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Introduction: The pragmatic explanatory continuum indicator summary (PRECIS) tool, initially published in 2009 and revised in 2015, was created to assist trialists to align their design choices with the intended purpose of their randomised controlled trial (RCT): either to guide real-world decisions between alternative interventions (pragmatic) or to test hypotheses about intervention mechanisms by minimising sources of variation (explanatory). There have been many comments, suggestions, and criticisms of PRECIS-2. This summary will be used to facilitate the development of to the next revision, which is PRECIS-3., Methods: We used Web of Science to identify all publication types citing PRECIS-2, published between May 2015 and July 2023. Citations were eligible if they contained 'substantive' suggestions, comments, or criticism of the PRECIS-2 tool. We defined 'substantive' as comments explicitly referencing at least one PRECIS-2 domain or a concept directly linked to an existing or newly proposed domain. Two reviewers independently extracted comments, suggestions, and criticisms, noting their implications for the update. These were discussed among authors to achieve consensus on the interpretation of each comment and its implications for PRECIS-3., Results: The search yielded 885 publications, and after full-text review, 89 articles met the inclusion criteria. Comments pertained to new domains, changes in existing domains, or were relevant across several or all domains. Proposed new domains included assessment of the comparator arm and a domain to describe blinding. There were concerns about scoring eligibility and recruitment domains for cluster trials. Suggested areas for improvement across domains included the need for more scoring guidance for explanatory design choices., Discussion: Published comments recognise PRECIS-2's success in aiding trialists with pragmatic or explanatory design choices. Enhancing its implementation and widespread use will involve adding new domains, refining domain definitions, and addressing overall tool issues. This citation review offers valuable user feedback, pivotal for shaping the upcoming version of the PRECIS tool, PRECIS-3., Competing Interests: Declaration of competing interest All authors declare no conflict of interest. Dr Kirsty Loudon developed the PRECIS-2 tool as part of a DPhil., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We sought to improve the immediate and subsequent care of emergency department (ED) patients with acute atrial fibrillation (AF) and flutter (AFL) by implementing the principles of the Canadian Association of Emergency Physicians AF/AFL Best Practices Checklist., Methods: This cohort study included 3 periods: before (7 months), intervention introduction (1 month), and after (7 months), and was conducted at a major academic centre. We included patients who presented with an episode of acute AF or AFL and used multiple strategies to support ED adoption of the Canadian Association of Emergency Physicians checklist. We developed new cardiology rapid-access follow-up processes. The main outcomes were unsafe and suboptimal treatments in the ED., Results: We included 1108 patient visits, with 559 in the before and 549 in the after period. In a comparison of the periods, there was an increase in use of chemical cardioversion (20.6% vs 25.0%; absolute difference [AD], 4.4%) and in electrical cardioversion (39.2% vs 51.2%; AD, 12.0%). More patients were discharged with sinus rhythm restored (66.9% vs 75.0%; AD, 8.1%). The proportion seen in a follow-up cardiology clinic increased from 24.2% to 39.9% (AD, 15.7%) and the mean time until seen decreased substantially (103.3 vs 49.0 days; AD, -54.3 days). There were very few unsafe cases (0.4% vs 0.7%) and, although there was an increase in suboptimal care (19.5% vs 23.1%), overall patient outcomes were excellent., Conclusions: We successfully improved the care for ED patients with acute AF/AFL and achieved more frequent and more rapid cardiology follow-up. Although cases of unsafe management were uncommon and patient outcomes were excellent, there are opportunities for physicians to improve their care of acute AF/AFL patients., Gov Identifier: NCT05468281., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The prevalence of gestational diabetes mellitus (GDM) has been increasing globally over recent decades; however, underlying reasons for the increase remain unclear. We analyzed trends in GDM rates and evaluated risk factors associated with the observed trends in Ontario, Canada., Methods: We conducted a retrospective population-based cohort study using the Better Outcomes Registry and Network Ontario, linked with the Canadian Institute for Health Information Discharge Abstract Database. All pregnant individuals who had a singleton hospital delivery from 1 April 2012 to 31 March 2020 were included. We calculated rates and 95% CIs for GDM by year of delivery and contrasted fiscal year 2019/20 with 2012/13. Temporal trends in GDM were quantified using crude and adjusted risk ratios by modified Poisson regression. We further quantified the temporal increase attributable to changes in maternal characteristics by decomposition analysis., Results: Among 1 044 258 pregnant individuals, 82 896 (7.9%) were diagnosed with GDM over the 8 years. GDM rate rose from 6.1 to 10.4 per 100 deliveries between fiscal years 2012/13 and 2019/20. The risk of GDM in 2019/20 was 1.53 times (95% CI 1.50-1.56) higher compared with 2012/13. 27% of the increase in GDM was due to changes in maternal age, 8 BMI, and Asian ethnicity., Conclusions: The GDM rate has been consistently increasing in Ontario, Canada. The contribution of increasing maternal age, pre-pregnancy obesity, and Asian ethnicity to the recent increase in GDM is notable. Further investigation is required to better understand the contributors to increasing GDM., (Copyright © 2024 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Research teams are increasingly interested in using cluster randomized trial (CRT) designs to generate practice-guiding evidence for in-center maintenance hemodialysis. However, CRTs raise complex ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues arising within 7 domains: justifying the CRT design, research ethics committee review, identifying research participants, obtaining informed consent, gatekeepers, assessing benefits and harms, and protecting vulnerable participants. But applying the Ottawa Statement recommendations to CRTs in the hemodialysis setting is complicated by the unique features of the setting and population. Here, with the help of content experts and patient partners, we co-developed this implementation guidance document to provide research teams, research ethics committees, and other stakeholders with detailed guidance on how to apply the Ottawa Statement recommendations to CRTs in the hemodialysis setting, the result of a 4-year research project. Thus, our work demonstrates how the voices of patients, caregivers, and all stakeholders may be included in the development of research ethics guidance., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: Children and families are increasingly involved as equal partners in child health research, however, considerations around authorship have received little attention and there is limited guidance on the topic. Our objective was to determine the frequency and nature of patient partner authorship and/or acknowledgment among articles focused on patient engagement in child health research., Study Design and Setting: In this umbrella review, we searched MEDLINE, Embase, APA PsycINFO, Cochrane Database of Systematic Reviews, CINAHL, and Web of Science for systematic/scoping reviews on patient engagement in child health research. Individual articles included in eligible reviews comprised the sample of articles for analysis and were examined to identify patient partner authorship. Descriptive statistics were used to quantify patient partner authorship and/or acknowledgment and to summarize article characteristics., Results: Twelve systematic/scoping reviews met eligibility criteria, from which 230 individual articles were examined. In 16/230 (7%) articles, there was at least one patient partner author, and in 6/230 (3%) articles, patient partners were included as group authors. Within article Acknowledgments sections, patient partners were acknowledged by name in 41/230 (18%) articles, and anonymously or as a group in 98/230 (43%) articles. Patient partner authorship and/or acknowledgment was more frequent among articles published more recently (after 2015) and among articles where patient engagement was explicitly reported in the article., Conclusion: Patient partners were more likely to be acknowledged than listed as an author on articles on patient engagement in child health research. Understanding patient partner preferences about authorship and acknowledgment, examination of the unique aspects of child and youth authorship and developing supports to empower patient partner authorship are needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Registry-based randomized controlled trials (RRCTs) have potential to address limitations of traditional clinical trials. To describe their current use, information on planned and published RRCTs was identified and synthesized., Study Design and Setting: A scoping review of published RRCT protocols and reports was conducted. Articles published between 2010 and 2021 identified from electronic database searching, a recent review of RRCTs, and targeted searching for recent RRCT protocols (2018-2021) were screened. Data on trial data sources, types of primary outcomes, and how these primary outcomes were described, selected, and reported were extracted., Results: Ninety RRCT articles (77 reports; 13 protocols) were included. Forty nine (54%) used or planned to rely on registry data for their trial, 26 (29%) used both registry and additional data, and 15 (17%) used the registry solely for recruitment. Primary outcomes were routinely collected from the registry for 66 articles (73%). Only 28 articles (31%) described any methods to promote outcome data quality during or after data collection. Core outcome sets were not used in