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Introduction: The commonly used frequentist paradigm of null hypothesis statistics testing with its reliance on the p-value and the corresponding notion of 'statistical significance' has been under ongoing criticism. Misinterpretation and misuse of the p-value have contributed to publication bias, unreliable studies, frequent false positives, fraud and mistrust in results of scientific studies. While p-values themselves are still useful, part of the problem may be the confusion between statistical and clinical significance. In randomised controlled trials of health interventions, this confusion could lead to erroneous conclusions about treatment efficacy, research waste and compromised patient outcomes. The extent to which clinical and statistical significance of published randomised clinical trials do not match is not known. This is a protocol for a methodological study to understand the extent of the problem of disparities between statistical and clinical significance in published clinical trials, and to identify and assess the factors associated with discrepant results in these studies., Methods and Analysis: A methodological survey of published randomised controlled trials is planned. Trials published between 2018 and 2022 and their protocols will be searched and screened for inclusion, with a planned sample size of 500 studies. The reported minimum clinically important difference, the study effect size and confidence intervals will be used to assess clinical importance of trial results. Comparison of statistical significance and clinical importance of the trial results will be used to determine disparity. Data will be analysed to estimate the outcomes, and factors associated with disparate study results will be assessed using logistic regression analysis., Ethics and Dissemination: Ethical approval for the study has been granted by Stellenbosch University's Health Research Ethics Committee. This is part of a larger study towards a PhD in Biostatistics and will be disseminated as a thesis, conference abstract and peer-reviewed manuscript., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Patent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in extremely preterm infants and is associated with poor clinical outcomes. Uncertainty exists on whether early pharmacotherapeutic treatment of a clinically symptomatic and echocardiography-confirmed haemodynamically significant PDA in extremely preterm infants improves outcomes. Given the wide variation in the approach to PDA treatment in this gestational age (GA) group, a randomised trial design is essential to address the question. Before embarking on a large RCT in this vulnerable population, it is important to establish the feasibility of such a trial., Methods and Analysis: Design: a multi-centre, open-labelled, parallel-designed pilot randomised controlled trial. Participants: preterm infants born <26 weeks of gestation with a PDA diagnosed within 72 hours after birth. Intervention (selective early medical treatment (SMART) strategy): selective early pharmacological treatment of a moderate-severe PDA shunt (identified based on pre-defined clinical signs and routine screening echocardiography) within the first 72 postnatal hours with provision for repeat treatment if moderate-severe shunt persists. Comparison (early conservative management strategy): no treatment of PDA in the first postnatal week. Primary outcomes: (1) proportion of eligible infants recruited during the study period; (2) proportion of randomised infants treated outside of protocol-mandated therapy. Sites and sample size: the study is being conducted in seven neonatal intensive care units across Canada and the USA with a target of 100 randomised infants. Analysis: the primary feasibility outcomes will be expressed as proportions. A pre-planned Bayesian analysis will be conducted for secondary clinical outcomes such as mortality, severe intraventricular haemorrhage, procedural PDA closure and chronic lung disease to aid stakeholders including parent representatives decide on the appropriateness of enrolling this vulnerable population in a larger trial if the feasibility of recruitment in the pilot trial is established., Ethics and Dissemination: The study has been approved by the IWK Research Ethics Board (#1027298) and six additional participating sites. On the completion of the study, results will be presented at national and international meetings, published in peer-reviewed journals and incorporated into existing systematic reviews., Trial Registration Number: NCT05011149 (WHO Trial Registration Data Set in Appendix A)., Protocol Version: Ver 7.2 (dated July 19, 2023)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To characterise sex and gender-based analysis (SGBA) and diversity metric reporting, representation of female/women participants in acute care trials and temporal changes