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Most randomized controlled trials (RCTs) and meta-analyses of RCTs examine effect modification (also called a subgroup effect or interaction), in which the effect of an intervention varies by another variable (e.g., age or disease severity). Assessing the credibility of an apparent effect modification presents challenges; therefore, we developed the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN). To develop ICEMAN, we established a detailed concept; identified candidate credibility considerations in a systematic survey of the literature; together with experts, performed a consensus study to identify key considerations and develop them into instrument items; and refined the instrument based on feedback from trial investigators, systematic review authors and journal editors, who applied drafts of ICEMAN to published claims of effect modification. The final instrument consists of a set of preliminary considerations, core questions (5 for RCTs, 8 for meta-analyses) with 4 response options, 1 optional item for additional considerations and a rating of credibility on a visual analogue scale ranging from very low to high. An accompanying manual provides rationales, detailed instructions and examples from the literature. Seventeen potential users tested ICEMAN; their suggestions improved the user-friendliness of the instrument. The Instrument for assessing the Credibility of Effect Modification Analyses offers explicit guidance for investigators, systematic reviewers, journal editors and others considering making a claim of effect modification or interpreting a claim made by others.

This analysis of previously reported trials shows that low tidal volumes, a key component of safer ventilation strategies, confer a protective effect against complications only if the lower volume results in a lower pulmonary driving pressure. Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (V T ), and higher positive end-expiratory pressures (PEEPs) — collectively termed lung-protective strategies — have been associated with survival benefits in randomized clinical trials involving patients with the acute respiratory distress syndrome (ARDS). 1 – 4 The different components of lung protection in those strategies, such as lower V T , lower plateau pressure, and higher PEEP, can all reduce mechanical stresses on the lung, which are thought to induce ventilator-induced lung injury. 5 – 9 Clinical trials, however, have reported conflicting responses to the manipulation of separate components of lung . . .

A meta-analysis as part of a systematic review aims to provide a thorough, comprehensive and unbiased statistical summary of data from the literature. However, relevant study results could be missing from a meta-analysis because of selective publication and inadequate dissemination. If missing outcome data differ systematically from published ones, a meta-analysis will be biased with an inaccurate assessment of the intervention effect. As part of the EU-funded OPEN project (www.open-project.eu) we conducted a systematic review that assessed whether the inclusion of data that were not published at all and/or published only in the grey literature influences pooled effect estimates in meta-analyses and leads to different interpretation. Systematic review of published literature (methodological research projects). Four bibliographic databases were searched up to February 2016 without restriction of publication year or language. Methodological research projects were considered eligible for inclusion if they reviewed a cohort of meta-analyses which (i) compared pooled effect estimates of meta-analyses of health care interventions according to publication status of data or (ii) examined whether the inclusion of unpublished or grey literature data impacts the result of a meta-analysis. Seven methodological research projects including 187 meta-analyses comparing pooled treatment effect estimates according to different publication status were identified. Two research projects showed that published data showed larger pooled treatment effects in favour of the intervention than unpublished or grey literature data (Ratio of ORs 1.15, 95% CI 1.04-1.28 and 1.34, 95% CI 1.09-1.66). In the remaining research projects pooled effect estimates and/or overall findings were not significantly changed by the inclusion of unpublished and/or grey literature data. The precision of the pooled estimate was increased with narrower 95% confidence interval. Although we may anticipate that systematic reviews and meta-analyses not including unpublished or grey literature study results are likely to overestimate the treatment effects, current empirical research shows that this is only the case in a minority of reviews. Therefore, currently, a meta-analyst should particularly consider time, effort and costs when adding such data to their analysis. Future research is needed to identify which reviews may benefit most from including unpublished or grey data.

