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Background: Health equity concerns the absence of avoidable and unfair differences in health. Randomized controlled trials (RCTs) can provide evidence about the impact of an intervention on health equity for specific disadvantaged populations or in general populations; this is important for equity-focused decision-making. Previous work has identified a lack of adequate reporting guidelines for assessing health equity in RCTs. The objective of this study is to develop guidelines to improve the reporting of health equity considerations in RCTs, as an extension of the Consolidated Standards of Reporting Trials (CONSORT).Methods/design: A six-phase study using integrated knowledge translation governed by a study executive and advisory board will assemble empirical evidence to inform the CONSORT-equity extension. To create the guideline, the following steps are proposed: (1) develop a conceptual framework for identifying "equity-relevant trials," (2) assess empirical evidence regarding reporting of equity-relevant trials, (3) consult with global methods and content experts on how to improve reporting of health equity in RCTs, (4) collect broad feedback and prioritize items needed to improve reporting of health equity in RCTs, (5) establish consensus on the CONSORT-equity extension: the guideline for equity-relevant trials, and (6) broadly disseminate and implement the CONSORT-equity extension.Discussion: This work will be relevant to a broad range of RCTs addressing questions of effectiveness for strategies to improve practice and policy in the areas of social determinants of health, clinical care, health systems, public health, and international development, where health and/or access to health care is a primary outcome. The outcomes include a reporting guideline (CONSORT-equity extension) for equity-relevant RCTs and a knowledge translation strategy to broadly encourage its uptake and use by journal editors, authors, and funding agencies. [ABSTRACT FROM AUTHOR]

Background: Cluster randomized trials (CRTs) are increasingly important for evaluating interventions embedded in health care systems. An essential parameter in sample size calculation to detect both overall and heterogeneous treatment effects for CRTs is the intra-cluster correlation coefficient (ICC) of both outcome and covariates of interest. However, obtaining advance estimates for the ICC can be challenging. When trial outcomes will be obtained from routinely collected data sources, there is an opportunity to obtain reliable ICC estimates in advance of the trial. Using USA national Medicare data, we estimated ICCs for a range of outcomes to inform the design of CRTs for people living with Alzheimer's and related dementias (ADRD)., Method: Data from 2018 Medicare Fee-for-Service beneficiaries, specifically, 1,898,812 individuals (≥ 65 years) with diagnosis of ADRD within 3436 hospital service areas (treated as clusters) and 306 hospital referral regions (treated as fixed strata), were used to calculate unadjusted and adjusted ICC estimates for three outcomes: death, any hospitalizations, and any emergency department (ED) visits and three covariates: age, race and sex. We present both overall and stratum-specific ICC estimates. We illustrate their use in sample size calculations for overall treatment effects as well as detecting treatment effect heterogeneity., Results: The unadjusted overall ICCs for death, hospitalizations, and ED visits were 0.001, 0.010, and 0.017 respectively. Stratum-specific ICCs varied widely across the 306 HRRs: median 0.001, 0.010 and 0.025 for death, hospitalizations, and ED visits respectively and 0.007, 0.001, and 0.080 for age, sex and race. An interactive R Shiny app is provided that allows users to retrieve estimates overlayed on a map of the USA., Conclusions: We presented both adjusted and unadjusted ICCs for outcomes as well as unadjusted ICCs for covariates of potential interest from population-level data in the USA and demonstrated how the estimates may be used in sample size calculations for CRTs in ADRD., (© 2024. The Author(s).)

Background: Dichotomisation of statistical significance, rather than interpretation of effect sizes supported by confidence intervals, is a long-standing problem., Methods: We distributed an online survey to clinical trial statisticians across the UK, Australia and Canada asking about their experiences, perspectives and practices with respect to interpretation of statistical findings from randomised trials. We report a descriptive analysis of the closed-ended questions and a thematic analysis of the open-ended questions., Results: We obtained 101 responses across a broad range of career stages (24% professors; 51% senior lecturers; 22% junior statisticians) and areas of work (28% early phase trials; 44% drug trials; 38% health service trials). The majority (93%) believed that statistical findings should be interpreted by considering (minimal) clinical importance of treatment effects, but many (61%) said quantifying clinically important effect sizes was difficult, and fewer (54%) followed this approach in practice. Thematic analysis identified several barriers to forming a consensus on the statistical interpretation of the study findings, including: the dynamics within teams, lack of knowledge or difficulties in communicating that knowledge, as well as external pressures. External pressures included the pressure to publish definitive findings and statistical review which can sometimes be unhelpful but can at times be a saving grace. However, the concept of the minimally important difference was identified as a particularly poorly defined, even nebulous, construct which lies at the heart of much disagreement and confusion in the field., Conclusion: The majority of participating statisticians believed that it is important to interpret statistical findings based on the clinically important effect size, but report this is difficult to operationalise. Reaching a consensus on the interpretation of a study is a social process involving disparate members of the research team along with editors and reviewers, as well as patients who likely have a role in the elicitation of minimally important differences., (© 2024. The Author(s).)

Background: Unnecessary antibiotic prescriptions in primary care are common and contribute to antimicrobial resistance in the population. Audit and feedback (A&F) on antibiotic prescribing to primary care can improve the appropriateness of antibiotic prescribing, but the optimal approach is uncertain. We performed two pragmatic randomized controlled trials of different approaches to audit and feedback. The trial results showed that A&F was associated with significantly reducing antibiotic prescribing. Still, the effect size was small, and the modifications to the A&F interventions tested in the trials were not associated with any change. Herein, we report a theory-informed qualitative process evaluation to explore potential mechanisms underlying the observed effects., Methods: Ontario family physicians in the intervention arms of both trials who were sent A&F letters were invited for one-on-one interviews. Purposive sampling was used to seek variation across interested participants in personal and practice characteristics. Qualitative analysis utilized inductive and deductive techniques informed by the Clinical Performance Feedback Intervention Theory., Results: Modifications to the intervention design tested in the trial did not alter prescribing patterns beyond the changes made in response to the A&F overall for various reasons. Change in antibiotic prescribing in response to A&F depended on whether it led to the formation of specific intentions and whether those intentions translated to particular behaviours. Those without intentions to change tended to feel that their unique clinical context was not represented in the A&F. Those with intentions but without specific actions taken tended to express a lack of self-efficacy for avoiding a prescription in contexts with time constraints and/or without an ongoing patient relationship. Many participants noted that compared to overall prescribing, A&F on antibiotic prescription duration was perceived as new information and easily actionable., Conclusion: Our findings indicate that contextual factors, including the types of patients and the setting where they are seen, affect how clinicians react to audit and feedback. These results suggest a need to test tailored feedback reports that reflect the context of how, where, and why physicians prescribe antibiotics so that they might be perceived as more personal and more actionable., Trial Registration: Clinical Trial registration IDs: NCT04594200, NCT05044052., (© 2024. The Author(s).)

Background: Recruiting participants to clinical trials is an ongoing challenge, and relatively little is known about what recruitment strategies lead to better recruitment. Recruitment interventions can be considered complex interventions, often involving multiple components, targeting a variety of groups, and tailoring to different groups. We used the Template for Intervention Description and Replication (TIDieR) reporting checklist (which comprises 12 items recommended for reporting complex interventions) to guide the assessment of how recruitment interventions are described. We aimed to (1) examine to what extent we could identify information about each TIDieR item within recruitment intervention studies, and (2) observe additional detail for each item to describe useful variation among these studies., Methods: We identified randomized, nested recruitment intervention studies providing recruitment or willingness to participate rates from two sources: a Cochrane review of trials evaluating strategies to improve recruitment to randomized trials, and the Online Resource for Research in Clinical triAls database. First, we assessed to what extent authors reported information about each TIDieR item. Second, we developed descriptive categorical variables for 7 TIDieR items and extracting relevant quotes for the other 5 items., Results: We assessed 122 recruitment intervention studies. We were able to extract information relevant to most TIDieR items (e.g., brief rationale, materials, procedure) with the exception of a few items that were only rarely reported (e.g., tailoring, modifications, planned/actual fidelity). The descriptive variables provided a useful overview of study characteristics, with most studies using various forms of informational interventions (55%) delivered at a single time point (90%), often by a member of the research team (59%) in a clinical care setting (41%)., Conclusions: Our TIDieR-based variables provide a useful description of the core elements of complex trial recruitment interventions. Recruitment intervention studies report core elements of complex interventions variably; some process elements (e.g., mode of delivery, location) are almost always described, while others (e.g., duration, fidelity) are reported infrequently, with little indication of a reason for their absence. Future research should explore whether these TIDieR-based variables can form the basis of an approach to better reporting of elements of successful recruitment interventions., (© 2024. The Author(s).)