in reporting before and after publication of the 2016 Sex and Gender Equity in Research guideline., Design: Systematic review., Data Sources: We searched MEDLINE for trials published in five leading medical journals in 2014, 2018 and 2020., Study Selection: Trials that enrolled acutely ill adults, compared two or more interventions and reported at least one clinical outcome., Data Abstraction and Synthesis: 4 reviewers screened citations and 22 reviewers abstracted data, in duplicate. We compared reporting differences between intensive care unit (ICU) and cardiology trials., Results: We included 88 trials (75 (85.2%) ICU and 13 (14.8%) cardiology) (n=111 428; 38 140 (34.2%) females/women). Of 23 (26.1%) trials that reported an SGBA, most used a forest plot (22 (95.7%)), were prespecified (21 (91.3%)) and reported a sex-by-intervention interaction with a significance test (19 (82.6%)). Discordant sex and gender terminology were found between headings and subheadings within baseline characteristics tables (17/32 (53.1%)) and between baseline characteristics tables and SGBA (4/23 (17.4%)). Only 25 acute care trials (28.4%) reported race or ethnicity. Participants were predominantly white (78.8%) and male/men (65.8%). No trial reported gendered-social factors. SGBA reporting and female/women representation did not improve temporally. Compared with ICU trials, cardiology trials reported significantly more SGBA (15/75 (20%) vs 8/13 (61.5%) p=0.005)., Conclusions: Acute care trials in leading medical journals infrequently included SGBA, female/women and non-white trial participants, reported race or ethnicity and never reported gender-related factors. Substantial opportunity exists to improve SGBA and diversity metric reporting and recruitment of female/women participants in acute care trials., Prospero Registration Number: CRD42022282565., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/. EB-C has received investigator-initiated grant funding from Bayer, BMS-Pfizer and Roche Diagnostics and consulting honoraria from Trimedic Therapeutics, which were unrelated to the current work. JR is a co-methodologist on the Society of Critical Care Medicine Guideline Committee–End of Life Care in the ICU Guidelines. VP is a member of the Canadian Critical Care Society–Equity, Diversity, Decolonisation and Inclusion Committee. KEAB is President of the Canadian Critical Care Society and an Ex-officio member of the Canadian Critical Care Trials Group Executive Committee. There are no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate whether a focused, expert medication management intervention is feasible and potentially effective in preventing anticoagulation-related adverse events for patients transitioning from hospital to home., Design: Randomised, parallel design., Setting: Medical wards at six hospital sites in southern Ontario, Canada., Participants: Adults 18 years of age or older being discharged to home on an oral anticoagulant (OAC) to be taken for at least 4 weeks., Interventions: Clinical pharmacologist-led intervention, including a detailed discharge medication management plan, a circle of care handover and early postdischarge virtual check-up visits to 1 month with 3-month follow-up. The control group received the usual care., Outcomes Measures: Primary outcomes were study feasibility outcomes (recruitment, retention and cost per patient). Secondary outcomes included adverse anticoagulant safety events composite, quality of transitional care, quality of life, anticoagulant knowledge, satisfaction with care, problems with medications and health resource utilisation., Results: Extensive periods of restriction of recruitment plus difficulties accessing patients at the time of discharge negatively impacted feasibility, especially cost per patient recruited. Of 845 patients screened, 167 were eligible and 56 were randomised. The mean age (±SD) was 71.2±12.5 years, 42.9% females, with two lost to follow-up. Intervention patients were more likely to rate their ability to manage their OAC as improved (17/27 (63.0%) vs 7/22 (31.8%), OR 3.6 (95% CI 1.1 to 12.0)) and their continuity of care as improved (21/27 (77.8%) vs 2/22 (9.1%), OR 35.0 (95% CI 6.3 to 194.2)). Fewer intervention patients were taking one or more inappropriate medications (7 (22.5%) vs 15 (60%), OR 0.19 (95% CI 0.06 to 0.62))., Conclusion: This pilot randomised controlled trial suggests that a transitional care intervention at hospital discharge for older adults taking OACs was well received and potentially effective for some surrogate outcomes, but overly costly to proceed to a definitive large trial., Trial Registration Number: NCT02777047., Competing Interests: Competing interests: DMS has received honoraria paid indirectly to her research institute from AstraZeneca, BMS-Pfizer, Roche and Servier. DMS is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The aim of this methodological review is to