Background Poor participant recruitment is the most frequent reason for premature discontinuation of randomized clinical trials (RCTs), particularly if they are investigator-initiated. The aims of this qualitative study were to investigate (1) the views of clinical trial stakeholders from three different countries regarding reasons for recruitment failure in RCTs and (2) how these compare and contrast with the causes identified in a previous systematic review of RCT publications. Methods From August 2015 to November 2016, we conducted 49 semi-structured interviews with a purposive sample of clinical trial stakeholders. This included investigators based in Germany ( n = 9), Switzerland ( n = 6) and Canada ( n = 1) with personal experience of a discontinued RCT and 33 other stakeholders (e.g., representatives of ethics committees, clinical trial units, pharmaceutical industry) in Switzerland. Individual semi-structured qualitative interviews were conducted and analyzed using thematic analysis. Results Interviewees identified a total of 29 different reasons for recruitment failure. Overoptimistic recruitment estimates, too narrow eligibility criteria, lack of engagement of recruiters/trial team, lack of competence/training/experience of recruiters, insufficient initial funding, and high burden for trial participants were mentioned most frequently. The interview findings largely confirm the previous systematic review on published reasons for recruitment failure. However, eight new reasons for recruitment failure were identified in the interviews, which led to the checklist of reasons for recruitment failure being revised and a new category describing research environment-related factors being added. Conclusions This study highlights the diversity of often interlinked reasons for recruitment failure in RCTs. Integrating the findings of this interview study with a previous systematic review of RCT publications led to a comprehensive, structured checklist of empirically-informed reasons for recruitment failure. The checklist may be useful to guide further research on interventions to improve participant recruitment in RCTs and helpful for trial investigators, research ethics committees, and funding agencies when assessing trial feasibility with respect to recruitment.

Background HRQoL is an indicator of individuals’ perception of their overall health, including social and environmental aspects. As a multidimensional concept, HRQoL can be influenced by a multitude of factors. Studies of HRQoL and factors associated with it among home-dwelling older adults have often been limited to inpatient settings or to a sub-population with a chronic disease. Studying HRQoL and its correlating factors among this population, by providing an ecological lens on factors beyond the individual level, can provide a better understanding of the construct and the role of the environment on how they perceive their HRQoL. Thus, we aimed to assess the HRQoL and investigate the correlates of HRQOL among home-dwelling older adults, guided by the levels of the ecological model. Methods This is a cross-sectional population survey conducted in 2019 in Canton Basel-Landschaft, in northwestern Switzerland, and includes a sample of 8786 home-dwelling older adults aged 75 and above. We assessed HRQoL by using the EQ-index and the EQ-VAS. The influence of independent variables at the macro, meso and micro level on HRQoL was tested using Tobit multiple linear regression modelling. Results We found that having a better socio-economic status as denoted by higher income, having supplementary insurance and a higher level of education were all associated with a better HRQoL among home-dwelling older adults. Furthermore, being engaged in social activities was also related to an improved HRQoL. On the other hand, older age, female gender, presence of multimorbidity and polypharmacy as well as social isolation and loneliness were found to all have a negative impact on HRQoL. Conclusions Understanding factors related to HRQoL by using an ecological lens can help identify factors beyond the individual level that impact the HRQoL of home-dwelling older adults. Our study emphasises the importance of social determinants of health and potential disparities that exists, encouraging policymakers to focus on policies to reduce socio-economic disparities using a life-course approach, which consequently could also impact HRQoL in later stages of life.

Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5–3·4) than in the placebo group (4·4 days, 4·0–5·0; hazard ratio [HR] 1·33, 95% CI 1·15–1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23–1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31–2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

IntroductionThere is an urgent need to better understand how information from circulating tumour DNA (ctDNA) can be integrated into routine care for patients with advanced solid cancer.Methods and analysisThe implementation of liquid biopsies in routine care of patients with advanced solid cancer trial (LIQPLAT) is a single-centre, single-arm trial investigating the implementation of ctDNA in the routine care of patients with advanced solid cancer. We present a mixed-methods process evaluation embedded in the LIQPLAT trial, following Medical Research Council guidance and the Reach, Effectiveness, Adoption, Implementation, Maintenance framework. We show a logic model, which details the causal chain and related assumptions from recruiting patients into the trial to the goal of improving quality of life and survival. Data collection is longitudinal and includes: semistructured interviews with healthcare professionals (pathologists, biologists, oncologists; planned n=20) and patients (planned n=15) to identify implementation barriers and facilitators; recordings of molecular tumour board meetings to analyse clinical decision-making; the 23-item Normalisation MeAsure Development survey for healthcare professionals (planned n=20) at four time points. Quantitative data from hospital records will be used to assess implementation outcomes like patient acceptance rates and ctDNA workflow success. Qualitative data will undergo thematic and content analysis, and quantitative data will be analysed using a Bayesian framework.Ethics and disseminationThe LIQPLAT trial was approved by the regional ethics committee of Northwestern and Central Switzerland (BASEC 2024-00358). The qualitative aspects of the process evaluation were exempted from ethics review according to the Swiss Human Research Act. We follow guidelines for data security, confidentiality and information governance. Results will be submitted for publication in peer-reviewed journals and discussed at conferences.Trial registration numberNCT06367751, SNCTP000005844.