Background: Childhood cancer treatment while often curative, leads to elevated risks of morbidity and mortality. Survivors require lifelong periodic surveillance for late effects of treatment, yet adherence to guideline-recommended tests is suboptimal. We created ONLOOP to provide adult survivors of childhood cancer with detailed health information, including summaries of their childhood cancer treatment and recommended surveillance tests for early detection of cardiomyopathy, breast cancer, and/or colorectal cancer, with personalized reminders over time., Methods: This is an individually randomized, registry-based pragmatic trial with an embedded process and economic evaluation to understand ONLOOP's impact and whether it can be readily implemented at scale. All adult survivors of childhood cancer in Ontario overdue for guideline-recommended tests will be randomly assigned to one of two arms: (1) intervention or (2) delayed intervention. A letter of information and invitation will detail the ONLOOP program. Those who sign up will receive a personalized toolkit and a screening reminder 6 months later. With the participants' consent, ONLOOP will also send their primary care clinician a letter detailing the recommended tests and a reminder 6 months later. The primary outcome will be the proportion of survivors who complete one or more of the guideline-recommended cardiac, breast, or colon surveillance tests during the 12 months after randomization. Data will be obtained from administrative databases. The intent-to-treat principle will be followed. Based on our analyses of administrative data, we anticipate allocating at least 862 individuals to each trial arm, providing 90% power to detect an absolute increase of 6% in targeted surveillance tests completed. We will interview childhood cancer survivors and family physicians in an embedded process evaluation to examine why and how ONLOOP achieved success or failed. A cost-effectiveness evaluation will be performed., Discussion: The results of this study will determine if ONLOOP is effective at helping adult survivors of childhood cancer complete their recommended surveillance tests. This study will also inform ongoing provincial programs for this high-risk population., Trial Registration: ClinicalTrials.gov NCT05832138., (© 2024. The Author(s).)

Background: The Interrupted Time Series (ITS) is a robust design for evaluating public health and policy interventions or exposures when randomisation may be infeasible. Several statistical methods are available for the analysis and meta-analysis of ITS studies. We sought to empirically compare available methods when applied to real-world ITS data., Methods: We sourced ITS data from published meta-analyses to create an online data repository. Each dataset was re-analysed using two ITS estimation methods. The level- and slope-change effect estimates (and standard errors) were calculated and combined using fixed-effect and four random-effects meta-analysis methods. We examined differences in meta-analytic level- and slope-change estimates, their 95% confidence intervals, p-values, and estimates of heterogeneity across the statistical methods., Results: Of 40 eligible meta-analyses, data from 17 meta-analyses including 282 ITS studies were obtained (predominantly investigating the effects of public health interruptions (88%)) and analysed. We found that on average, the meta-analytic effect estimates, their standard errors and between-study variances were not sensitive to meta-analysis method choice, irrespective of the ITS analysis method. However, across ITS analysis methods, for any given meta-analysis, there could be small to moderate differences in meta-analytic effect estimates, and important differences in the meta-analytic standard errors. Furthermore, the confidence interval widths and p-values for the meta-analytic effect estimates varied depending on the choice of confidence interval method and ITS analysis method., Conclusions: Our empirical study showed that meta-analysis effect estimates, their standard errors, confidence interval widths and p-values can be affected by statistical method choice. These differences may importantly impact interpretations and conclusions of a meta-analysis and suggest that the statistical methods are not interchangeable in practice., (© 2024. The Author(s).)

Background: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits., Methods: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death., Results: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated., Conclusions: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented., (© 2024. The Author(s).)

Background: Ongoing high neonatal mortality rates (NMRs) represent a global challenge. In 2021, of the 5 million deaths reported worldwide for children under five years of age, 47% were newborns. Pakistan has one of the five highest national NMRs in the world, with an estimated 39 neonatal deaths per 1,000 live births. Reducing newborn deaths requires sustainable, evidence-based, and cost-effective interventions that can be integrated within existing community healthcare infrastructure across regions with high NMR., Methods: This pragmatic, community-based, parallel-arm, open-label, cluster randomized controlled trial aims to estimate the effect of Lady Health Workers (LHWs) providing an integrated newborn care kit (iNCK) with educational instructions to pregnant women in their third trimester, compared to the local standard of care in Gilgit-Baltistan, Pakistan, on neonatal mortality and other newborn and maternal health outcomes. The iNCK contains a clean birth kit, 4% chlorhexidine topical gel, sunflower oil emollient, a ThermoSpot™ temperature monitoring sticker, a fleece blanket, a click-to-heat reusable warmer, three 200 μg misoprostol tablets, and a pictorial instruction guide and diary. LHWs are also provided with a handheld scale to weigh the newborn. The primary study outcome is neonatal mortality, defined as a newborn death in the first 28 days of life., Discussion: This study will generate policy-relevant knowledge on the effectiveness of integrating evidence-based maternal and newborn interventions and delivering them directly to pregnant women via existing community health infrastructure, for reducing neonatal mortality and morbidity, in a remote, mountainous area with a high NMR., Trial Registration: NCT04798833, March 15, 2021., (© 2023. The Author(s).)

Background: Induction at 38-40 weeks of gestation has been broadly suggested for women with gestational diabetes mellitus (GDM), yet its benefits and risks remain unclear. This study aimed to systematically review and meta-analyze existing evidence on the effect of induction at term gestation among women with GDM., Methods: We searched MEDLINE, EMBASE, Cochrane Libraries, and Web of Science from inception to June 2021. We included randomized controlled trials (RCTs) and observational studies comparing induction with expectant management among GDM term pregnancies. Primary outcomes included caesarean section (CS) and macrosomia. All screening and extraction were conducted independently and in duplicates. Meta-analyses with random-effects models were conducted to generate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method. Methodological quality was assessed independently by two reviewers using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale for observational studies., Results: Of the 4,791 citations, 11 studies were included (3 RCTs and 8 observational studies). Compared to expectant management, GDM women with induction had a significantly lower odds for macrosomia (RCTs 0.49 [0.30-0.81]); observational studies 0.64 [0.54-0.77]), but not for CS (RCTs 0.95 [0.64-1.43]); observational studies 1.03 [0.79-1.34]). Induction was associated with a lower odds of severe perineal lacerations in observational studies (0.59 [0.39-0.88]). No significant difference was observed for other maternal or neonatal morbidities, or perinatal mortality between groups., Conclusions: For GDM women, induction may reduce the risk of macrosomia and severe perineal lacerations compared to expectant management. Further rigorous studies with large sample sizes are warranted to better inform clinical implications., (© 2023. The Author(s).)

Background: While simple Audit & Feedback (A&F) has shown modest effectiveness in reducing low-value care, there is a knowledge gap on the effectiveness of multifaceted interventions to support de-implementation efforts. Given the need to make rapid decisions in a context of multiple diagnostic and therapeutic options, trauma is a high-risk setting for low-value care. Furthermore, trauma systems are a favorable setting for de-implementation interventions as they have quality improvement teams with medical leadership, routinely collected clinical data, and performance-linked to accreditation. We aim to evaluate the effectiveness of a multifaceted intervention for reducing low-value clinical practices in acute adult trauma care., Methods: We will conduct a pragmatic cluster randomized controlled trial (cRCT) embedded in a Canadian provincial quality assurance program. Level I-III trauma centers (n = 30) will be randomized (1:1) to receive simple A&F (control) or a multifaceted intervention (intervention). The intervention, developed using extensive background work and UK Medical Research Council guidelines, includes an A&F report, educational meetings, and facilitation visits. The primary outcome will be the use of low-value initial diagnostic imaging, assessed at the patient level using routinely collected trauma registry data. Secondary outcomes will be low-value specialist consultation, low-value repeat imaging after a patient transfer, unintended consequences, determinants for successful implementation, and incremental cost-effectiveness ratios., Discussion: On completion of the cRCT, if the intervention is effective and cost-effective, the multifaceted intervention will be integrated into trauma systems across Canada. Medium and long-term benefits may include a reduction in adverse events for patients and an increase in resource availability. The proposed intervention targets a problem identified by stakeholders, is based on extensive background work, was developed using a partnership approach, is low-cost, and is linked to accreditation. There will be no attrition, identification, or recruitment bias as the intervention is mandatory in line with trauma center designation requirements, and all outcomes will be assessed with routinely collected data. However, investigators cannot be blinded to group allocation and there is a possibility of contamination bias that will be minimized by conducting intervention refinement only with participants in the intervention arm., Trial Registration: This protocol has been registered on ClinicalTrials.gov (February 24, 2023, # NCT05744154 )., (© 2023. The Author(s).)

Background: Older adults with frailty are at an increased risk of adverse outcomes after surgery. Exercise before surgery (exercise prehabilitation) may reduce adverse events and improve recovery after surgery. However, adherence with exercise therapy is often low, especially in older populations. The purpose of this study was to qualitatively assess the barriers and facilitators to participating in exercise prehabilitation from the perspective of older people with frailty participating in the intervention arm of a randomized trial., Methods: This was a research ethics approved, nested descriptive qualitative study within a randomized controlled trial of home-based exercise prehabilitation vs. standard care with older patients (≥ 60 years) having elective cancer surgery, and who were living with frailty (Clinical Frailty Scale ≥ 4). The intervention was a home-based prehabilitation program for at least 3 weeks before surgery that involved aerobic activity, strength and stretching, and nutritional advice. After completing the prehabilitation program, participants were asked to partake in a semi-structured interview informed by the Theoretical Domains Framework (TDF). Qualitative analysis was guided by the TDF., Results: Fifteen qualitative interviews were completed. Facilitators included: 1) the program being manageable and suitable to older adults with frailty, 2) adequate resources to support engagement, 3) support from others, 4) a sense of control, intrinsic value, noticing progress and improving health outcomes and 5) the program was enjoyable and facilitated by previous experience. Barriers included: 1) pre-existing conditions, fatigue and baseline fitness, 2) weather, and 3) guilt and frustration when unable to exercise. A need for individualization and variety was offered as a suggestion by participants and was therefore described as both a barrier and facilitator., Conclusions: Home-based exercise prehabilitation is feasible and acceptable to older people with frailty preparing for cancer surgery. Participants identified that a home-based program was manageable, easy to follow with helpful resources, included valuable support from the research team, and they reported self-perceived health benefits and a sense of control over their health. Future studies and implementation should consider increased personalization based on health and fitness, psychosocial support and modifications to aerobic exercises in response to adverse weather conditions., (© 2023. The Author(s).)