evaluate the completeness of reporting of surgical pilot and feasibility randomised trials as per the Consolidated Standards of Reporting Trials (CONSORT) extension to randomised pilot and feasibility trials. Moreover, we aim to assess for the presence of spin reporting and inconsistency between abstract and main text reporting in surgical pilot and feasibility randomised trials., Methods and Analysis: A comprehensive, electronic search strategy will be used to identify studies indexed in Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Studies will be included if they are pilot or feasibility randomised trials of surgical interventions. The primary outcome will be overall CONSORT statement extension to randomised pilot and feasibility trials checklist completeness. This will be defined as trials reporting each of the 40 items in the CONSORT statement extension to randomised pilot and feasibility trials checklist. Secondary outcomes will include the reporting of individual studies as per the CONSORT extension to randomised pilot and feasibility trials, the use of spin reporting strategies, trial factors associated with reporting quality and spin strategy use, and consistency between abstract and main text reporting. Poisson and logistic regressions will be performed to explore the association between trial factors and completeness of reporting as measured by the number of reported CONSORT items., Ethics and Dissemination: This is a methodological survey that has been registered a priori on the International Prospective Register for Systematic Reviews (PROSPERO) (CRD42023475512). Local ethics approval is not required. We plan to disseminate study results through peer-reviewed publication and conference presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Polycystic ovary syndrome (PCOS) is a globally prevalent endocrinological disorder and has been associated with poor pregnancy outcomes, including a higher rate of gestational diabetes and miscarriage. Metformin is among the drugs investigated to improve the prognosis of pregnant women with PCOS., Objective: To conduct an overview of systematic reviews examining the effects of metformin versus placebo or no intervention throughout pregnancy among pregnant women with a preconception PCOS diagnosis to reduce the incidence of miscarriage and gestational diabetes., Methods and Analysis: We will perform an overview of systematic reviews by searching Embase, PubMed, Virtual Health Library, Cochrane Central Register of Controlled Trials, Trip Database, Scopus, Web of Science and Cumulative Index to Nursing and Allied Health Literature from inception to 17 August 2023. Language, publication status and year indexed or published filters will not be applied. Two reviewers will independently screen and select papers, assess their quality, evaluate their risk of bias and collect the data. The included reviews will be summarised narratively. The quality and risk of bias of the systematic review and meta-analysis studies included will be assessed using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews, Second Version) and ROBIS (Risk of Bias in Systematic Reviews), respectively., Ethics and Dissemination: This overview of reviews will analyse data from systematic reviews on the use of metformin for prepregnancy diagnosis of PCOS to reduce adverse outcomes. As there will be no primary data collection, a formal ethical analysis is unnecessary. The study outcomes will be submitted to a peer-reviewed journal and presented at conferences., Prospero Registration Number: CRD42023441488., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The R e- Ev aluating the I nhibition of S tress E rosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE., Methods and Analysis: REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial., Ethics and Dissemination: All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to - Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide., Trial Registration Number: NCT03374800., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We assessed the feasibility of an appropriately powered randomised trial by evaluating whether participants could be recruited and retained, and sought preliminary information on exclusive breastfeeding rates., Setting: Primary healthcare facility, serving a rural community., Participants: Women initiating breast feeding within 24 hours of giving birth, on antiretroviral treatment and aged ≥18 years., Interventions: We randomised mother-infant pairs to receive weekly text messaging encouraging exclusive breast feeding plus in-person individual motivational interviews post partum at weeks 2, 6 and 10, or standard infant feeding counselling., Outcome Measures: The feasibility endpoints included number of participants who consented to participate and number with complete evaluation of infant feeding practices at study visits. Exploratory endpoints included number of