any of the trials., Conclusion: With improvements in registry design, outcome selection, measurement, and reporting, future RRCTs may deliver on promises of efficient, high-quality trials that address clinically relevant questions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: In stepped-wedge cluster randomized trials (SW-CRTs), clusters are randomized not to treatment and control arms but to sequences dictating the times of crossing from control to intervention conditions. Randomization is an essential feature of this design but application of standard methods to promote and report on balance at baseline is not straightforward. We aimed to describe current methods of randomization and reporting of balance at baseline in SW-CRTs., Study Design and Setting: We used electronic searches to identify primary reports of SW-CRTs published between 2016 and 2022., Results: Across 160 identified trials, the median number of clusters randomized was 11 (Q1-Q3: 8-18). Sixty-three (39%) used restricted randomization-most often stratification based on a single cluster-level covariate; 12 (19%) of these adjusted for the covariate(s) in the primary analysis. Overall, 50 (31%) and 134 (84%) reported on balance at baseline on cluster- and individual-level characteristics, respectively. Balance on individual-level characteristics was most often reported by condition in cross-sectional designs and by sequence in cohort designs. Authors reported baseline imbalances in 72 (45%) trials., Conclusion: SW-CRTs often randomize a small number of clusters using unrestricted allocation. Investigators need guidance on appropriate methods of randomization and assessment and reporting of balance at baseline., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Randomized trials labelled as "pragmatic" are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g., by referring to one or more PRECIS [PRagmatic Explanatory Continuum Indicator Summary]-2 domains)., Study Design and Setting: We reviewed primary trial reports published 2014-2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report., Results: Among 415 trials, the label was justified by reference to at least one design element in 282 (68.0%); of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility delivery (89, 31.6%), and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%), and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels., Conclusion: Current use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To explore challenges in recruitment and intervention implementation in recent stepped-wedge cluster randomized trials (SW-CRTs)., Study Design and Setting: We searched PubMed to identify primary reports of SW-CRTs (2019-2020). Two reviewers independently screened studies and extracted data from each report. A recruitment challenge was defined as a planned number of clusters or participants not achieved or any reported changes made to the design to address recruitment difficulties. An implementation challenge was defined as early, late, or no implementation of the intervention in at least one cluster., Results: Of 55 SW-CRTs, 18 (33%) had a recruitment challenge, 23 (42%) had none, and for 14 (26%) it was impossible to judge. At least one implementation challenge was present in 24 (44%), eight (15%) had none, and for 23 (42%) it was impossible to judge. Of the 35 (64%) trials with recruitment or implementation challenges, 18 (72%) had one or more modifications of their design, most often a modification of the trial duration., Conclusion: Investigators must be aware of the risks of recruitment or implementation challenges when considering the use of an SW-CRT design. Mitigating strategies should be adopted when planning the trial. More transparent reporting of planned and actual design features is required., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Over the past decade, visits to American and Canadian emergency departments (EDs) for child and youth mental health care have increased substantially. 1,2 Acute mental health crises can occur as a result of a variety of concerns, including those that are life threatening (eg, suicide attempts), pose safety concerns (eg, suicidal intentions, aggressive behaviors, alcohol and other drug use), and are physically distressing to the child or youth (eg, panic attacks). ED health care providers play a vital role in assessing the safety and well-being of the child or youth and referring them to services for ongoing care. 3,4 During the ED visit, assessment and care should pinpoint risks, inform treatment, and consider family needs and preferences as part of a patient-centered approach. Yet, this approach to care is not widely adopted in EDs. Most EDs do not require the use of pediatric-specific mental health tools to guide assessments or have patient-centered procedures in place to guide the care of patients with mental health emergencies. 5-7 Our team believes these limitations have led to the provision of acute mental health care that can lack sufficient quality and efficiency. This study protocol describes a trial designed to evaluate if a novel mental health care bundle that was co-designed with parents and youth results in greater improvements in the well-being of children and youth 30 days after seeking ED care for mental health and/or substance misuse concerns compared with existing care protocols. We hypothesize that the bundle will positively impact child and youth well-being, while also providing cost-effective health care system benefits., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Frailty is a state of vulnerability as a result of decreased reserves. Prehabilitation may increase reserve and improve postoperative outcomes. Our objective was to determine if home-based prehabilitation improves postoperative functional recovery in older adults with frailty having cancer surgery., Methods: This double blind randomised trial enrolled people ≥60 yr having elective cancer surgery and ≥3 weeks from enrolment to surgery as eligible. Participation in a remotely supported, home-based exercise prehabilitation program plus nutritional guidance was compared with standard care plus written advice on age-appropriate activity and nutrition. The primary outcome was 6-min walk test (6MWT) distance at the first postoperative clinic visit. Secondary outcomes included physical performance, quality of life, disability, length of stay, non-home discharge, and 30-day readmission., Results: Of 543 patients assessed, 254 were eligible and 204 (80%) were randomised (102 per arm); 182 (94 intervention and 88 control) had surgery and were analysed. Mean age was 74 yr and 57% were female. Mean duration of participation was 5 weeks, mean adherence was 61% (range 0%-100%). We found no significant difference in 6MWT at follow-up (+14 m, 95% confidence interval -26-55 m, P=0.486), or for secondary outcomes. Analyses using a prespecified adherence definition of ≥80% supported improvements in 6MWT distance, complication count, and disability., Conclusions: A home-based prehabilitation program did not significantly improve postoperative recovery or other outcomes in older adults with frailty having cancer surgery. Program adherence may be a key mediator of prehabilitation efficacy., Clinical Trial Registration: NCT02934230., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: To determine the population-level impact of COVID-19 pandemic-related obstetric practice changes on maternal and newborn outcomes., Methods: Segmented regression analysis examined changes that occurred 240 weeks pre-pandemic through the first 32 weeks of the pandemic using data from Ontario's Better Outcomes Registry & Network. Outcomes included birth location, length of stay, labour analgesia, mode of delivery, preterm birth, and stillbirth. Immediate and gradual effects were modelled with terms representing changes in intercepts and slopes, corresponding to the start of the pandemic., Results: There were 799 893 eligible pregnant individuals included in the analysis; 705 767 delivered in the pre-pandemic period and 94 126 during the pandemic wave 1 period. Significant immediate decreases were observed for hospital births (relative risk [RR] 0.99; 95% CI 0.98-0.99), length of stay (median change -3.29 h; 95% CI -3.81 to -2.77), use of nitrous oxide (RR 0.11; 95% CI 0.09-0.13) and general anesthesia (RR 0.69; 95% CI 0.58- 0.81), and trial of labour after cesarean (RR 0.89; 95% CI 0.83-0.96). Conversely, there were significant immediate increases in home births (RR 1.35; 95% CI 1.21-1.51), and use of epidural (RR 1.02; 95% CI 1.01-1.04) and regional anesthesia (RR 1.01; 95% CI 1.01-1.02). There were no significant immediate changes for any other outcomes, including preterm birth (RR 0.99; 95% CI 0.93-1.05) and stillbirth (RR 1.11; 95% CI 0.87-1.42)., Conclusion: Provincial health system changes implemented at the start of the pandemic resulted in immediate clinical practice changes but not insignificant increases in adverse outcomes., (Copyright © 2022 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Meta-research is the discipline of studying research itself. A core investigative tool in meta-research is the use of systematic or scoping reviews to study the characteristics, methods and reporting of primary research studies. In the context of identifying eligible publications for methodological reviews of randomized controlled trials (RCTs), a challenge is to efficiently distinguish the primary trial report - which reports results for the primary outcome - from other types of reports, including design papers and secondary or supplementary analyses, or what we collectively refer to as non-primary reports. This may not be a straightforward task and may contribute to inefficiencies in the review process. Here, we draw on our recent methodological review of over 13,000 records to identify primary reports of pragmatic RCTs. We offer recommendations to improve the reporting of RCTs to facilitate more efficient identification of primary trial reports. We suggest that future updates to existing CONSORT guidelines include consideration of multiple trial reports and recommendations to clarify the primary or non-primary nature of each report. Our recommendations, together with improved adherence to inclusion of