Background: While audit & feedback (A&F) is an effective implementation intervention, the design elements which maximize effectiveness are unclear. Partnering with a healthcare quality advisory organization already delivering feedback, we conducted a pragmatic, 2 × 2 factorial, cluster-randomized trial to test the impact of variations in two factors: (A) the benchmark used for comparison and (B) information framing. An embedded process evaluation explored hypothesized mechanisms of effect., Methods: Eligible physicians worked in nursing homes in Ontario, Canada, and had voluntarily signed up to receive the report. Groups of nursing homes sharing physicians were randomized to (A) physicians' individual prescribing rates compared to top-performing peers (the top quartile) or the provincial median and (B) risk-framed information (reporting the number of patients prescribed high-risk medication) or benefit-framed information (reporting the number of patients not prescribed). We hypothesized that the top quartile comparator and risk-framing would lead to greater practice improvements. The primary outcome was the mean number of central nervous system-active medications per resident per month. Primary analyses compared the four arms at 6 months post-intervention. Factorial analyses were secondary. The process evaluation comprised a follow-up questionnaire and semi-structured interviews., Results: Two hundred sixty-seven physicians (152 clusters) were randomized: 67 to arm 1 (median benchmark, benefit framing), 65 to arm 2 (top quartile benchmark, benefit framing), 75 to arm 3 (median benchmark, risk framing), and 60 to arm 4 (top quartile benchmark, risk framing). There were no significant differences in the primary outcome across arms or for each factor. However, engagement was low (27-31% of physicians across arms downloaded the report). The process evaluation indicated that both factors minimally impacted the proposed mechanisms. However, risk-framed feedback was perceived as more actionable and more compatible with current workflows, whilst a higher target might encourage behaviour change when physicians identified with the comparator., Conclusions: Risk framing and a top quartile comparator have the potential to achieve change. Further work to establish the strategies most likely to enhance A&F engagement, particularly with physicians who may be most likely to benefit from feedback, is required to support meaningfully addressing intricate research questions concerning the design of A&F., Trial Registration: ClinicalTrials.gov, NCT02979964 . Registered 29 November 2016., (© 2023. The Author(s).)

Background: The effectiveness of malaria vector control interventions is often evaluated using cluster randomized trials (CRT) with outcomes assessed using repeated cross-sectional surveys. A key requirement for appropriate design and analysis of longitudinal CRTs is accounting for the intra-cluster correlation coefficient (ICC). In addition to exchangeable correlation (constant ICC over time), correlation structures proposed for longitudinal CRT are block exchangeable (allows a different within- and between-period ICC) and exponential decay (allows between-period ICC to decay exponentially). More flexible correlation structures are available in statistical software packages and, although not formally proposed for longitudinal CRTs, may offer some advantages. Our objectives were to empirically explore the impact of these correlation structures on treatment effect inferences, identify gaps in the methodological literature, and make practical recommendations., Methods: We obtained data from a parallel-arm CRT conducted in Tanzania to compare four different types of insecticide-treated bed-nets. Malaria prevalence was assessed in cross-sectional surveys of 45 households in each of 84 villages at baseline, 12-, 18- and 24-months post-randomization. We re-analyzed the data using mixed-effects logistic regression according to a prespecified analysis plan but under five different correlation structures as well as a robust variance estimator under exchangeable correlation and compared the estimated correlations and treatment effects. A proof-of-concept simulation was conducted to explore general conclusions., Results: The estimated correlation structures varied substantially across different models. The unstructured model was the best-fitting model based on information criteria. Although point estimates and confidence intervals for the treatment effect were similar, allowing for more flexible correlation structures led to different conclusions based on statistical significance. Use of robust variance estimators generally led to wider confidence intervals. Simulation results showed that under-specification can lead to coverage probabilities much lower than nominal levels, but over-specification is more likely to maintain nominal coverage., Conclusion: More flexible correlation structures should not be ruled out in longitudinal CRTs. This may be particularly important in malaria trials where outcomes may fluctuate over time. In the absence of robust methods for selecting the best-fitting correlation structure, researchers should examine sensitivity of results to different assumptions about the ICC and consider robust variance estimators., (© 2023. The Author(s).)

Background: Empowering adolescent girls is an important component of combating malnutrition in this age group. Because empowerment is multidimensional and context specific, it can be difficult for policymakers and practitioners to target the dimensions of empowerment associated with adolescent girls' nutrition in a particular setting. This study sought to identify the empowerment dimensions significantly associated with married adolescent girls' nutritional status in East Africa; a region where malnutrition and gender inequality stubbornly persist., Methods: We used cross-sectional Demographic and Health Survey (DHS) data from Ethiopia (2016), Kenya (2014), Tanzania (2015-16) and Uganda (2016) to construct and test theoretically informed structural equation models of the relationship between six dimensions of empowerment and BMI-for-age and haemoglobin levels for married adolescent girls aged 15-19 years., Results: Our models were found to be a good fit for the data. Married adolescent girls' access to information, measured by their education level and mass media use, was directly and positively associated with their BMI-for-age (p < 0.05). Asset ownership, measured by owning a house or land alone or jointly, was directly and positively associated with haemoglobin (p < 0.05) and reduced odds of being moderately to severely anemic. Rejecting justifications for intimate partner violence, a measure of respondents' intrinsic agency, was directly and positively associated with the odds of being overweight or obese. Adolescent girls' level of empowerment across all dimensions had a direct relationship with their country of residence and household wealth., Conclusions: Our findings suggest that investment in girls' access to information through education and mass/social media and their economic empowerment may be important contributors to their overall empowerment and nutritional status. However, caution is needed as greater autonomy may contribute to increased consumption of unhealthy foods that can contribute to overweight and obesity. Strategies to empower married adolescent girls should be tailored to their specific circumstances. There is an urgent need for better data on adolescent empowerment and health, including increased research into age-, sex- and gender-appropriate empowerment measures and longitudinal data to assess causality. The use of statistical models should be complemented by robust qualitative research to further results interpretation., (© 2023. The Author(s).)

Background: Pragmatic trials aim to generate evidence to directly inform patient, caregiver and health-system manager policies and decisions. Heterogeneity in patient characteristics contributes to heterogeneity in their response to the intervention. However, there are many other sources of heterogeneity in outcomes. Based on the expertise and judgements of the authors, we identify different sources of clinical and methodological heterogeneity, which translate into heterogeneity in patient responses-some we consider as desirable and some as undesirable. For each of them, we discuss and, using real-world trial examples, illustrate how heterogeneity should be managed over the whole course of the trial., Main Text: Heterogeneity in centres and patients should be welcomed rather than limited. Interventions can be flexible or tailored and control interventions are expected to reflect usual care, avoiding use of a placebo. Co-interventions should be allowed; adherence should not be enforced. All these elements introduce heterogeneity in interventions (experimental or control), which has to be welcomed because it mimics reality. Outcomes should be objective and possibly routinely collected; standardised assessment, blinding and adjudication should be avoided as much as possible because this is not how assessment would be done outside a trial setting. The statistical analysis strategy must be guided by the objective to inform decision-making, thus favouring the intention-to-treat principle. Pragmatic trials should consider including process analyses to inform an understanding of the trial results. Needed data to conduct these analyses should be collected unobtrusively. Finally, ethical principles must be respected, even though this may seem to conflict with goals of pragmatism; consent procedures could be incorporated in the flow of care., (© 2022. The Author(s).)

Background: Cluster randomized trials (CRTs) are becoming an increasingly important design. However, authors of CRTs do not always adhere to requirements to explicitly identify the design as cluster randomized in titles and abstracts, making retrieval from bibliographic databases difficult. Machine learning algorithms may improve their identification and retrieval. Therefore, we aimed to develop machine learning algorithms that accurately determine whether a bibliographic citation is a CRT report., Methods: We trained, internally validated, and externally validated two convolutional neural networks and one support vector machine (SVM) algorithm to predict whether a citation is a CRT report or not. We exclusively used the information in an article citation, including the title, abstract, keywords, and subject headings. The algorithms' output was a probability from 0 to 1. We assessed algorithm performance using the area under the receiver operating characteristic (AUC) curves. Each algorithm's performance was evaluated individually and together as an ensemble. We randomly selected 5000 from 87,633 citations to train and internally validate our algorithms. Of the 5000 selected citations, 589 (12%) were confirmed CRT reports. We then externally validated our algorithms on an independent set of 1916 randomized trial citations, with 665 (35%) confirmed CRT reports., Results: In internal validation, the ensemble algorithm discriminated best for identifying CRT reports with an AUC of 98.6% (95% confidence interval: 97.8%, 99.4%), sensitivity of 97.7% (94.3%, 100%), and specificity of 85.0% (81.8%, 88.1%). In external validation, the ensemble algorithm had an AUC of 97.8% (97.0%, 98.5%), sensitivity of 97.6% (96.4%, 98.6%), and specificity of 78.2% (75.9%, 80.4%)). All three individual algorithms performed well, but less so than the ensemble., Conclusions: We successfully developed high-performance algorithms that identified whether a citation was a CRT report with high sensitivity and moderately high specificity. We provide open-source software to facilitate the use of our algorithms in practice., (© 2022. The Author(s).)

