years, clean colonand exclusions of the individual patients in eight participating departments. Results  Between January 2006 and September 2007, 1309 patients have been operated upon. Of these 502 (38.3 %) met the inclusion criteria, 148 (29.5%) had exclusion criteria. Of the final eligible patients 241 (68.1 %) were randomized. No specific barriers to inclusion were identified. Conclusion  Of an overall population of patients operated for colorectal cancer about one in five were randomized. Bearing the rigorous inclusion and exclusion criteria in mind, this is considered satisfactory, and the investigated population may be representative of patients meeting the inclusion criteria. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "An estimation of intrapartum-related perinatal mortality rates for booked home births in England and Wales between 1994 and 2003" that was published in a previous issue of the periodical.