participants who exclusively breast fed at 24 weeks post partum and number of participants adhering to study protocol., Results: Of 123 mothers screened, 52 participants consented for participation. We recruited an average of five participants per month over 11 months. Most participants were unemployed (75%), had some high school education (84%) and had disclosed their HIV status to someone close (88%). About 65% participants completed outcome evaluation at week 10, decreasing to 35% at week 24. Twenty participants had the week 24 visit planned between 20 March and August 2020, during COVID-19 lockdown. Of these, 4 completed the visit telephonically, 16 were lost to follow-up. Exclusive breastfeeding rate remained relatively high across both groups through week 24. The difference in exclusive breastfeeding rates between the intervention and control groups was minimal: rate difference 22.2% (95% CI -20.1% to 64.5%)., Conclusions: With a large eligible target population, recruitment targets could be achieved for a large trial. Strategies to retain participants, such as remote monitoring and in-person follow-up visits, will be essential., Trial Registration Number: ClinicalTrials.gov Registry (NCT02949713) and Pan African Clinical Trial Registry (PACTR201611001855404)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Severe mitral regurgitation (MR) with left ventricular dysfunction portends worse outcomes. Over the course of the last two decades, transcatheter repair of the mitral valve offered an alternative therapeutic modality for those deemed inoperable or high risk. Landmark studies such as the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation and Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation trials have shown conflicting results with respect to all-cause death and heart failure rehospitalisations. The Gulf Mitral Transcatheter Edge to Edge Repair registry (Gulf MTEER registry) is a regional registry that captured outcomes in those undergoing transcatheter repair of the mitral valve. The objectives of this study were to describe the baseline characteristics of patients undergoing transcatheter mitral valve repair in the Gulf region and estimate the cardiovascular effects of the mitral transcatheter therapies in routine practice., Methods: The Gulf MTEER registry is an observational, multicentre, retrospective registry that enrolled all patients undergoing transcatheter repair of the mitral valve from four of the Gulf countries (Saudi Arabia, Kuwait, Bahrain, Oman) between 1 January 2017 and 31 December 2019. Baseline characteristics, echocardiographic parameters and immediate procedural success were reported. The primary outcome was a composite of death and rehospitalisations at 1 year. The secondary outcomes were the individual components of the composite endpoint; that is, death and rehospitalisations at 1 year as well as residual or recurrent MR or worsening New York Heart Association class and a need for repeat repair., Results: A total of 176 patients were enrolled. Men constituted 56.3% of the total. At 1 year the primary outcome occurred in 21.1% (95% CI 15.6, 27.9). The secondary outcomes of death occurred in 5.4% (CI 2.9, 10.0) and rehospitalisations occurred in 16.9% (CI 11.9, 23.3). Univariate analysis revealed that the odds of having death or re-hospitalisation was two times higher if the effective regurgitant orifice (ERO) >40 mm 2 irrespective of the therapy., Conclusions: The Gulf MTEER registry is the first registry in the Gulf region defining the patient population receiving MTEER therapies and evaluating 1-year outcomes. This is a low risk cohort with a high rate of immediate procedural success and low rate of all-cause death and rehospitalisations at 1 year. The odds of an event was two times higher if the ERO ≥40 mm 2 with only a signal to higher odds for low left ventricular ejection fraction and larger end systolic dimension., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We explored the magnitude of attrition, its pattern and risk factors for different forms of attrition in the cohort from the Global Longitudinal Study of Osteoporosis in Women., Design: Prospective cohort study., Setting: Participants were recruited from physician practices in Hamilton, Ontario., Participants: Postmenopausal women aged ≥55 years who had consulted their primary care physician within the last 2 years., Outcome Measures: Time to all-cause, non-death, death, preventable and non-preventable attrition., Results: All 3985 women enrolled in the study were included in the analyses. The mean age of the cohort was 69.4 (SD: 8.9) years. At the end of the follow-up, 30.2% (1206/3985) of the study participants had either died or were lost to follow-up. The pattern of attrition was monotone with most participants failing to return after a missed survey. The different types of attrition examined shared common risk factors including age, smoking