Background: Preliminary evidence suggests that providing longer duration prescriptions at discharge may improve long-term adherence to secondary preventative cardiac medications among post-myocardial infarction (MI) patients. We implemented and assessed the effects of two hospital-based interventions-(1) standardized prolonged discharge prescription forms (90-day supply with 3 repeats for recommended cardiac medications) plus education and (2) education only-on long-term cardiac medication adherence among elderly patients post-MI., Methods: We conducted an interrupted time series study of all post-MI patients aged 65-104 years in Ontario, Canada, discharged from hospital between September 2015 and August 2018 with ≥ 1 dispensation(s) for a statin, beta blocker, angiotensin system inhibitor, and/or secondary antiplatelet within 7 days post-discharge. The standardized prolonged discharge prescription forms plus education and education-only interventions were implemented at 2 (1,414 patients) and 4 (926 patients) non-randomly selected hospitals in September 2017 for 12 months, with all other Ontario hospitals (n = 143; 18,556 patients) comprising an external control group. The primary outcome, long-term cardiac medication adherence, was defined at the patient-level as an average proportion of days covered (over 1-year post-discharge) ≥ 80% across cardiac medication classes dispensed at their index fill. Primary outcome data were aggregated within hospital groups (intervention 1, 2, or control) to monthly proportions and independently analyzed using segmented regression to evaluate intervention effects. A process evaluation was conducted to assess intervention fidelity., Results: At 12 months post-implementation, there was no statistically significant effect on long-term cardiac medication adherence for either intervention-standardized prolonged discharge prescription forms plus education (5.4%; 95% CI - 6.4%, 17.2%) or education only (1.0%; 95% CI - 28.6%, 30.6%)-over and above the counterfactual trend; similarly, no change was observed in the control group (- 0.3%; 95% CI - 3.6%, 3.1%). During the intervention period, only 10.8% of patients in the intervention groups received ≥ 90 days, on average, for cardiac medications at their index fill., Conclusions: Recognizing intervention fidelity was low at the pharmacy level, and no statistically significant post-implementation differences in adherence were found, the trends in this study-coupled with other published retrospective analyses of administrative data-support further evaluation of this simple intervention to improve long-term adherence to cardiac medications., Trial Registration: ClinicalTrials.gov : NCT03257579 , registered June 16, 2017 Protocol available at: https://pubmed.ncbi.nlm.nih.gov/33146624/ ., (© 2022. The Author(s).)

Background: Clinical prediction models/scores help clinicians make optimal evidence-based decisions when caring for their patients. To critically appraise such prediction models for use in a clinical setting, essential information on the derivation and validation of the models needs to be transparently reported. In this systematic review, we assessed the quality of reporting of derivation and validation studies of prediction models for the prognosis of recurrent stroke in patients with transient ischemic attack or minor stroke., Methods: MEDLINE and EMBASE databases were searched up to February 04, 2020. Studies reporting development or validation of multivariable prognostic models predicting recurrent stroke within 90 days in patients with TIA or minor stroke were included. Included studies were appraised for reporting quality and conduct using a select list of items from the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) Statement., Results: After screening 7026 articles, 60 eligible articles were retained, consisting of 100 derivation and validation studies of 27 unique prediction models. Four models were newly derived while 23 were developed by validating and updating existing models. Of the 60 articles, 15 (25%) reported an informative title. Among the 100 derivation and validation studies, few reported whether assessment of the outcome (24%) and predictors (12%) was blinded. Similarly, sample size justifications (49%), description of methods for handling missing data (16.1%), and model calibration (5%) were seldom reported. Among the 96 validation studies, 17 (17.7%) clearly reported on similarity (in terms of setting, eligibility criteria, predictors, and outcomes) between the validation and the derivation datasets. Items with the highest prevalence of adherence were the source of data (99%), eligibility criteria (93%), measures of discrimination (81%) and study setting (65%)., Conclusions: The majority of derivation and validation studies for the prognosis of recurrent stroke in TIA and minor stroke patients suffer from poor reporting quality. We recommend that all prediction model derivation and validation studies follow the TRIPOD statement to improve transparency and promote uptake of more reliable prediction models in practice., Trial Registration: The protocol for this review was registered with PROSPERO (Registration number CRD42020201130 )., (© 2022. The Author(s).)

Background: Modern health surveillance and planning requires an understanding of how preventable risk factors impact population health, and how these effects vary between populations. In this study, we compare how smoking, alcohol consumption, diet and physical activity are associated with all-cause mortality in Canada and the United States using comparable individual-level, linked population health survey data and identical model specifications., Methods: The Canadian Community Health Survey (CCHS) (2003-2007) and the United States National Health Interview Survey (NHIS) (2000, 2005) linked to individual-level mortality outcomes with follow up to December 31, 2011 were used. Consistent variable definitions were used to estimate country-specific mortality hazard ratios with sex-specific Cox proportional hazard models, including smoking, alcohol, diet and physical activity, sociodemographic indicators and proximal factors including disease history., Results: A total of 296,407 respondents and 1,813,884 million person-years of follow-up from the CCHS and 58,232 respondents and 497,909 person-years from the NHIS were included. Absolute mortality risk among those with a 'healthy profile' was higher in the United States compared to Canada, especially among women. Adjusted mortality hazard ratios associated with health behaviours were generally of similar magnitude and direction but often stronger in Canada., Conclusion: Even when methodological and population differences are minimal, the association of health behaviours and mortality can vary across populations. It is therefore important to be cautious of between-study variation when aggregating relative effect estimates from differing populations, and when using external effect estimates for population health research and policy development., (© 2022. The Author(s).)

Background: The shortage of available organs for life-saving transplants persists worldwide. While a majority support donating their organs or tissue when they die, many have not registered their wish to do so. When registered, next of kin are much more likely to follow-through with the decision to donate. In many countries, most people visit their family physician office each year and this setting is a promising, yet underused, site where more people could register for deceased organ donation. Our primary aim was to evaluate the effectiveness of an intervention to promote organ donation registration in family physician's offices., Methods: We developed an intervention to address barriers and enablers to organ donation registration that involved physician office reception staff inviting patients to register on a tablet in the waiting room while they waited for their appointment. We conducted a cross-sectional stepped-wedge cluster randomized controlled registry trial to evaluate the intervention. We recruited six family physician offices in Canada. All offices began with usual care and then every two weeks, one office (randomly assigned) started the intervention until all offices delivered the intervention. The primary outcome was registration for deceased organ donation in the provincial organ registration registry, assessed within the 7 days of the physician visit. At the end of the trial, we also conducted interviews with clinic staff to assess any barriers and enablers to delivering the intervention., Results: The trial involved 24,616 patient visits by 13,562 unique patients: 12,484 visits in the intervention period and 12,132 in the control period. There was no statistically significant difference in the percentage of patients registered for deceased organ donation in the intervention versus control period (48.0% vs 46.2%; absolute difference after accounting for the secular trend: 0.12%; 95% CI: - 2.30, 2.54; p=0.92). Interviews with clinic staff indicated location of the tablet within a waiting room, patient rapport, existing registration, confidence and motivation to deliver the intervention and competing priorities as barriers and enablers to delivery., Conclusions: Our intervention did not increase donor registration. Nonetheless, family physician offices may still remain a promising setting to develop and evaluate better interventions to increase organ donation registration., Trial Registration: NCT03213171., (© 2022. The Author(s).)

Background: Rates of maternal mortality and morbidity in Africa remain unacceptably high, as many women deliver at home, without access to skilled birth attendants and life-saving medications. In rural Tanzania, women face significant barriers accessing health care facilities for their deliveries., Methods: From January 2017 to February 2019 we conducted a multiple baseline (interrupted time series) trial within the four divisions of Rorya District, Tanzania. We collected baseline data, then sequentially introduced a complex intervention in each of the divisions, in randomized order, over 3 month intervals. We allowed for a 6 month transition period to avoid contamination between the pre- and post-intervention periods. The intervention included using community health workers to educate about safe delivery, distribution of birth kits with misoprostol, and a transport subsidy for women living a distance from the health care facility. The primary outcome was the health facility birth rate, while the secondary outcomes were the rates of antenatal and postpartum care and postpartum hemorrhage. Outcomes were analyzed using fixed effects segmented logistic regression, adjusting for age, marital status, education, and parity. Maternal and baby morbidity/mortality were analyzed descriptively., Results: We analyzed data from 9565 pregnant women (2634 before and 6913 after the intervention was implemented). Facility births increased from 1892 (71.8%) before to 5895 (85.1%) after implementation of the intervention. After accounting for the secular trend, the intervention was associated with an immediate increase in the odds of facility births (OR = 1.51, 95% CI 1.14 to 2.01, p = 0.0045) as well as a small gradual effect (OR = 1.03 per month, 95% CI 1.00 to 1.07, p = 0.0633). For the secondary outcomes, there were no statistically significant immediate changes associated with the intervention. Rates of maternal and baby morbidity/mortality were low and similar between the pre- and post-implementation periods., Conclusions: Access to health care facilities can be improved through implementation of education of the population by community health workers about the importance of a health care facility birth, provision of birth kits with misoprostol to women in late pregnancy, and access to a transport subsidy for delivery for women living at a distance from the health facility., Clinical Trials Registration: NCT03024905 19/01/2017., (© 2022. The Author(s).)