the trial registration number in the abstract and citation of a protocol or previously published primary report, would facilitate the conduct of methodological reviews., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To determine the prevalence of poor interpretation practices, such as conflating evidence of absence with absence of evidence and over-emphasis of statistical non-significance in abstract conclusions, in a sample of randomized controlled trials (RCTs) with non-statistically significant primary outcomes published after the 2016 American Statistical Association statement on the interpretation of P-values., Design and Setting: Review of 50 two-arm individually randomized superiority trials with non-statistically significant results in four high impact journals published between 2017 and 2020, to determine the proportion that conclude evidence of no impact (thus, likely conflating evidence of absence with absence of evidence) or place emphasis on statistical non-significance (technically correct but arguably uninformative) in the abstract conclusion., Results: Of the 50 RCTs with non-statistically significant results for primary outcomes, 28 (56%) of abstract were classified as concluding there was no difference between the two treatments; 19 (38%) placed an over-emphasis on statistical significance; only one acknowledged any uncertainty and the remaining 2 (4%) concluded that one treatment was more effective. Only four studies provided any justification for a finding of no difference, for example that the confidence interval gave no support to values of importance., Conclusions: RCTs with non-statistically significant primary outcomes almost always present their conclusion in the abstract as evidence of no impact or ambiguously as "not statistically significant" without giving due attention to values supported by the confidence interval., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Interrupted Time Series (ITS) are a type of nonrandomized design commonly used to evaluate public health policy interventions, and the impact of exposures, at the population level. Meta-analysis may be used to combine results from ITS across studies (in the context of systematic reviews) or across sites within the same study. We aimed to examine the statistical approaches, methods, and completeness of reporting in reviews that meta-analyze results from ITS., Study Design and Settings: Eight electronic databases were searched to identify reviews (published 2000-2019) that meta-analyzed at least two ITS. Characteristics of the included reviews, the statistical methods used to analyze the ITS and meta-analyze their results, effect measures, and risk of bias assessment tools were extracted., Results: Of the 4213 identified records, 54 reviews were included. Nearly all reviews (94%) used two-stage meta-analysis, most commonly fitting a random effects model (69%). Among the 41 reviews that re-analyzed the ITS, linear regression (39%) and ARIMA (20%) were most commonly used; 38% adjusted for autocorrelation. The most common effect measure meta-analyzed was an immediate level-change (46/54). Reporting of the statistical methods and ITS characteristics was often incomplete., Conclusion: Improvement is needed in the conduct and reporting of reviews that meta-analyze results from ITS., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to determine if offering a 12-dose once-weekly treatment (3HP) as an additional treatment option would result in an increase in the overall proportion of patients completing TB preventive treatment (TPT) above the baseline rate., Methods: We analyzed outcomes in consecutive adults referred to a TB clinic from January 2010 to May 2019. Starting December 2016, 3HP was offered as an alternative to standard clinic regimens which included 9 months of daily isoniazid or 4 months of daily rifampin. The primary outcome was the proportion of patients who completed TPT among all patients who started treatment. Using segmented autoregression analysis, we compared completion at the end of the study with projected completion had the intervention not been introduced., Results: A total of 2803 adults were referred for assessment over the study period. There was an absolute increase in completions among those who started a treatment of 19.0% at the end of the study between the observed intervention completion rate and the projected completion rate from the baseline study period (the completion rate had the 3HP intervention not been introduced) (76% observed vs 57% projected; 95% CI 6.6 to 31.4%; p = 0.004) and an absolute increase among those who were offered treatment (17.3%; 95% CI, 2.3 to 32.3%; p = 0.025)., Conclusions: The introduction of 3HP for TPT as an alternative to the regular regimens offered resulted in a significant increase in the proportion of patients completing treatment. Our study provides evidence to support accelerated use of 3HP in Canada., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread resistance to insecticides among vectors. We evaluated new classes of LLINs with two active ingredients with differing modes of action against resistant malaria vectors., Methods: We did a four-arm, cluster-randomised trial in Misungwi, Tanzania. Clusters were villages, or groups of hamlets, with at least 119 households containing children aged 6 months to 14 years living in the cluster's core area. Constrained randomisation was used to allocate clusters (1:1:1:1) to receive one of four types of LLIN treated with the following: α-cypermethrin only (pyrethroid-only [reference] group); pyriproxyfen and α-cypermethrin (pyriproxyfen group); chlorfenapyr and α-cypermethrin (chlorfenapyr group); or the synergist piperonyl butoxide and permethrin (piperonyl butoxide group). At least one LLIN was distributed for every two people. Community members and the field team were masked to group allocation. Malaria prevalence data were collected through cross-sectional surveys of randomly selected households from each cluster, in which children aged 6 months to 14 years were assessed for Plasmodium falciparum malaria infection by rapid diagnostic tests. The primary outcome was malaria infection prevalence at 24 months after LLIN distribution, comparing each of the dual-active-ingredient LLINs to the standard pyrethroid-only LLINs in the intention-to-treat population. The primary economic outcome was cost-effectiveness of dual-active-ingredient LLINs, based on incremental cost per disability-adjusted life-year (DALY) averted compared with pyrethroid-only LLINs, modelled over a 2-year period; we included costs of net procurement and malaria diagnosis and treatment, and estimated DALYs in all age groups. This study is registered with ClinicalTrials.gov (NCT03554616), and is ongoing but no longer recruiting., Findings: 84 clusters comprising 39 307 households were included in the study between May 11 and July 2, 2018. 147 230 LLINs were distributed among households between Jan 26 and Jan 28, 2019. Use of study LLINs was reported in 3155 (72·1%) of 4378 participants surveyed at 3 months post-distribution and decreased to 8694 (40·9%) of 21 246 at 24 months, with varying rates of decline between groups. Malaria infection prevalence at 24 months was 549 (45·8%) of 1199 children in the pyrethroid-only reference group, 472 (37·5%) of 1258 in the pyriproxyfen group (adjusted odds ratio 0·79 [95% CI 0·54-1·17], p=0·2354), 512 (40·7%) of 1259 in the piperonyl butoxide group (0·99 [0·67-1·45], p=0·9607), and 326 [25·6%] of 1272 in the chlorfenapyr group (0·45 [0·30-0·67], p=0·0001). Skin irritation or paraesthesia was the most commonly reported side-effect in all groups. Chlorfenapyr LLINs were the most cost-effective LLINs, costing only US$19 (95% uncertainty interval 1-105) more to public providers or $28 (11-120) more to donors per DALY averted over a 2-year period compared with pyrethroid-only LLINs, and saving costs from societal and household perspectives., Interpretation: After 2 years, chlorfenapyr LLINs provided significantly better protection than pyrethroid-only LLINs against malaria in an area with pyrethroid-resistant mosquitoes, and the additional cost of these nets would be considerably below plausible cost-effectiveness thresholds ($292-393 per DALY averted). Before scale-up of chlorfenapyr LLINs, resistance management strategies are needed to preserve their effectiveness. Poor textile and active ingredient durability in the piperonyl butoxide and pyriproxyfen LLINs might have contributed to their relative lack of effectiveness compared with standard LLINs., Funding: Joint Global Health Trials scheme (UK Foreign, Commonwealth and Development Office; UK Medical Research Council; Wellcome; UK Department of Health and Social Care), US Agency for International Development, President's Malaria Initiative., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To describe prevalence of multiple primary outcomes, changes in primary outcomes and target sample sizes between protocols and final reports, and how issues of multiplicity are addressed in pragmatic trials., Study Design and Setting: Individually randomized trials labeled as pragmatic, published 2014-2019 in MEDLINE and registered with ClinicalTrials.gov., Results: We identified 262 final reports and located protocols for 159 (61%); primary outcomes were clearly reported in 145 (91%) protocols and 256 (98%) final reports. Thirty (19%) protocols and 38 (15%) final reports had multiple primary outcomes. Primary outcomes were present and identical in 128 (81%) matched protocol-final reports. Among 140 pairs with target sample sizes reported, 28 (20.0%) reduced their target sample size (mean 543 fewer participants per trial) and 16 (11.4%) increased it (mean 192 more participants per trial). Thirteen (29.5%) provided an explanation. Only 2 of 30 (7%) protocols and 4 of 38 (11%) final reports with co-primary outcomes explained how results would be interpreted in light of multiplicity; 21 of 30 (70%) protocols and 20 of 38 (53%) final reports accounted for co-primary outcomes in power calculations., Conclusion: Co-primary outcomes are common in pragmatic trials; improved transparency around design and analysis decisions involving co-primary outcomes is required., (Copyright © 2021. Published by Elsevier Inc.)