and being frail but differed on factors such as educational level, race, hospitalisation, quality of life and being prefrail., Conclusion: Attrition in this ageing cohort was selective to some participant characteristics. Minimising potential bias associated with such non-random attrition would require targeted measures to achieve maximum possible follow-rates among the high-risk groups identified and dealing with specific reasons for attrition in the study design and analysis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In-bed leg cycling with critically ill patients is a promising intervention aimed at minimising immobility, thus improving physical function following intensive care unit (ICU) discharge. We previously completed a pilot randomised controlled trial (RCT) which supported the feasibility of a large RCT. In this report, we describe the protocol for an international, multicentre RCT to determine the effectiveness of early in-bed cycling versus routine physiotherapy (PT) in critically ill, mechanically ventilated adults., Methods and Analysis: We report a parallel group RCT of 360 patients in 17 medical-surgical ICUs and three countries. We include adults (≥18 years old), who could ambulate independently before their critical illness (with or without a gait aid), ≤4 days of invasive mechanical ventilation and ≤7 days ICU length of stay, and an expected additional 2-day ICU stay, and who do not fulfil any of the exclusion criteria. After obtaining informed consent, patients are randomised using a web-based, centralised system to either 30 min of in-bed cycling in addition to routine PT, 5 days per week, up to 28 days maximum, or routine PT alone. The primary outcome is the Physical Function ICU Test-scored (PFIT-s) at 3 days post-ICU discharge measured by assessors blinded to treatment allocation. Participants, ICU clinicians and research coordinators are not blinded to group assignment. Our sample size estimate was based on the identification of a 1-point mean difference in PFIT-s between groups., Ethics and Dissemination: C ritical Care C yc ling to improve L ower E xtremity (CYCLE) is approved by the Research Ethics Boards of all participating centres and Clinical Trials Ontario (Project 1345). We will disseminate trial results through publications and conference presentations., Trial Registration Number: NCT03471247 (Full RCT); NCT02377830 (CYCLE Vanguard 46 patient internal pilot)., Competing Interests: Competing interests: MEK received an equipment loan of 4 RT300 supine cycles from Restorative Therapies, Baltimore, Maryland, USA for this study. On behalf of the remaining authors, the corresponding author states there is no conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients., Setting: Outpatient treatment., Participants: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities., Interventions: Drug interventions authorised by EMA or FDA., Primary Outcome Measures: Primary outcomes were all-cause mortality and serious adverse events., Results: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p < 0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups., Conclusions: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression., Prospero Registration Number: CRD42020178787., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: It is essential to choose a realistic anticipated intervention effect when calculating a sample size for a randomised clinical trial. Unfortunately, anticipated intervention effects are often inflated, when compared with the 'true' intervention effects. This is documented for mortality in critical care trials. A similar pattern might exist across different medical specialties. This study aims to estimate the range of observed intervention effects for all-cause mortality in trials included in Cochrane Reviews, within each Cochrane Review Group., Methods and Analysis: We will include randomised clinical trials assessing all-cause mortality as an outcome. Trials will be identified from Cochrane Reviews published in the Cochrane Database of Systematic Reviews. Cochrane Reviews will be clustered according to the registered Cochrane Review Group (eg, Anaesthesia, Emergency and Critical Care) and the statistical analyses will be conducted for each Cochrane Review Group and overall. The median relative risk and IQR for all-cause mortality and the proportion of trials with a relative all-cause mortality risk within seven different ranges will be reported (relative risk below 0.70, 0.70-0.79, 0.80-0.89, 0.90-1.09, 1.10-1.19, 1.20-1.30 and above 1.30). Subgroup analyses will explore the effects of original design, sample size, risk of bias, disease, intervention type, follow-up length, participating centres, funding type, information size and outcome hierarchy., Ethics and Dissemination: Since we will use summary data from trials already approved by relevant ethical committees, this study does not require ethical