Background: Interrupted time series (ITS) studies are frequently used to evaluate the effects of population-level interventions or exposures. However, examination of the performance of statistical methods for this design has received relatively little attention., Methods: We simulated continuous data to compare the performance of a set of statistical methods under a range of scenarios which included different level and slope changes, varying lengths of series and magnitudes of lag-1 autocorrelation. We also examined the performance of the Durbin-Watson (DW) test for detecting autocorrelation., Results: All methods yielded unbiased estimates of the level and slope changes over all scenarios. The magnitude of autocorrelation was underestimated by all methods, however, restricted maximum likelihood (REML) yielded the least biased estimates. Underestimation of autocorrelation led to standard errors that were too small and coverage less than the nominal 95%. All methods performed better with longer time series, except for ordinary least squares (OLS) in the presence of autocorrelation and Newey-West for high values of autocorrelation. The DW test for the presence of autocorrelation performed poorly except for long series and large autocorrelation., Conclusions: From the methods evaluated, OLS was the preferred method in series with fewer than 12 points, while in longer series, REML was preferred. The DW test should not be relied upon to detect autocorrelation, except when the series is long. Care is needed when interpreting results from all methods, given confidence intervals will generally be too narrow. Further research is required to develop better performing methods for ITS, especially for short series., (© 2021. The Author(s).)

Background: The Interrupted Time Series (ITS) is a quasi-experimental design commonly used in public health to evaluate the impact of interventions or exposures. Multiple statistical methods are available to analyse data from ITS studies, but no empirical investigation has examined how the different methods compare when applied to real-world datasets., Methods: A random sample of 200 ITS studies identified in a previous methods review were included. Time series data from each of these studies was sought. Each dataset was re-analysed using six statistical methods. Point and confidence interval estimates for level and slope changes, standard errors, p-values and estimates of autocorrelation were compared between methods., Results: From the 200 ITS studies, including 230 time series, 190 datasets were obtained. We found that the choice of statistical method can importantly affect the level and slope change point estimates, their standard errors, width of confidence intervals and p-values. Statistical significance (categorised at the 5% level) often differed across the pairwise comparisons of methods, ranging from 4 to 25% disagreement. Estimates of autocorrelation differed depending on the method used and the length of the series., Conclusions: The choice of statistical method in ITS studies can lead to substantially different conclusions about the impact of the interruption. Pre-specification of the statistical method is encouraged, and naive conclusions based on statistical significance should be avoided.

Background: Health care funding reforms are being used worldwide to improve system performance but may invoke unintended consequences. We assessed the effects of introducing a targeted hospital funding model, based on fixed price and volume, for hip fractures. We hypothesized the policy change was associated with reduction in wait times for hip fracture surgery, increase in wait times for non-hip fracture surgery, and increase in the incidence of after-hours hip fracture surgery., Methods: This was a population-based, interrupted time series analysis of 49,097 surgeries for hip fractures, 10,474 for ankle fractures, 1,594 for tibial plateau fractures, and 40,898 for appendectomy at all hospitals in Ontario, Canada between April 2012 and March 2017. We used segmented regression analysis of interrupted monthly time series data to evaluate the impact of funding reform enacted April 1, 2014 on wait time for hip fracture repair (from hospital presentation to surgery) and after-hours provision of surgery (occurring between 1700 and 0700 h). To assess potential adverse consequences of the reform, we also evaluated two control procedures, ankle and tibial plateau fracture surgery. Appendectomy served as a non-orthopedic tracer for assessment of secular trends., Results: The difference (95 % confidence interval) between the actual mean wait time and the predicted rate had the policy change not occurred was - 0.46 h (-3.94 h, 3.03 h) for hip fractures, 1.46 h (-3.58 h, 6.50 h) for ankle fractures, -3.22 h (-39.39 h, 32.95 h) for tibial plateau fractures, and 0.33 h (-0.57 h, 1.24 h) for appendectomy (Figure 1; Table 3). The difference (95 % confidence interval) between the actual and predicted percentage of surgeries performed after-hours - 0.90 % (-3.91 %, 2.11 %) for hip fractures, -3.54 % (-11.25 %, 4.16 %) for ankle fractures, 7.09 % (-7.97 %, 22.14 %) for tibial plateau fractures, and 1.07 % (-2.45 %, 4.59 %) for appendectomy., Conclusions: We found no significant effects of a targeted hospital funding model based on fixed price and volume on wait times or the provision of after-hours surgery. Other approaches for improving hip fracture wait times may be worth pursuing instead of funding reform.

Background: Persisting within-country disparities in maternal health service access are significant barriers to attaining the Sustainable Development Goals aimed at reducing inequalities and ensuring good health for all. Sub-national decision-makers mandated to deliver health services play a central role in advancing equity but require appropriate evidence to craft effective responses. We use spatial analyses to identify locally-relevant barriers to access using sub-national data from rural areas in Jimma Zone, Ethiopia., Methods: Cross-sectional data from 3727 households, in three districts, collected at baseline in a cluster randomized controlled trial were analysed using geographically-weighted regressions. These models help to quantify associations within women's proximal contexts by generating local parameter estimates. Data subsets, representing an empirically-identified scale for neighbourhood, were used. Local associations between outcomes (antenatal, delivery, and postnatal care use) and potential explanatory factors at individual-level (ex: health information source), interpersonal-level (ex: companion support availability) and health service-levels (ex: nearby health facility type) were modelled. Statistically significant local odds ratios were mapped to demonstrate how relevance and magnitude of associations between various explanatory factors and service outcomes change depending on locality., Results: Significant spatial variability in relationships between all services and their explanatory factors (p < 0.001) was detected, apart from the association between delivery care and women's decision-making involvement (p = 0.124). Local models helped to pinpoint factors, such as danger sign awareness, that were relevant for some localities but not others. Among factors with more widespread influence, such as that of prior service use, variation in estimate magnitudes between localities was uncovered. Prominence of factors also differed between services; companion support, for example, had wider influence for delivery than postnatal care. No significant local associations with postnatal care use were detected for some factors, including wealth and decision involvement, at the selected neighbourhood scale., Conclusions: Spatial variability in service use associations means that the relative importance of explanatory factors changes with locality. These differences have important implications for the design of equity-oriented and responsive health systems. Reductions in within-country disparities are also unlikely if uniform solutions are applied to heterogeneous contexts. Multi-scale models, accommodating factor-specific neighbourhood scaling, may help to improve estimated local associations.

Background: Sudden cardiac death remains a leading cause of mortality in Canada, resulting in more than 35,000 deaths annually. Most cardiac arrest victims collapse in their own home (85% of the time) and 50% are witnessed by a family member or bystander. Survivors have a quality of life similar to the general population, but the overall survival rate for out-of-hospital cardiac arrest (OHCA) rarely exceeds 8%. Victims are almost four times more likely to survive when receiving bystander CPR, but bystander CPR rates have remained low in Canada over the past decade, not exceeding 15-25% until recently. Telecommunication-assisted CPR instructions have been shown to significantly increase bystander CPR rates, but agonal breathing may be misinterpreted as a sign of life by 9-1-1 callers and telecommunicators, and is responsible for as much as 50% of missed OHCA diagnoses. We sought to improve the ability and speed with which ambulance telecommunicators can recognize OHCA over the phone, initiate timely CPR instructions, and improve survival., Methods: In this multi-center national study, we will implement and evaluate an educational program developed for ambulance telecommunicators using a multiple baseline interrupted time-series design. We will compare outcomes 12 months before and after the implementation of a 20-min theory-based educational video addressing barriers to recognition of OHCA while in the presence of agonal breathing. Participating Canadian sites demonstrated prior ability to collect standardized data on OHCA. Data will be collected from eligible 9-1-1 recordings, paramedic documentation and hospital medical records. Eligible cases will include suspected or confirmed OHCA of presumed cardiac origin in patients of any age with attempted resuscitation., Discussion: The ability of telecommunication-assisted CPR instructions to improve bystander CPR and survival rates for OHCA victims is undeniable. The ability of telecommunicators to recognize OHCA over the phone is unequivocally impeded by relative lack of training on agonal breathing, and reluctance to initiate CPR instructions when in doubt. Our pilot data suggests the potential impact of this project will be to increase absolute OHCA recognition and bystander CPR rates by at least 10%, and absolute out-of-hospital cardiac arrest survival by 5% or more., Trial Registration: Prospectively registered on March 28, 2019 at ClinicalTrials.gov identifier: NCT03894059 .