Background: Incorporating cluster randomized trials (CRTs) into meta-analyses is challenging because appropriate standard errors of study estimates accounting for clustering are not always reported. Systematic reviews of CRTs often use a single constant external estimate of the intraclass correlation coefficient (ICC) to adjust study estimate standard errors and facilitate meta-analyses; an approach that fails to account for possible variation of ICCs among studies and the imprecision with which they are estimated. Using a large systematic review of the effects of diabetes quality improvement interventions, we investigated whether we could better account for ICC variation and uncertainty in meta-analyzed effect estimates by imputing missing ICCs from a posterior predictive distribution constructed from a database of relevant ICCs., Methods: We constructed a dataset of ICC estimates from applicable studies. For outcomes with two or more available ICC estimates, we constructed posterior predictive ICC distributions in a Bayesian framework. For a selected continuous outcome, glycosylated hemoglobin (HbA1c), we compared the impact of incorporating a single constant ICC versus imputing ICCs drawn from the posterior predictive distribution when estimating the effect of intervention components on post treatment mean in a case study of diabetes quality improvement trials., Results: Using internal and external ICC estimates, we were able to construct a database of 59 ICCs for 12 of the 13 review outcomes (range 1-10 per outcome) and estimate the posterior predictive ICC distribution for 11 review outcomes. Synthesized results were not markedly changed by our approach for HbA1c., Conclusion: Building posterior predictive distributions to impute missing ICCs is a feasible approach to facilitate principled meta-analyses of cluster randomized trials using prior data. Further work is needed to establish whether the application of these methods leads to improved review inferences for different reviews based on different factors (e.g., proportion of CRTs and CRTs with missing ICCs, different outcomes, variation and precision of ICCs)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We sought to evaluate safety of electrical cardioversion (ECV) for patients with acute atrial fibrillation (AF) or atrial flutter (AFL) in the emergency department (ED)., Methods: This was an analysis of data from 4 multicentre AF/AFL studies conducted from 2008 to 2019 at 23 large EDs. We included adult patients who received attempts at ECV and who had presented acutely after symptom onset. Staff manually reviewed study and clinical records to abstract data., Results: We evaluated 1736 ECV cases with a mean age of 60.1 years and 67.1% male. The overall success of ECV was 90.2% (95% confidence interval 88.7%-91.6%), with 4.9% of patients admitted. ED physicians performed the ECV in 95.2% and provided sedation in 96.5%; 13.9% (12.3%-15.7%) of cases experienced important adverse events that required treatment, and 0.4% were classified as life threatening. Another 5.6% had adverse events that did not require treatment. Logistic regression found that the RAFF-3 study cohort (odds ratio [OR] 2.0), age ≥ 85 years (OR 2.1), coronary artery disease (OR 1.5), midazolam (OR 1.9), and fentanyl (OR 1.5) were associated with important adverse events., Conclusions: This large evaluation of the safety of ECV for acute AF/AFL in the ED found that while serious adverse events were rare, there were a concerning number of events following sedation that required intervention. Physicians should be aware that older age, coronary artery disease, and fentanyl are associated with higher risks of important adverse events. This study provides more information for shared decision making discussions with patients when choosing between drug-shock and shock-only cardioversion strategies., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the prevalence of risks of bias in cluster-randomized trials of individual-level interventions, according to the Cochrane Risk of Bias tool., Study Design and Setting: Review undertaken in duplicate of a random sample of 40 primary reports of cluster-randomized trials of individual-level interventions., Results: The most common reported reasons for adopting cluster randomization were the need to avoid contamination (17, 42.5%) and practical considerations (14, 35%). Of the 40 trials all but one was assessed as being at risk of bias. A majority (27, 67.5%) were assessed as at risk due to the timing of identification and recruitment of participants; many (21, 52.5%) due to an apparent lack of adequate allocation concealment; and many due to selectively reported results (22, 55%), arising from a mixture of reasons including lack of documentation of primary outcome. Other risks mostly occurred infrequently., Conclusion: Many cluster-randomized trials evaluating individual-level interventions appear to be at risk of bias, mostly due to identification and recruitment biases. We recommend that investigators carefully consider the need for cluster randomization; follow recommended procedures to mitigate risks of identification and recruitment bias; and adhere to good reporting practices including clear documentation of primary outcome and allocation concealment methods., (Copyright © 2021. Published by Elsevier Inc.)

Background: We sought to improve care of patients with acute atrial fibrillation (AF) and flutter (AFL) in the emergency department (ED) by implementing the Canadian Association of Emergency Physicians (CAEP) Acute AF/AFL Best Practices Checklist., Methods: We conducted a stepped-wedge cluster randomised trial at 11 large community and academic hospital EDs in 5 Canadian provinces and enrolled consecutive AF/AFL patients. The study intervention was introduction of the CAEP Checklist with the use of a knowledge translation-implementation approach that included behaviour change techniques and organisation/system-level strategies. The primary outcome was length of stay in ED, and secondary outcomes were discharge home, use of rhythm control, adverse events, and 30-day status. Analysis used mixed-effects regression adjusting for covariates., Results: Patient visits in the control (n = 314) and intervention (n = 404) periods were similar with mean age 62.9 years, 54% male, 71% onset < 12 hours, and 86% AF, 14% AFL. We observed a reduction in length of stay of 20.9% (95% confidence interval [CI] 5.5%-33.8%; P = 0.01), an increase in use of rhythm control (adjusted odds ratio [OR] 4.5, 95% CI 1.8-11.6; P = 0.002), and a decrease in use of rate-control medications (OR 0.5, 95% CI 0.2-0.9; P = 0.02). There was no change in adverse events and no strokes or deaths by 30 days., Conclusions: The RAFF-3 trial led to optimised care of AF/AFL patients with decreased ED lengths of stay, increased ED rhythm control by drug or electricity, and no increase in adverse events. Early cardioversion allows AF/AFL patients to quickly resume normal activities., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be designed with either a pragmatic or explanatory mindset. Whereas pragmatic trials aim to inform the choice between different care options and thus, are designed to resemble conditions outside of a clinical trial environment, explanatory trials examine the benefit of a treatment under more controlled conditions. There is existing guidance for designing feasibility studies, but none that explicitly considers the goals of pragmatic designs. We aimed to identify unique areas of uncertainty that are relevant to planning a pragmatic trial., Results: We identified ten relevant domains, partly based on the pragmatic-explanatory continuum indicator summary-2 (PRECIS-2) framework, and describe potential questions of uncertainty within each: intervention development, research ethics, participant identification and eligibility, recruitment of individuals, setting, organization, flexibility of delivery, flexibility of adherence, follow-up, and importance of primary outcome to patients and decision-makers. We present examples to illustrate how uncertainty in these domains might be addressed within a feasibility study., Conclusion: Researchers planning a feasibility study in advance of a pragmatic trial should consider feasibility objectives specifically relevant to areas of uncertainty for pragmatic trials., (Copyright © 2021. Published by Elsevier Inc.)