approval. Regardless of our findings, the results will be published in an international peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Low pressure nasal continuous positive airway pressure (nCPAP) has long been the mainstay of non-invasive respiratory support for preterm neonates, at a constant distending pressure of 5-8 cmH2O. When traditional nCPAP pressures are insufficient, other modes including nasal intermittent positive pressure ventilation (NIPPV) are used. In recent years, high nCPAP pressures (≥9 cmH2O) have also emerged as an alternative. However, the comparative benefits and risks of these modalities remain unknown., Methods and Analysis: In this multicentre pilot randomised controlled trial, infants <29 weeks' gestational age (GA) who either: (A) fail treatment with traditional nCPAP or (B) being extubated from invasive mechanical ventilation with mean airway pressure ≥10 cmH2O, will be randomised to receive either high nCPAP (positive end-expiratory pressure 9-15 cmH2O) or NIPPV (target mean Paw 9-15 cmH2O). Primary outcome is feasibility of the conduct of a larger, definitive trial as assessed by rates of recruitment and protocol violations. The main secondary outcome is failure of assigned treatment within 7 days postrandomisation. Multiple other clinical outcomes including bronchopulmonary dysplasia will be ascertained. All randomised participants will be analysed using intention to treat. Baseline and demographic variables as well as outcomes will be summarised and compared using univariate analyses, and a p<0.05 will be considered significant., Ethics and Dissemination: The trial has been approved by the respective research ethics boards at each institution (McMaster Children's Hospital: Hamilton integrated REB approval #2113; Royal Alexandra Hospital: Health Research Ethics Board approval ID Pro00090244; Westmead Hospital: Human Research Ethics Committee approval ID 2022/ETH01343). Written, informed consent will be obtained from all parents/guardians prior to study enrolment. The findings of this pilot study will be disseminated via presentations at national and international conferences and via publication in a peer-reviewed journal. Social media platforms including Twitter will also be used to generate awareness., Trial Registration Number: NCT03512158., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To quantify the prognostic effects of demographic and modifiable factors in streptococcal toxic shock syndrome (STSS)., Design: Systematic review and meta-analysis., Data Sources: MEDLINE, EMBASE and CINAHL from inception to 19 September 2022, along with citations of included studies., Eligibility Criteria: Pairs of reviewers independently screened potentially eligible studies of patients with Group A Streptococcus -induced STSS that quantified the association between at least one prognostic factor and outcome of interest., Data Extraction and Synthesis: We performed random-effects meta-analysis after duplicate data extraction and risk of bias assessments. We rated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach., Results: One randomised trial and 40 observational studies were eligible (n=1918 patients). We found a statistically significant association between clindamycin treatment and mortality (n=144; OR 0.14, 95% CI 0.06 to 0.37), but the certainty of evidence was low. Within clindamycin-treated STSS patients, we found a statistically significant association between intravenous Ig treatment and mortality (n=188; OR 0.34, 95% CI 0.15 to 0.75), but the certainty of evidence was also low. The odds of mortality may increase in patients ≥65 years when compared with patients 18-64 years (n=396; OR 2.37, 95% CI 1.47 to 3.84), but the certainty of evidence was low. We are uncertain whether non-steroidal anti-inflammatory drugs increase the odds of mortality (n=50; OR 4.14, 95% CI 1.13 to 15.14; very low certainty). Results failed to show a significant association between any other prognostic factor and outcome combination (very low to low certainty evidence) and no studies quantified the association between a prognostic factor and morbidity post-infection in STSS survivors., Conclusions: Treatment with clindamycin and within clindamycin-treated patients, IVIG, was each significantly associated with mortality, but the certainty of evidence was low. Future research should focus on morbidity post-infection in STSS survivors., Prospero Registration Number: CRD42020166961., Competing Interests: Competing interests: ML declares grants or contracts from the WHO, consulting fees from AVIR Pharma, and participating on data safety monitoring or advisory boards for Paladin Labs and Sunovion Pharmaceuticals., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Evidence-based recommendations for paediatric community-acquired pneumonia (CAP) diagnosis and management are needed. Uncomplicated CAP is often caused by respiratory viruses, especially