Background: Patients who present to emergency departments after intentional self-harm are at an increased risk of dying by suicide. This applies particularly to men, who represent nearly two-thirds of those who die by suicide in Ontario. One way of potentially addressing this gap is to offer a course of blended problem-solving therapy, comprised of a brief course of evidence-based psychotherapy for individuals at risk for suicide, facilitated by the use of a patient-facing smartphone application and a clinician-facing "dashboard." This approach has the potential to combine the benefits of face-to-face therapy and technology to create a novel intervention., Methods: This is a cohort study nested within a larger pragmatic multicentre pre- and post-design cluster randomised trial. Suicidal ideation assessed by the Beck Scale for Suicide Ideation is the primary outcome variable. Secondary outcome measures include depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder 7-item scale), post-traumatic stress disorder (Primary Care PTSD Screen), health-related quality of life (EuroQol 5-dimension 5-level questionnaire), meaning in life (Experienced Meaning in Life Scale), perceived social supports (Multidimensional Scale of Perceived Social Support), alcohol use (Alcohol Use Disorders Identification Test), drug use (Drug Abuse Screening Test Short Form 10), problem-solving skills (Social Problem-Solving Inventory-Revised Short Form), and self-reported healthcare costs, as well as health service use measured using Ontario administrative health data. A process evaluation will also be conducted following study completion., Discussion: The cohort study will test whether better adherence to the intervention results in better outcomes. The value of the cohort study design is that we can examine in more detail certain subgroups or other variables that are not available in the larger cluster randomised trial. This trial will aim to improve standards by informing best practice in management of men who self-harm and present to hospitals in Ontario., Trial Registration: ClinicalTrials.gov , NCT03473535 . Registered on March 22, 2018.

Background: Maternity waiting homes (MWHs), residential spaces for pregnant women close to obstetric care facilities, are being used to tackle physical barriers to access. However, their effectiveness has not been rigorously assessed. The objective of this cluster randomized trial was to evaluate the effectiveness of functional MWHs combined with community mobilization by trained local leaders in improving institutional births in Jimma Zone, Ethiopia., Methods: A pragmatic, parallel arm cluster-randomized trial was conducted in three districts. Twenty-four primary health care units (PHCUs) were randomly assigned to either (i) upgraded MWHs combined with local leader training on safe motherhood strategies, (ii) local leader training only, or (iii) usual care. Data were collected using repeat cross-sectional surveys at baseline and 21 months after intervention to assess the effect of intervention on the primary outcome, defined as institutional births, at the individual level. Women who had a pregnancy outcome (livebirth, stillbirth or abortion) 12 months prior to being surveyed were eligible for interview. Random effects logistic regression was used to evaluate the effect of the interventions., Results: Data from 24 PHCUs and 7593 women were analysed using intention-to-treat. The proportion of institutional births was comparable at baseline between the three arms. At endline, institutional births were slightly higher in the MWH + training (54% [n = 671/1239]) and training only arms (65% [n = 821/1263]) compared to usual care (51% [n = 646/1271]). MWH use at baseline was 6.7% (n = 256/3784) and 5.8% at endline (n = 219/3809). Both intervention groups exhibited a non-statistically significant higher odds of institutional births compared to usual care (MWH + & leader training odds ratio [OR] = 1.09, 97.5% confidence interval [CI] 0.67 to 1.75; leader training OR = 1.37, 97.5% CI 0.85 to 2.22)., Conclusions: Both the combined MWH + & leader training and the leader training alone intervention led to a small but non-significant increase in institutional births when compared to usual care. Implementation challenges and short intervention duration may have hindered intervention effectiveness. Nevertheless, the observed increases suggest the interventions have potential to improve women's use of maternal healthcare services. Optimal distances at which MWHs are most beneficial to women need to be investigated., Trial Registration: The trial was retrospectively registered on the Clinical Trials website ( https://clinicaltrials.gov ) on 3rd October 2017. The trial identifier is NCT03299491 .

Background: The hemodialysis setting is suitable for trials that use cluster randomization, where intact groups of individuals are randomized. However, cluster randomized trials (CRTs) are complicated in their design, analysis, and reporting and can pose ethical challenges. We reviewed CRTs in the hemodialysis setting with respect to reporting of key methodological and ethical issues., Methods: We conducted a systematic review of CRTs in the hemodialysis setting, published in English, between 2000 and 2019, and indexed in MEDLINE or Embase. Two reviewers extracted data, and study results were summarized using descriptive statistics., Results: We identified 26 completed CRTs and five study protocols of CRTs. These studies randomized hemodialysis centers (n = 17, 55%), hemodialysis shifts (n = 12, 39%), healthcare providers (n = 1, 3%), and nephrology units (n = 1, 3%). Trials included a median of 28 clusters with a median cluster size of 20 patients. Justification for using a clustered design was provided by 15 trials (48%). Methods that accounted for clustering were used during sample size calculation in 14 (45%), during analyses in 22 (71%), and during both sample size calculation and analyses in 13 trials (42%). Among all CRTs, 26 (84%) reported receiving research ethics committee approval; patient consent was reported in 22 trials: 10 (32%) reported the method of consent for trial participation and 12 (39%) reported no details about how consent was obtained or its purpose. Four trials (13%) reported receiving waivers of consent, and the remaining 5 (16%) provided no or unclear information about the consent process., Conclusion: There is an opportunity to improve the conduct and reporting of essential methodological and ethical issues in future CRTs in hemodialysis., Review Registration: We conducted this systematic review using a pre-specified protocol that was not registered.

Background: Up to 75% of women diagnosed with breast cancer report chemotherapy-related cognitive changes (CRCC) during treatment, including decreased memory, attention, and processing speed. Though CRCC negatively impacts everyday functioning and reduces overall quality of life in women diagnosed with breast cancer, effective interventions to prevent and/or manage CRCC are elusive. Consequently, women seldom receive advice on how to prevent or manage CRCC. Aerobic exercise is associated with improved cognitive functioning in healthy older adults and adults with cognitive impairments. Accordingly, it holds promise as an intervention to prevent and/or manage CRCC. However, evidence from randomized controlled trials (RCTs) supporting a beneficial effect of aerobic exercise on CRCC is limited. The primary aim of the ACTIVATE trial is to evaluate the impact of supervised aerobic exercise on CRCC in women receiving chemotherapy for breast cancer., Methods: The ACTIVATE trial is a two-arm, two-centre RCT. Women diagnosed with stage I-III breast cancer and awaiting neo-adjuvant or adjuvant chemotherapy are recruited from hospitals in Ottawa (Ontario) and Vancouver (British Columbia), Canada. Recruits are randomized to the intervention group (aerobic exercise during chemotherapy) or the wait-list control group (usual care during chemotherapy and aerobic exercise post-chemotherapy). The primary outcome is cognitive functioning as measured by a composite cognitive summary score (COGSUM) of several neuropsychological tests. Secondary outcomes are self-reported cognitive functioning, quality of life, and brain structure and functioning (measured by magnetic resonance imaging (MRI)/functional MRI and electroencephalography). Assessments take place pre-chemotherapy (pre-intervention), mid-way through chemotherapy (mid-intervention/mid-wait period), end of chemotherapy (post-intervention/post-wait period; primary endpoint), 16-weeks post-chemotherapy, and at 1-year post-baseline., Discussion: Aerobic exercise is a promising intervention for preventing and/or managing CRCC and enhancing quality of life among women diagnosed with breast cancer. The ACTIVATE trial tests several novel hypotheses, including that aerobic exercise can prevent and/or mitigate CRCC and that this effect is mediated by the timing of intervention delivery (i.e., during versus post-chemotherapy). Findings may support prescribing exercise during (or post-) chemotherapy for breast cancer and elucidate the potential role of aerobic exercise as a management strategy for CRCC in women with early-stage breast cancer., Trial Registration: The trial was registered with the ClinicalTrials.gov database ( NCT03277898 ) on September 11, 2017.

Background: The randomized controlled trial (RCT) is considered the gold standard study design to inform decisions about the effectiveness of interventions. However, a common limitation is inadequate reporting of the applicability of the intervention and trial results for people who are "socially disadvantaged" and this can affect policy-makers' decisions. We previously developed a framework for identifying health-equity-relevant trials, along with a reporting guideline for transparent reporting. In this study, we provide a descriptive assessment of health-equity considerations in 200 randomly sampled equity-relevant trials., Methods: We developed a search strategy to identify health-equity-relevant trials published between 2013 and 2015. We randomly sorted the 4316 records identified by the search and screened studies until 100 individually randomized (RCTs) and 100 cluster randomized controlled trials (CRTs) were identified. We developed and pilot-tested a data extraction form based on our initial work, to inform the development of our reporting guideline for equity-relevant randomized trials., Results: In total, 39 trials (20%) were conducted in a low- and middle-income country and 157 trials (79%) in a high-income country focused on socially disadvantaged populations (78% CRTs, 79% RCTs). Seventy-four trials (37%) reported a subgroup analysis across a population characteristic associated with disadvantage (25% CRT, 49% RCTs), with 19% of included studies reporting subgroup analyses across sex, 9% across race/ethnicity/culture, and 4% across socioeconomic status. No subgroup analyses were reported for place of residence, occupation, religion, education, or social capital. One hundred and forty-one trials (71%) discussed the applicability of their results to one or more socially disadvantaged populations (68% of CRT, 73% of RCT)., Discussion: In this set of trials, selected for their relevance to health equity, data that were disaggregated for socially disadvantaged populations were rarely reported. We found that even when the data are available, opportunities to analyze health-equity considerations are frequently missed. The recently published equity extension of the Consolidated Reporting Standards for Randomized Trials (CONSORT-Equity) may help improve delineation of hypotheses related to socially disadvantaged populations, and transparency and completeness of reporting of health-equity considerations in RCTs. This study can serve as a baseline assessment of the reporting of equity considerations.