Objective: We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape of pragmatic trials including research areas, identification as pragmatic, quality of trial registry data and enrolment., Study Design and Setting: Trials were identified by a validated search filter and included if a primary report of a health-related randomized trial published January 2014-April 2019. Data were collated from MEDLINE, Web of Science, ClinicalTrials.gov, and full text., Results: 4337 eligible trials were identified from 13,065 records, of which 1988 were registered in ClinicalTrials.gov. Research areas were diverse, with the most common being general and internal medicine; public, environmental and occupational health; and health care sciences and services. The term "pragmatic" was seldom used in titles or abstracts. Several domains in ClinicalTrials.gov had questionable data quality. We estimated that one-fifth of trials under-accrued by at least 15%., Conclusion: There is a need to improve reporting of pragmatic trials and quality of trial registry data. Under accrual remains a challenge in pragmatic RCTs despite calls for more streamlined recruitment approaches. The diversity of pragmatic trials should be reflected in future ethical analyses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Acute heart failure and exacerbation of chronic obstructive pulmonary disease (COPD) are sometimes difficult to differentiate in the emergency department (ED)., Objectives: We sought to determine the classification performance of lung point-of-care ultrasound (POCUS) compared with chest x-ray study to identify acute heart failure in an older population., Methods: We conducted a cohort study with additional health records review between March and September 2017. We included consecutive patients aged 50 years and older with shortness of breath from suspected acute heart failure or COPD. The reference standard was discharged diagnosis, ED diagnosis with confirmation by another physician, or diagnosis made by health record reviews. We calculated the classification performance of lung POCUS to diagnose acute heart failure as well as that of chest x-ray study, and compared them by exact McNemar test., Results: There were 81 patients evaluated with lung POCUS, and 67 had acute heart failure. Emergency physicians identified acute heart failure by lung POCUS with sensitivity of 92.5% (95% confidence interval [CI] 83.4-97.5%) and specificity of 85.7% (95% CI 57.2-98.2%). The radiology reading of chest x-ray study had sensitivity of 63.6% (95% CI 50.9-75.1%) and specificity of 92.9% (95% CI 66.1-99.8%). The sensitivity of lung POCUS was significantly higher than that of chest x-ray study (p = 0.0003)., Conclusions: Lung POCUS in a real clinical setting was highly sensitive and specific in identifying acute heart failure, and performed better than chest x-ray in an older population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To estimate the prevalence of time-to-event (TTE) outcomes in cluster randomized trials (CRTs) and to examine their statistical management., Study Design and Setting: We searched PubMed to identify primary reports of CRTs published in six major general medical journals (2013-2018). Nature of outcomes and, for TTE outcomes, statistical methods for sample size, analysis, and measures of intracluster correlation were extracted., Results: A TTE analysis was used in 17% of the CRTs (32/184) either as a primary or secondary outcome analysis, or in a sensitivity analysis. Among the five CRTs with a TTE primary outcome, two accounted for both intracluster correlation and the TTE nature of the outcome in sample size calculation; one reported a measure of intracluster correlation in the analysis. Among the 32 CRTs with a least one TTE analysis, 44% (14/32) accounted for clustering in all TTE analyses. We identified 12 additional CRTs in which there was at least one outcome not analyzed as TTE for which a TTE analysis might have been preferred., Conclusion: TTE outcomes are not uncommon in CRTs but appropriate statistical methods are infrequently used. Our results suggest that further methodological development and explicit recommendations for TTE outcomes in CRTs are needed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Frailty is associated with early postoperative outcomes. How frailty influences long-term postoperative recovery is poorly described. Our objective was to evaluate the association of frailty with postoperative disability trajectories in the year after surgery., Methods: Prespecified 1-yr follow-up of a prospective multicentre cohort study. Patients ≥65 yr were assessed for frailty before major elective noncardiac surgery (Clinical Frailty Scale [CFS] and Fried Phenotype [FP]). The primary outcome was patient-reported disability score (using the WHO Disability Assessment Schedule 2.0) at baseline, 30, 90, and 365 days after surgery. Repeated measures linear regression estimated the association of preoperative frailty with changes in disability scores over time, adjusted for procedure. Group-based trajectory modelling was used to identify subgroup trajectories of people with frailty., Results: One-year follow-up was complete for 687/702 (97.9%) participants. Frailty was associated with a significant difference in disability trajectory (P<0.0001). Compared with baseline, people with frailty experienced a decrease in disability score at 365 days (CFS frailty: -7.3 points, 95% confidence interval [CI] -10.2 to -4.5); (FP frailty: -5.4 points, 95% CI -8.5 to -2.3); people without frailty had no significant change in their disability score from baseline (no CFS frailty: +0.8 points, 95% CI -1.7 to 3.2; no FP frailty: +1.1 points, 95% CI -3.5 to 1.3). More than one-third of people with frailty experienced an early increase in disability before achieving a net decrease in disability., Conclusions: Decision-making and care planning should integrate the possible trade-offs between early adverse outcomes with longer-term benefit when frailty is present in older surgical patients., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: It is now more than 50 years since the concepts of explanatory and pragmatic attitudes toward trials were first discussed by Schwartz and Lellouch in their influential 1967 paper. Since then, there has been increasing focus on design aspects that may be consistent with more pragmatic attitudes within clinical trials, and a number of tools developed to assist investigators prospectively think about their trial design. Researchers have subsequently expressed interest in using these tools retrospectively to characterize trials as pragmatic or explanatory., Results: We suggest that recent attempts to retrospectively dichotomize trials solely on the basis of quantitative scoring of trial design features are flawed. Instead, we argue that there is a need to consider both the intent and design when assessing the degree of pragmatism within a trial., Conclusion: The practical implication of our suggestion for trial reporting is that investigators should explicitly state the intent of the trial through a clear articulation of the decision that they hope will be informed by the trial results. This should be coupled with a completed PRagmatic-Explanatory Continuum Indicator Summary 2 assessment (or similar) with an explanation of study design choices to appropriately assess whether the study design is consistent with the study intent. We believe this will assist reviewers and knowledge users in making assessments of trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Identifying pragmatic trials from among all randomized trials is challenging because of inconsistent reporting. Our objective was to develop and validate a search filter to identify reports of pragmatic trials from Ovid MEDLINE., Study Design and Setting: Two sets of known and probable pragmatic trial records were analyzed using text mining to generate candidate terms. Two large population sets comprising clinical trials and explanatory trials were used to select discriminating terms. Various combinations of terms were tested iteratively to achieve optimal search performance. Two externally derived sets were used to validate sensitivity and specificity of the derived filters., Results: Our validated sensitivity-maximizing filter (combines trial design terms with terms relating to attributes of pragmatic trials) retrieves over 42,000 records in MEDLINE and has sensitivity of 46.4% (95% confidence interval (CI) 37.2 to 55.7%) and estimated specificity of 98.1% (95% CI 93.4 to 99.8%). Search performance is superior to other ad hoc filters for pragmatic trials. The Cochrane search for randomized trials has much better sensitivity (98.2%), but poorer specificity (1.9%) and retrieves 4.5 million records., Conclusion: A highly specific filter (low false positive rate) with moderate sensitivity is available for identifying reports of trials more likely to be pragmatic., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Interrupted time series (ITS) designs are frequently used in public health to examine whether an intervention or exposure has influenced health outcomes. Few reviews have been undertaken to examine the design characteristics, statistical methods, and completeness of reporting of published ITS studies., Study Design and Setting: We used stratified random sampling to identify 200 ITS studies that evaluated public health interventions or exposures from PubMed (2013-2017). Study characteristics, details of statistical models and estimation methods used, effect metrics, and parameter estimates were extracted. From the 200 studies, 230 time series were examined., Results: Common statistical methods used were linear regression (31%, 72/230) and autoregressive integrated moving average (19%, 43/230). In 17% (40/230) of the series, we could not determine the statistical method used. Autocorrelation was acknowledged in 63% (145/230) of the series. An estimate of the autocorrelation coefficient was given for only 1% of the series (3/230). Measures of precision were reported for 63% of effect measures (541/852)., Conclusion: Many aspects of the design, methods, analysis, and reporting of ITS studies can be improved, particularly description of the