The second study by Amanda Blatch-Jones and colleagues [3] asked staff at UK Clinical Trial Units what digital recruitment and retention tools they use and asked staff at the National Institute for Health Research (a UK trial funder) about the digital tools their funded trials use. Clinical Trial Unit staff mentioned more recruitment tools (41) than retention ones (29), though that is a smaller difference than we might have expected. Blatch-Jones AJ, Nuttall J, Bull A, Mullee M, Peveler R, Falk S, Tape N, Hinks J, Lane AJ, Wyatt JC, Griffiths G. Using digital tools in the recruitment and retention in randomised controlled trials: survey of UK clinical trial units and a qualitative study.

Background More than a quarter of randomized controlled trials (RCTs) are prematurely discontinued, mostly due to poor recruitment of patients. In this study, we systematically compared RCTs discontinued or revised for poor recruitment and completed RCTs with the same underlying research question to better understand the causes of poor recruitment, particularly related to methodological aspects and context-specific study settings. Methods We compared RCTs that were discontinued or revised for poor recruitment to RCTs that were completed as planned, matching in terms of population and intervention. Based on an existing sample of RCTs discontinued or revised due to poor recruitment, we identified matching RCTs through a literature search for systematic reviews that cited the discontinued or revised RCT and matching completed RCTs without poor recruitment. Based on extracted data, we explored differences in the design, conduct, and study settings between RCTs with and without poor recruitment, separately for each research question using semi-structured discussions. Results We identified 15 separate research questions with a total of 29 RCTs discontinued or revised for poor recruitment and 48 RCTs completed as planned. Prominent research areas in the sample were cancer and acute care. The mean number of RCTs with poor recruitment per research question was 1.9 ranging from 1 to 4 suggesting clusters of research questions or settings prone to recruitment problems. The reporting quality of the recruitment process in RCT publications was generally low. We found that RCTs with poor recruitment often had narrower eligibility criteria, were investigator- rather than industry-sponsored, were associated with a higher burden for patients and recruiters, sometimes used outdated control interventions, and were often launched later in time than RCTs without poor recruitment compromising uncertainty about tested interventions through emerging evidence. Whether a multi- or single-center setting was advantageous for patient recruitment seemed to depend on the research context. Conclusions Our study confirmed previously identified causes for poor recruitment, i.e., narrow eligibility criteria, investigator sponsorship, and a reduced motivation of patients and recruiters. Newly identified aspects were that researchers need to be aware of all other RCTs on a research question so that compromising effects on the recruitment can be minimized and that a larger number of centers is not always advantageous.

This work aims to assess the performance of two post-arrest (out-of-hospital cardiac arrest, OHCA, and cardiac arrest hospital prognosis, CAHP) and one pre-arrest (good outcome following attempted resuscitation, GO-FAR) prediction model for the prognostication of neurological outcome after cardiac arrest in a systematic review and meta-analysis. A systematic search was conducted in Embase, Medline, and Web of Science Core Collection from November 2006 to December 2021, and by forward citation tracking of key score publications. The search identified 1′021 records, of which 25 studies with a total of 124′168 patients were included in the review. A random-effects meta-analysis of C-statistics and overall calibration (total observed vs. expected [O:E] ratio) was conducted. Discriminatory performance was good for the OHCA (summary C-statistic: 0.83 [95% CI 0.81–0.85], 16 cohorts) and CAHP score (summary C-statistic: 0.84 [95% CI 0.82–0.87], 14 cohorts) and acceptable for the GO-FAR score (summary C-statistic: 0.78 [95% CI 0.72–0.84], five cohorts). Overall calibration was good for the OHCA (total O:E ratio: 0.78 [95% CI 0.67–0.92], nine cohorts) and the CAHP score (total O:E ratio: 0.78 [95% CI 0.72–0.84], nine cohorts) with an overestimation of poor outcome. Overall calibration of the GO-FAR score was poor with an underestimation of good outcome (total O:E ratio: 1.62 [95% CI 1.28–2.04], five cohorts). Two post-arrest scores showed good prognostic accuracy for predicting neurological outcome after cardiac arrest and may support early discussions about goals-of-care and therapeutic planning on the intensive care unit. A pre-arrest score showed acceptable prognostic accuracy and may support code status discussions. Graphical Abstract