Background: As part of their professional role, healthcare providers enact multiple competing goal-directed behaviours in time-constrained environments. Better understanding healthcare providers' motivation to engage in the pursuit of particular goals may help inform the development of implementation interventions. We investigated healthcare providers' pursuit of multiple goals as part of a trial evaluating the effectiveness of an audit and feedback intervention in supporting appropriate adjustment of high-risk medication prescribing by physicians working in nursing homes. Our objectives were to determine whether goal priority and constructs from Social Cognitive Theory (self-efficacy, outcome expectations, and descriptive norms) predicted intention to adjust prescribing of multiple high-risk medications and to investigate how physicians in nursing homes prioritise their goals related to high-risk medication prescribing., Methods: Physicians in Ontario, Canada, who signed up for and accessed the audit and feedback report were invited to complete a questionnaire assessing goal priority, self-efficacy, outcome expectations, descriptive norms, and intention in relation to the three targeted behaviours (adjusting prescribing of antipsychotics, benzodiazepines, and antidepressants) and a control behaviour (adjusting statin prescribing). We conducted multiple linear regression analyses to identify predictors of intention. We also conducted semi-structured qualitative interviews to investigate how physicians in nursing homes prioritise their goals in relation to appropriately adjusting prescribing of the medications included in the report: analysis was informed by the framework analysis method., Results: Thirty-three of 89 (37%) physicians completed the questionnaire. Goal priority was the only significant predictor of intention for each medication type; the greater a priority it was for physicians to appropriately adjust their prescribing, the stronger was their intention to do so. Across five interviews, physicians reported prioritising adjustment of antipsychotic prescribing specifically. This was influenced by negative media coverage of antipsychotic prescribing in nursing homes, the provincial government's mandate to address antipsychotic prescribing, and by the deprescribing initiatives or best practice routines in place in their nursing homes., Conclusions: Goal priority predicted nursing home physicians' intention to adjust prescribing. Targeting goal priority through implementation interventions therefore has the potential to influence behaviour via increased motivation. Implementation intervention developers should consider the external factors that may drive physicians' prioritization., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes., Methods: We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death., Results: For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles., Conclusions: Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.

Background: Ontario's birth Registry (BORN) was established in 2009 to collect, interpret, and share critical data about pregnancy, birth and the early childhood period to facilitate and improve the provision of healthcare. Since the use of routinely-collected health data has been prioritized internationally by governments and funding agencies to improve patient care, support health system planning, and facilitate epidemiological surveillance and research, high quality data is essential. The purpose of this study was to verify the accuracy of a selection of data elements that are entered in the Registry., Methods: Data quality was assessed by comparing data re-abstracted from patient records to data entered into the Ontario birth Registry. A purposive sample of 10 hospitals representative of hospitals in Ontario based on level of care, birth volume and geography was selected and a random sample of 100 linked mother and newborn charts were audited for each site. Data for 29 data elements were compared to the corresponding data entered in the Ontario birth Registry using percent agreement, kappa statistics for categorical data elements and intra-class correlation coefficients (ICCs) for continuous data elements., Results: Agreement ranged from 56.9 to 99.8%, but 76% of the data elements (22 of 29) had greater than 90% agreement. There was almost perfect (kappa 0.81-0.99) or substantial (kappa 0.61-0.80) agreement for 12 of the categorical elements. Six elements showed fair-to-moderate agreement (kappa <0.60). We found moderate-to-excellent agreement for four continuous data elements (ICC >0.50)., Conclusion: Overall, the data elements we evaluated in the birth Registry were found to have good agreement with data from the patients' charts. Data elements that showed moderate kappa or low ICC require further investigation.

Background: There is a concern that the apparent effectiveness of interventions tested in clinical trials may not be an accurate reflection of their actual effectiveness in usual practice. Pragmatic randomized controlled trials (RCTs) are designed with the intent of addressing this discrepancy. While pragmatic RCTs may increase the relevance of research findings to practice they may also raise new ethical concerns (even while reducing others). To explore this question, we interviewed key stakeholders with the aim of identifying potential ethical challenges in the design and conduct of pragmatic RCTs with a view to developing future guidance on these issues., Methods: Interviews were conducted with clinical investigators, methodologists, patient partners, ethicists, and other knowledge users (e.g., regulators). Interviews covered experiences with pragmatic RCTs, ethical issues relevant to pragmatic RCTs, and perspectives on the appropriate oversight of pragmatic RCTs. Interviews were coded inductively by two coders. Interim and final analyses were presented to the broader team for comment and discussion before the analytic framework was finalized., Results: We conducted 45 interviews between April and September 2018. Interviewees represented a range of disciplines and jurisdictions as well as varying content expertise. Issues of importance in pragmatic RCTs were (1) identification of relevant risks from trial participation and determination of what constitutes minimal risk; (2) determining when alterations to traditional informed consent approaches are appropriate; (3) the distinction between research, quality improvement, and practice; (4) the potential for broader populations to be affected by the trial and what protections they might be owed; (5) the broader range of trial stakeholders in pragmatic RCTs, and determining their roles and responsibilities; and (6) determining what constitutes "usual care" and implications for trial reporting., Conclusions: Our findings suggest both the need to discuss familiar ethical topics in new ways and that there are new ethical issues in pragmatic RCTs that need greater attention. Addressing the highlighted issues and developing guidance will require multidisciplinary input, including patient and community members, within a broader and more comprehensive analysis that extends beyond consent and attends to the identified considerations relating to risk and stakeholder roles and responsibilities.

Background: Ethiopia is one of the ten countries in the world that together account for almost 60% of all maternal deaths. Recent reductions in maternal mortality have been seen, yet just 26% of women who gave birth in Ethiopia in 2016 reported doing so at a health facility. Maternity waiting homes (MWHs) have been introduced to overcome geographical and financial barriers to institutional births but there is no conclusive evidence as to their effectiveness. We aim to evaluate the effects of upgraded MWHs and local leader training in increasing institutional births in the Jimma zone of Ethiopia., Methods: A parallel, three-arm, stratified, cluster-randomized controlled trial design is being employed to evaluate intervention effects on institutional births, which is the primary outcome. Trial arms are: (1) upgraded MWH + religious/community leader training; (2) leader training alone; and (3) standard care. Twenty-four primary health care unit catchment areas (clusters) have been randomized and 3840 women of reproductive age who had a pregnancy outcome (livebirth, stillbirth or abortion) are being randomly recruited for each survey round. Outcome assessments will be made using repeat cross-sectional surveys at baseline and 24 months postintervention. An intention to treat approach will be used and the primary outcome analysed using generalized linear mixed models with a random effect for cluster and time. A cost-effectiveness analysis will also be conducted from a societal perspective., Discussion: This is one of the first trials to evaluate the effectiveness of upgraded MWHs and will provide much needed evidence to policy makers about aspects of functionality and the community engagement required as they scale-up this programme in Ethiopia., Trial Registration: ClinicalTrial.gov, NCT03299491. Retrospectively registered on 3 October 2017.

Background: MORE OB (Managing Obstetrical Risk Efficiently) is a patient safety program for health care providers and administrators in hospital obstetric units. MORE OB has been implemented widely in Canada and gradually spread to the United States. The main goal of MORE OB is to build a patient safety culture and improve clinical outcomes. In 2013, 26 Ontario hospitals voluntarily accepted provincial funding to participate in MORE OB . The purpose of our study was to assess the effect of MORE OB on participant knowledge, organizational culture, and experiences implementing and participating in the program at these 26 Ontario hospitals., Methods: A convergent parallel mixed-methods study in Ontario, Canada, with MORE OB participants from 26 hospitals. The quantitative component used a descriptive pre-post repeated measures design to assess participant knowledge and perception of culture, administered pre-MORE OB and after each of the three MORE OB modules. Changes in mean scores were assessed using mixed-effects regression. The qualitative component used a qualitative descriptive design with individual semi-structured interviews. We used content analysis to code, categorize, and thematically describe data. A convergent parallel design was used to triangulate findings from data sources., Results: 308 participants completed the knowledge test, and 329 completed the culture assessment at all four time points. Between baseline and post-Module 3, statistically significant increases on both scores were observed, with an increase of 7.9% (95% CI: 7.1 to 8.8) on the knowledge test and an increase of 0.45 (on a scale of 1-5, 95% CI: 0.38 to 0.52) on the culture assessment. Interview participants (n = 15) described improvements in knowledge, interprofessional communication, ability to provide safe care, and confidence in skills. Facilitators and barriers to program implementation and sustainability were identified., Conclusions: Participants were satisfied with their participation in the MORE OB program and perceived that it increased health care provider knowledge and confidence, improved safety for patients, and improved communication between team members. Additionally, mean scores on knowledge tests for obstetric content and culture assessment improved. The MORE OB program can help organizations and individuals improve care by concentrating on the human and organizational aspects of patient safety. Further work to improve program implementation and sustainability is required.