statistical methods and approaches to adjust for and estimate autocorrelation. More guidance on the conduct and reporting of ITS studies is needed to improve this study design., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Acute atrial fibrillation is the most common arrythmia treated in the emergency department. Our primary aim was to compare conversion to sinus rhythm between pharmacological cardioversion followed by electrical cardioversion (drug-shock), and electrical cardioversion alone (shock-only). Our secondary aim was to compare the effectiveness of two pad positions for electrical cardioversion., Methods: We did a partial factorial trial of two protocols for patients with acute atrial fibrillation at 11 academic hospital emergency departments in Canada. We enrolled adult patients with acute atrial fibrillation. Protocol 1 was a randomised, blinded, placebo-controlled comparison of attempted pharmacological cardioversion with intravenous procainamide (15 mg/kg over 30 min) followed by electrical cardioversion if necessary (up to three shocks, each of ≥200 J), and placebo infusion followed by electrical cardioversion. For patients having electrical cardioversion, we used Protocol 2, a randomised, open-label, nested comparison of anteroposterior versus anterolateral pad positions. Patients were randomly assigned (1:1, stratified by study site) for Protocol 1 by on-site research personnel using an online electronic data capture system. Randomisation for Protocol 2 occurred 30 min after drug infusion for patients who had not converted and was stratified by site and Protocol 1 allocation. Patients and all research and emergency department staff were masked to treatment allocation for Protocol 1. The primary outcome was conversion to normal sinus rhythm for at least 30 min at any time after randomisation and up to a point immediately after three shocks. Protocol 1 was analysed by intention to treat and Protocol 2 excluded patients who did not receive electrical cardioversion. This study is registered at ClinicalTrials.gov, number NCT01891058., Findings: Between July 18, 2013, and Oct 17, 2018, we enrolled 396 patients, and none were lost to follow-up. In the drug-shock group (n=204), conversion to sinus rhythm occurred in 196 (96%) patients and in the shock-only group (n=192), conversion occurred in 176 (92%) patients (absolute difference 4%; 95% CI 0-9; p=0·07). The proportion of patients discharged home was 97% (n=198) versus 95% (n=183; p=0·60). 106 (52%) patients in the drug-shock group converted after drug infusion only. No patients had serious adverse events in follow-up. The different pad positions in Protocol 2 (n=244), had similar conversions to sinus rhythm (119 [94%] of 127 in anterolateral group vs 108 [92%] of 117 in anteroposterior group; p=0·68)., Interpretation: Both the drug-shock and shock-only strategies were highly effective, rapid, and safe in restoring sinus rhythm for patients in the emergency department with acute atrial fibrillation, avoiding the need for return to hospital. The drug infusion worked for about half of patients and avoided the resource intensive procedural sedation required for electrical cardioversion. We also found no significant difference between the anterolateral and anteroposterior pad positions for electrical cardioversion. Immediate rhythm control for patients in the emergency department with acute atrial fibrillation leads to excellent outcomes., Funding: Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Objectives: Cluster randomized trials are commonly used to evaluate public health, knowledge translation, and health service interventions. Cluster trials raise novel ethical issues, however, and the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials (2012) provides researchers and research ethics committees with needed guidance. In this journal, van der Graaf et al. reflect on the Ottawa Statement and propose three revisions. In this paper, we respond to each of these proposed revisions., Results: First, van der Graaf et al. argue that patients who are merely indirectly affected by study interventions ought nonetheless to be considered research participants. We disagree. So long as the practice change is evidence based and the physician continues to make individualized judgments regarding patient care, patient liberty and welfare interests are not substantially affected. Second, although they agree that health providers who are targeted are research participants, they argue that such providers ought to be treated differently and should not be allowed to withdraw from a study too easily. In our view, this position fails to weigh adequately the potential for coercion and harms faced by employees in research. Third, they argue that the potential for bias may require blinding participants to allocation and study interventions in the consent process of a cluster trial. We agree on this point and support this approach in a limited set of cases., Conclusion: While we reject two of van der Graaf et al.'s proposed revisions, we agree that further guidance on informed consent and study bias is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Influenza is a leading cause of avoidable admissions for nursing home (NH) residents. We previously evaluated the effectiveness of a high-dose trivalent influenza vaccine (HD) compared to a standard-dose influenza vaccine (SD) through a cluster-randomized trial of NH residents. Fewer residents from facilities randomized to HD were hospitalized. In this article, we extend our analyses to consider direct medical care costs relative to vaccine costs for HD ($31.82/dose) as compared to SD ($12.04/dose)., Design: Post hoc, cost-benefit analysis., Setting and Participants: From the participating NH facilities (n = 817), we identified Medicare fee-for-service enrollees who were long-stay residents (>100 days) at the start of the 2013-2014 influenza season (November 1-May 31). The intervention was residence in a facility randomized to HD or SD influenza vaccine., Methods: We summed expenditures from long-stay NH residents' Medicare Part A, B, and D fee-for-service claims and compared person-level expenditures between residents of facilities offering HD vs SD. Expenditures were adjusted for clustering of residents within NHs, person-time, and prespecified covariates using 2-part, generalized linear models with bootstrapped standard errors. We examined the incremental cost-benefit of HD vs SD vaccines from a payer perspective., Results: There were 18,605 and 18,658 Medicare fee-for-service long-stay residents in facilities offering HD and SD, respectively. Person- and facility-adjusted total expenditures differed by $546 (P = .006). The $20 incremental cost of HD to SD offset adjusted expenditures for a net benefit of $526 per NH resident and a financial return on investment of 546/20 = 27:1., Conclusions/implications: The use of HD influenza vaccine in long-stay NH residents reduced total health care expenditures for a net benefit despite HD being more expensive per dose. These cost offsets applied to Medicare beneficiaries residing in NHs could result in important savings to the Medicare program., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Multiple D-dimer cutoffs have been suggested for older patients to improve diagnostic specificity for venous thromboembolism. These approaches are better established for pulmonary embolism., Objectives: We evaluated the diagnostic performance and compared the health system cost for previously suggested cutoffs and a new D-dimer cutoff for low-risk emergency department (ED) deep venous thrombosis (DVT) patients., Methods: We conducted a retrospective cohort study in two large EDs involving patients aged > 50 years who had low pretest probability for DVT and had a D-dimer performed. The outcome was a diagnosis of DVT at 30 days. We evaluated the diagnostic accuracy and estimated the difference in cost for cutoffs of 500 ng/mL and the age-adjusted (age × 10) rule. A derived cutoff of 1000 ng/mL was also assessed., Results: Nine hundred and seventy-two patients were included (median age 66 years; 59.5% female); 63 (6.5%) patients were diagnosed with DVT. The conventional cutoff of < 500 ng/mL demonstrated a sensitivity of 100% (95% confidence interval [CI] 94.3-100%) and a specificity of 35.6% (95% CI 32.5-38.8%). The age-adjusted approach increased specificity while maintaining high sensitivity. A new cutoff of 1000 ng/mL demonstrated improved performance: sensitivity 100% (95% CI 94.3-00%) and specificity 66.3% (95% CI 63.2-69.4%). Compared to the conventional approach, both the 1000 ng/mL cutoff and the age-adjusted cutoffs could save healthcare dollars. A cutoff of 1000 ng/mL could have saved 310 ED length of stay hours and $166,909 (Canadian dollars) in our cohort, or an average savings of 0.32 h and $172 per patient., Conclusions: Among patients aged > 50 years with suspected DVT, the age-adjusted D-dimer and a cutoff of 1000 ng/mL improved specificity without compromising sensitivity, and lowered the health care system cost compared to that for the conventional approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The Consolidated Standards of Reporting Trials extension for the stepped-wedge cluster randomized trial (SW-CRT) is a recently published reporting guideline for SW-CRTs. We assess the quality of reporting of a recent sample of SW-CRTs., Study Design and Setting: Quality of reporting was asssessed according to the 26 items in the new guideline using a novel crowd sourcing methodology conducted independently and in duplicate, with random assignment, by 50 reviewers. We assessed reliability of the quality assessments, proposing this as a novel way to assess robustness of items in reporting guidelines., Results: Several items were well reported. Some items were very poorly reported, including several items that have unique requirements for the SW-CRT, such as the rationale for use of the design, description of the design, identification and recruitment of participants within clusters, and concealment of cluster allocation (not reported in more than 50% of the reports). Agreement across items was moderate (median percentage agreement was 76% [IQR 64 to 86]). Agreement was low