Background: Electronic consultation (eConsult) services are secure online applications facilitating provider-to-provider communication. They have been found to improve access to specialist care. However, little is known about eConsult's impact on family physicians' referral rates to specialty care. The objective of this study was to assess the impact of a multispecialty eConsult service on referral rates from primary care., Methods: In this parallel-arm, randomized controlled trial, we recruited primary care providers across Ontario not previously enrolled with eConsult. We randomly assigned participants to intervention and control arms. Participants in the intervention arm received access to eConsult for a period of 1 year while those in the control arm received no access to eConsult. The main outcome was specialist referral rate, expressed as the total number of referrals to (1) specialties available through eConsult, and (2) all medical specialties, per 100 patients seen. Multivariable negative binomial regression analysis was used to evaluate the effect of the intervention before and after adjusting for provider characteristics, using health administrative data., Results: One hundred and thirteen participants were randomized (56 to control and 57 to intervention). For the primary outcome (referrals to eConsult specialties), the results show a statistically significant reduction in the number of referrals in both arms (control-arm Rate Ratio (RR), 0.85, 95% CI 0.79 to 0.91; intervention-arm RR, 0.80, 95% CI 0.74 to 0.85; unadjusted and adjusted RR values almost identical), as compared to the baseline data collected during the 12-month period before randomization, with a non-statistically significant 6% greater reduction in referrals in the intervention arm, compared to the control arm (unadjusted RR 0.94, 95% CI 0.85 to 1.03; adjusted RR 0.93, 95% CI 0.85 to 1.03)., Conclusions: Our randomized controlled trial of a multispecialty eConsult service demonstrated inconclusive results in terms of the impact of eConsult on physician referral rates. Findings are discussed in light of important limitations associated with conducting randomized controlled trials (RCTs) of complex interventions in the primary care context with intent to inform the design and analysis of future trials., Trial Registration: Clinicaltrials.gov, ID: NCT02053467 . Registered prospectively on 3 February 2014.

Background: In 2002, the MORE OB (Managing Obstetrical Risk Efficiently) obstetrical patient safety program was phased-in across hospitals in Ontario, Canada. The purpose of our study was to evaluate the effect of the MORE OB program on rates of adverse maternal and neonatal outcomes., Methods: A retrospective cohort study, using province-wide administrative hospitalization data. We included maternal and neonatal records between fiscal years 2002-2003 and 2013-2014, for deliveries taking place at the 67 Ontario hospitals where the MORE OB program was implemented between 2002 and 2012. After accounting for institutional mergers and excluding very small hospitals, 55 hospitals (1,447,073 deliveries) were included. Multivariable logistic and linear mixed effects regression analysis were used, accounting for secular trends, within hospital correlation and over time correlation, and adjusting for a maternal comorbidity index, hospital annual birth volume, and level of care. The main outcome measure was a composite individual-level indicator of incidence of any adverse events, and a hospital-level score, called the Weighted Adverse Outcome Score (WAOS) capturing both maternal and neonatal adverse outcomes., Results: Across the 12 years of follow up, there were 98,789 adverse maternal and neonatal outcomes, a rate of 6.83 per 100 deliveries (6.66 per 100 occurring before, 6.91 per 100 during, and 6.84 per 100 after program implementation). The multivariable analysis found no statistically significant decrease in adverse events associated with program implementation (OR for adverse events after versus before =1.11 (95% CI: 1.06 to 1.17, change in mean WAOS score after minus before =0.15 (- 0.36 to 0.67))., Conclusions: We did not find a reduction in the incidence of maternal and neonatal adverse outcomes associated with the MORE OB program, and small yet statistically significant increases in some adverse events were observed.

Background: Homocysteine is an intermediate metabolite implicated in the risk of placenta-mediated complications, including preeclampsia, placental abruption, fetal growth restriction, and pregnancy loss. Large cohort and case-control studies have reported inconsistent associations between homocysteine and these complications. The purpose of this study was to investigate whether elevated maternal plasma homocysteine concentration in the early to mid-second trimester is associated with an increased risk of placenta-mediated complications. We examined the following potential moderating factors that may explain discrepancies among previous studies: high-risk pregnancy and the MTHFR 677C>T polymorphism., Methods: We analyzed data from participants recruited to the Ottawa and Kingston (OaK) Birth Cohort from 2002 to 2009 in Ottawa and Kingston, Canada. The primary outcome was a composite of any placenta-mediated complication, defined as a composite of small for gestational age (SGA) infant, preeclampsia, placental abruption, and pregnancy loss. Secondary outcomes were, individually: SGA infant, preeclampsia, placental abruption, and pregnancy loss. We conducted multivariable logistic regression analyses with homocysteine as the primary continuous exposure, adjusting for gestational age at the time of bloodwork and explanatory maternal characteristics. The functional form, i.e., the shape of the homocysteine association with the outcome was examined using restricted cubic splines and information criteria (Akaike's/Bayesian Information Criterion statistics). Missing data were handled with multiple imputation., Results: 7587 cohort participants were included in the study. Maternal plasma homocysteine concentration was significantly associated (linearly) with an increased risk of both the composite outcome of any placenta-mediated complication (p = 0.0007), SGA (p = 0.0010), severe SGA, and marginally with severe preeclampsia, but not preeclampsia, placental abruption and pregnancy loss. An increase in homocysteine concentration significantly increased the odds of any placenta-mediated complication (odds ratio (OR) for a 5 μmol/L increase: 1.63, 95% Confidence Interval (CI) 1.23-2.16) and SGA (OR 1.76, 95% CI 1.25-2.46). Subgroup analyses indicated some potential for modifying effects of the MTHFR 677C>T genotype and high-risk pregnancy, although the interaction was not statistically significant (high-risk subgroup OR 2.37, 95% CI 1.24-4.53, p-value for interaction =0.14)., Conclusions: Our results suggest an independent effect of early to mid-pregnancy elevated maternal homocysteine on placenta-mediated pregnancy complications.

Background: Randomized controlled trial (RCT) trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions (efficacy), whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices., Methods: Semi-structured interviews with key stakeholders (e.g. trialists, methodologists, lay members of study teams, bioethicists, and research ethics committee members), across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials., Discussion: We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications.

Background: There is a widely recognized need for more pragmatic trials that evaluate interventions in real-world settings to inform decision-making by patients, providers, and health system leaders. Increasing availability of electronic health records, centralized research ethics review, and novel trial designs, combined with support and resources from governments worldwide for patient-centered research, have created an unprecedented opportunity to advance the conduct of pragmatic trials, which can ultimately improve patient health and health system outcomes. Such trials raise ethical issues that have not yet been fully addressed, with existing literature concentrating on regulations in specific jurisdictions rather than arguments grounded in ethical principles. Proposed solutions (e.g. using different regulations in "learning healthcare systems") are speculative with no guarantee of improvement over existing oversight procedures. Most importantly, the literature does not reflect a broad vision of protecting the core liberty and welfare interests of research participants. Novel ethical guidance is required. We have assembled a team of ethicists, trialists, methodologists, social scientists, knowledge users, and community members with the goal of developing guidance for the ethical design and conduct of pragmatic trials., Methods: Our project will combine empirical and conceptual work and a consensus development process. Empirical work will: (1) identify a comprehensive list of ethical issues through interviews with a small group of key informants (e.g. trialists, ethicists, chairs of research ethics committees); (2) document current practices by reviewing a random sample of pragmatic trials and surveying authors; (3) elicit views of chairs of research ethics committees through surveys in Canada, UK, USA, France, and Australia; and (4) elicit views and experiences of community members and health system leaders through focus groups and surveys. Conceptual work will consist of an ethical analysis of identified issues and the development of new ethical solutions, outlining principles, policy options, and rationales. The consensus development process will involve an independent expert panel to develop a final guidance document., Discussion: Planned output includes manuscripts, educational materials, and tailored guidance documents to inform and support researchers, research ethics committees, journal editors, regulators, and funders in the ethical design and conduct of pragmatic trials.

Background: Primary care has been reformed in recent years in Ontario, Canada, with a move away from traditional fee-for-service to enhanced fee-for-service and capitation-based models. It is unclear how new models have affected disparities in cancer screening. We evaluated whether Ontario's enhanced fee-for-service model was associated with a change in the gaps in cancer screening for people living with low income and people who are foreign-born., Methods: We conducted a population-based longitudinal analysis from 2002 to 2013 of Ontario family physicians who transitioned from traditional fee-for-service to enhanced fee-for-service. The binary outcomes of interest were adherence to cervical, breast and colorectal cancer screening recommendations. Outcomes were analyzed using mixed-effects logistic regression. Analyses produced annual odds ratios comparing the odds of being up-to-date for screening among patients in enhanced fee-for-service versus patients in traditional fee-for-service for each social stratum separately. We calculated the ratios of stratum-specific odds ratios to assess whether the transition from traditional to enhanced fee-for-service was associated with a change in screening gaps between immigrants and long-term residents, and between people in the lowest and highest neighbourhood income quintiles., Results: Throughout the study period, cancer screening was consistently lower among immigrants and among people in the lowest income quintile. Transition to enhanced fee-for-service was generally associated with increased screening uptake for all, however for most years, ratios of ratios were significantly less than 1 for all three cancer screening types, indicating that there was a widening of the screening gap between immigrants and long-term residents and between people living in the lowest vs. highest income quintile associated with transitions., Conclusion: The transition to enhanced fee-for-service in Ontario was generally associated with a widening of screening inequities for foreign-born and low-income patients.