for several items including the description of the trial design and why trial ended or stopped for example., Conclusions: When reporting SW-CRTs, authors should pay particular attention to ensure clear reporting on the exact format of the design with justification, as well as how clusters and individuals were identified for inclusion in the study, and whether this was done before or after randomization of the clusters, which are crucial for risk of bias assessments. Some items, including why the trial ended, might either not be relevant to SW-CRTs or might be unclearly described in the statement., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Due to the challenge of identifying need for intervention in bleeding patients, there is a growing interest in prediction modeling. Massive transfusion (MT; 10 or more packed red cells in 24 h) is the most commonly studied dependent variable, serving as a surrogate for severe bleeding and its prediction guides the need for intervention. The critical administration threshold (CAT; 3 packed red cells in 1 h) has been proposed as an alternative. In this study, we aim to compare the classification accuracy of these two surrogates for hemorrhage-related outcomes in health administrative datasets., Methods: We performed a secondary analysis of major trauma patients from the prospectively collected Ottawa Trauma Registry, from September 2014 to September 2017. We conducted a logistic regression analysis utilizing need for hemostasis or hemorrhagic death as dependent variables. We compared classification accuracy in terms of sensitivity, specificity, positive predictive value, negative predictive value and AUC. CAT + and MT + status is not mutually exclusive., Results: We studied 890 major trauma patients, including 145 CAT + and 48 MT + patients. CAT + demonstrated a superior association for the composite outcome of 24-hour hemorrhage-related mortality and need for hemostasis (AUC 0.815 vs. 0.644, p < 0.0001). This performance was driven by a substantial difference in sensitivity, noted to be 70.0% (95% CI 62.1-77.9%) for CAT + but only 30.0% (95% CI 22.1-37.9%) for MT+. CAT + and MT + demonstrated specificities of 92.9% (95% CI 91.1-94.7%) and 98.9% (98.1-99.6%) respectively., Conclusion: This study illustrates the concepts of survivorship and competing risk bias for massive transfusion. Utilizing a composite outcome of need for hemostasis and early hemorrhagic death, we demonstrate that CAT + is more accurate for identifying significantly bleeding patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Immune responses to influenza vaccines decline with age, reducing clinical effectiveness. We compared the effect of the more immunogenic high-dose trivalent influenza vaccine with a standard-dose vaccine to identify the effect on reducing hospital admissions of nursing home residents in the USA., Methods: We did a single-blind, pragmatic, comparative effectiveness, cluster-randomised trial with a 2 × 2 factorial design. Medicare-certified nursing homes in the USA located within 50 miles of a Centers for Disease Control and Prevention influenza reporting city were recruited, so long as the facilities were not located in a hospital, had more than 50 long-stay residents, had less than 20% of the population aged under 65 years, and were not already planning to administer the high-dose influenza vaccine to residents. Enrolled nursing homes were randomised to a facility-wide standard of care for the residents of either high dose or standard dose as the vaccine for the 2013-14 influenza season and half of each group were randomly allocated to free vaccines for staff. Individual residents were included in the analysis group if they were aged 65 years or older and were long-stay residents (ie, had been in the facility 90 days or more before commencing the influenza vaccination programme). The analysts and investigators with access to the raw data were masked to study group by coding the groups until after the analyses were complete. The primary outcome was hospital admissions related to pulmonary and influenza-like illness between Nov 1, 2013, and May 31, 2014, identified from Medicare hospital claims available for residents who were without private health insurance (ie, those who were considered Medicare fee-for-service). We obtained data from the Centers for Medicare & Medicaid Services (CMS) and enrolled facilities. The analyses used marginal Poisson and Cox proportional hazards regression, accounting for clustering of residents within homes, on an intention-to-treat basis, adjusting for facility clustering and prespecified covariates. Safety data were voluntarily reported according to the standard of care. This trial is registered with ClinicalTrials.gov, number NCT01815268., Findings: 823 facilities were recruited to the study between March and August, 2013, to participate in the trial, of which 409 facilities were randomised for residents to receive high-dose vaccine, and 414 facilities for residents to receive standard-dose vaccine. The facilities housed 92 269, of whom 75 917 were aged 65 years or older and 53 008 were also long-stay residents, and 38 256 were matched to Medicare hospital claims as of Nov 1, 2013. Staff vaccination rates did not differ between groups, so analyses focused on the high-dose versus standard-dose vaccine comparison. On the basis of Medicare fee-for-service claims, the incidence of respiratory-related hospital admissions was significantly lower in facilities where residents received high-dose influenza vaccines than in those that received standard-dose influenza vaccines (0·185 per 1000 resident-days or 3·4% over 6 months vs 0·211 per 1000 resident-days or 3·9% over 6 months; unadjusted relative risk of 0·888, 95% CI 0·785-1·005, 0=0·061, and adjusted relative risk 0·873, 0·776-0·982, p=0·023)., Interpretation: When compared with standard-dose vaccine, high-dose influenza vaccine can reduce risk of respiratory-related hospital admissions from nursing home residents aged 65 years and older., Funding: Sanofi Pasteur, Swiftwater, PA, USA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To clarify and illustrate sample size calculations for the cross-sectional stepped wedge cluster randomized trial (SW-CRT) and to present a simple approach for comparing the efficiencies of competing designs within a unified framework., Study Design and Setting: We summarize design effects for the SW-CRT, the parallel cluster randomized trial (CRT), and the parallel cluster randomized trial with before and after observations (CRT-BA), assuming cross-sectional samples are selected over time. We present new formulas that enable trialists to determine the required cluster size for a given number of clusters. We illustrate by example how to implement the presented design effects and give practical guidance on the design of stepped wedge studies., Results: For a fixed total cluster size, the choice of study design that provides the greatest power depends on the intracluster correlation coefficient (ICC) and the cluster size. When the ICC is small, the CRT tends to be more efficient; when the ICC is large, the SW-CRT tends to be more efficient and can serve as an alternative design when the CRT is an infeasible design., Conclusion: Our unified approach allows trialists to easily compare the efficiencies of three competing designs to inform the decision about the most efficient design in a given scenario., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Building on an existing theoretical shared primary care/specialist care framework to (1) develop a unique typology of care for people living with human immunodeficiency virus (HIV) in Ontario, (2) assess sensitivity of the typology by varying typology definitions, and (3) describe characteristics of typology categories., Study Design and Setting: Retrospective population-based observational study from April 1, 2009, to March 31, 2012. A total of 13,480 eligible patients with HIV and receiving publicly funded health care in Ontario. We derived a typology of care by linking patients to usual family physicians and to HIV specialists with five possible patterns of care. Patient and physician characteristics and outpatient visits for HIV-related and non-HIV-related care were used to assess the robustness and characteristics of the typology., Results: Five possible patterns of care were described as low engagement (8.6%), exclusively primary care (52.7%), family physician-dominated comanagement (10.0%), specialist-dominated comanagement (30.5%), and exclusively specialist care (5.2%). Sensitivity analyses demonstrated robustness of typology assignments. Visit patterns varied in ways that conform to typology assignments., Conclusion: We anticipate this typology can be used to assess the impact of care patterns on the quality of primary care for people living with HIV., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Circulating PCSK9 levels are higher in women than men, in postmenopausal than premenopausal women, and in pregnant than non-pregnant women, suggesting that sex hormones may be related to PCSK9 levels. We have examined the relationship between serum estradiol (E2) and testosterone (T) and PCSK9, and the impact of E2 replacement therapy in women and T replacement and ablation therapy in men on circulating PCSK9., Methods: We conducted a cross-sectional study to examine the correlation between serum T (in males) and E2 (in females) and serum PCSK9. We also conducted interventional studies to examine the effect of hormonal therapy on serum PCSK9 levels., Results: In men, (1) serum T does not correlate with circulating PCSK9 or with LDLC in the basal state, (2) T replacement therapy does not have any effect on circulating PCSK9, and (3) T ablation therapy has mixed results. In women, (1) E2 correlates inversely with circulating PCSK9 and directly with serum LDLC, but (2) E2 replacement therapy does not have any effect on circulating PCSK9., Conclusions: We demonstrate differences between men and women in the relationship of their major sex hormones with circulating PCSK9. In men, circulating PCSK9 is not related to or affected by T except for a possible effect during T ablation therapy. In women, E2 is inversely related to circulating PCSK9 but the lack of effect of E2 therapy on circulating PCSK9 suggests that the E2-related differences in PCSK9 levels may be the result of differences in receptor-mediated PCSK9 clearance through E2-induced changes rather than production of PCSK9. The studies were registered with ClinicalTrials.gov NCT00848276., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: To assess the quality of reporting and accuracy of a priori estimates used in sample size calculations for cluster randomized trials (CRTs)., Study Design and Setting: We reviewed 300 CRTs published between 2000 and 2008. The prevalence of reporting sample size elements from the 2004 CONSORT recommendations was evaluated and a priori estimates compared with those observed in the trial., Results: Of the 300 trials, 166 (55%) reported a sample size calculation. Only 36 of 166 (22%) reported all recommended descriptive elements. Elements specific to CRTs were the worst reported: a measure of within-cluster correlation was specified in only 58 of 166 (35%). Only 18 of 166 articles (11%) reported both a priori and observed within-cluster correlation values. Except in two cases, observed within-cluster correlation values were either close to or less than a priori values., Conclusion: Even with the CONSORT extension for cluster randomization, the reporting of sample size elements specific to these trials remains below that necessary for transparent reporting. Journal editors and peer reviewers should implement stricter requirements for authors to follow CONSORT recommendations. Authors should report observed and a priori within-cluster correlation values to enable comparisons between these over a wider range of trials., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Reviews of the handling of covariates in trials have explicitly excluded cluster randomized trials (CRTs). In this study, we review the use of covariates in randomization, the reporting of covariates, and adjusted analyses in CRTs., Study Design and Setting: We reviewed a random sample of 300 CRTs published between 2000 and 2008 across 150 English language journals., Results: Fifty-eight percent of trials used covariates in randomization. Only 69 (23%) included tables of cluster- and individual-level covariates. Fifty-eight percent reported significance tests of baseline balance. Of 207 trials that reported baseline measures of the primary outcome, 155 (75%) subsequently adjusted for these in analyses. Of 174 trials that used covariates in randomization, 30 (17%) included an analysis adjusting for all those covariates. Of 219 trial reports that included an adjusted analysis of the primary outcome, only 71 (32%) reported that covariates were chosen a priori., Conclusion: There are some marked discrepancies between practice and guidance on the use of covariates in the design, analysis, and reporting of CRTs. It is essential that researchers follow guidelines on the use and reporting of covariates in CRTs, promoting the validity of trial conclusions and quality of trial reports., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Serum low density lipoprotein-cholesterol (LDL-C) correlates positively with serum PCSK9 in the general population, consistent with PCSK9 being a determinant of LDL-C levels. Patients with chronic kidney disease (CKD) on hemodialysis (HD) have lower total cholesterol (TC) and LDL-C compared to the general population. Serum PCSK9 and its relationship with serum lipids have not been reported in CKD patients on HD (CKD-HD)., Methods: We measured serum PCSK9 by ELISA and lipid levels in 66 CKD-HD patients and compared them to 178 non-CKD subjects. Since statins increase serum PCSK9 levels, CKD-HD patients were separated into those not on statin therapy (HD-NS, n = 32) and those taking statins (HD-S, n = 34). No control subjects were on statin therapy., Results: Serum PCSK9, TC, LDL-C and HDL-C levels were significantly lower in the CKD-HD group (n = 66) compared to the control group. HD-NS patients showed lower PCSK9, TC and LDL-C levels than control subjects and PCSK9 levels correlated with TC and LDL-C levels (r = 0.35, p = 0.050; r = 0.423, p = 0.0158 respectively) as well as TG levels (r = 0.413, p = 0.0188). In HD-S patients, PCSK9 levels were not significantly different from the non-CKD group. There was no correlation between PCSK9 levels and TC and LDL-C levels in the HD-S group., Conclusion: Our data are the first quantitative analysis of serum PCSK9 levels in CKD-HD patients. We show that serum PCSK9 in HD-NS patients is decreased and it retains a positive correlation with LDL-C, suggesting that PCSK9 may remain a significant determinant of LDL-C in CKD-HD subjects. We also show that statin therapy disrupts the correlation between LDL-C and PCSK9 in CKD-HD patients. These data suggest that the regulation of LDL-C by PCSK9 remains intact in CKD-HD patients. PCSK9 may also play a role in the metabolism of triglyceride-rich lipoproteins in CKD-HD patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Continuity of care is composed of provider and information continuity and can change value over time. Most studies that have quantitatively associated continuity of care and outcomes have ignored these characteristics. This study is a detailed examination of continuity of care in patients discharged from hospital that simultaneously measured separate components of continuity over time or determined the factors with which they are associated., Design Setting: Multicenter, prospective cohort study of patients discharged to the community after elective or emergent hospitalization. For all physician visits during 6 months after discharge, we identified the physician and the availability of particular information (including hospital discharge summary and any information from previous physician visits). Four physician continuity scores (preadmission; hospital admitting; hospital consultant; and postdischarge) and two information continuity scores (discharge summary and postdischarge visit information) were calculated for all patients (range: 0-1, where 0 is perfect discontinuity and 1 is perfect continuity)., Results: Four thousand five hundred fifty-three people were followed for a median of 175 days. Both provider (range of median values: 0-0.410) and information (range: 0.220-0.427) continuity scores were low and varied extensively over time. With a few exceptions, continuity measures were independent of each other. The influence of patient factors on continuity varied extensively between the continuity measures with the most influential factors being admission urgency, admitting service, and the number of physicians who regularly treated the patient., Conclusion: Both provider and information continuity was low in patients discharged from hospital. Continuity measures can change extensively over time, which are usually independent of each other, and are associated with patient and admission characteristics. Future studies should measure multiple components of provider and information continuity over time to completely capture continuity of care.

Objective: To meaningfully interpret trials using surrogate outcomes, one must translate changes in the surrogate outcome to changes in the clinical outcome. Formulae to do this are uncommon because they require primary data from multiple randomized trials that measure both the surrogate and clinical outcome., Study Design and Setting: We developed a model to translate changes in anticoagulation control (the surrogate outcome) into hemorrhagic and thromboembolic event rates (the clinical outcome). The model used Monte Carlo simulation and association measures between the surrogate and the clinical outcome from a meta-analysis. In randomized trials having interventions that improved anticoagulation control, we used the model to predict and statistically compare event rates between the study groups., Results: Seven randomized trials found significantly improved anticoagulation control (mean increase in proportion of time in therapeutic range: 8.4%; range: 1.8-18%). These improvements in anticoagulation control translated to small decreases in hemorrhagic and thromboembolic events (mean: 0.66%/yr; range: 0.13-1.42%). These changes were never statistically significant., Conclusion: Monte Carlo modeling can be used to translate surrogate outcomes into clinical outcomes. Statistically significant changes in anticoagulation control did not translate to significant differences in clinical outcomes. This methodology could be applied to other areas in medicine to assess surrogate outcomes.

Objective: To evaluate the brief Decision Support Analysis Tool (DSAT-10) for auditing the quality of nurse-standardized patient encounters, structuring feedback for nurses, and testing instrument reliability., Methods: A systematic process was used to develop standardized patient scenarios, pilot-test scenarios, calibrate DSAT-10 coders, analyze taped telephone encounters using DSAT-10, and provide feedback. Inter-rater reliability was calculated using coder agreement, kappa, and intra-class correlation coefficients., Results: Six scenarios portrayed patients' decisional uncertainty from either: pressure from others (n=2), unclear values (n=2), or inadequate information (n=2). Scenarios were easy to use over the telephone, produced realistic role performance, and were practical for audio-recording interactions. DSAT-10 analysis of 76 nurse-standardized patient encounters revealed nurses' strengths (e.g., information provision) and their limitations (e.g., lack of discussion of values and/or support needs). Scores discriminated between trained and untrained nurses. The kappa coefficient over all items was 0.55 (95% CI: 0.49, 0.61) with higher agreement for encounters involving trained nurses (0.62; 95% CI: 0.43, 0.80)., Conclusion: Auditing nurse-standardized patient encounters using DSAT-10 and providing feedback to nurses was feasible. Although DSAT-10 items had adequate inter-rater reliability and discriminated between trained/untrained nurses, some items were problematic., Practice Implications: Providing feedback on nurse encounters with standardized patients experiencing uncertainty has the potential to enhance nurses' decision support skills.