in younger children; these episodes self-resolve without antibiotic treatment. Unfortunately, there are no clinical criteria that reliably discriminate between viral and bacterial disease, and so the majority of children diagnosed with CAP are given antibiotics-even though these will often not help and may cause harm. We have developed a novel care pathway that incorporates point-of-care biomarkers, radiographic patterns, microbiological testing and targeted follow-up. The primary study objective is to determine if the care pathway will be associated with less antimicrobial prescribing., Methods and Analysis: A prospective, before-after, study. Previously well children aged≥6 months presenting to a paediatric emergency department (ED) that have at least one respiratory symptom/sign, receive chest radiography, and are diagnosed with CAP by the ED physician will be eligible. Those with medical comorbidities, recently diagnosed pulmonary infection, or ongoing fever after≥4 days of antimicrobial therapy will be excluded. In the control (before) phase, eligible participants will be managed as per the standard of care. In the intervention (after) phase, eligible participants will be managed as per the novel care pathway. The primary outcome will be the proportion of participants in each phase who receive antimicrobial treatment for CAP. The secondary outcomes include: clinical cure; re-presentation to the ED; hospitalisation; time to resolution of symptoms; drug adverse events; caregiver satisfaction; child absenteeism from daycare/school; and caregiver absenteeism from work., Ethics and Dissemination: All study documentation has been approved by the Hamilton Integrated Research Ethics Board and informed consent will be obtained from all participants. Data from this study will be presented at major conferences and published in peer-reviewed publications to facilitate collaborations with networks of clinicians experienced in the dissemination of clinical guidelines., Trial Registration Number: NCT05114161., Competing Interests: Competing interests: JMP’s institution has received grant funding from MedImmune for an RSV research study. ML is on the WHO EML Working group, a Paladin Labs advisory board, and a Sunovion Pharmaceuticals advisory board., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The rates of type 2 diabetes mellitus (T2DM) in children and adolescents have risen globally over the past few years. While a few diabetes pharmacotherapies have been used in this population, their comparative benefits and harms are unclear. Thus, we will conduct a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) to compare the efficacy and safety of pharmacotherapies for managing paediatric T2DM., Methods and Analysis: We will include RCTs that enrolled T2DM patients ≤18 years of age and who were randomised to monotherapy or combination pharmacotherapies with or without lifestyle interventions. Comparator groups will include placebo or non-pharmacological treatments including lifestyle interventions.Treatment outcomes will include change from baseline in glycated haemoglobin A1c, body mass index z-score, weight, systolic/diastolic blood pressure, fasting plasma glucose, fasting insulin and lipid profiles, T2DM-related complications, as well as the incidence of treatment-related adverse events.Literature searches will be conducted in Medline, Embase, CINAHL, CENTRAL and Web of Science. We will also search the grey literature and the reference list of included trials and relevant reviews. Two reviewers will assess the eligibility of articles identified through our searches and will extract data from eligible studies independently. We will use a modified Cochrane instrument to evaluate the risk of bias. Disagreements will be resolved through consensus or arbitration by a third reviewer.A frequentist random-effects model will be used for conducting NMA. The quality of evidence will be assessed using the Confidence in Network Meta-Analysis platform. We will assess the effect modification through network meta-regression and subgroup analyses for sex, age at study inclusion, duration of T2DM, follow-up duration and risk of bias ratings., Ethics and Dissemination: This study will not require ethics approval. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations., Prospero Registration Number: CRD42022310100., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Proton pump inhibitors (PPIs) are widely used for primary and secondary prevention of upper gastrointestinal bleeding. However, there remains controversy about the overall net clinical benefit of PPIs (omeprazole, rabeprazole, pantoprazole, lansoprazole) when coprescribed with direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, edoxaban). Our objective is to explore the risk of clinically relevant events, including bleeding, thromboembolic events and death, in patients prescribed DOACs while taking PPIs versus no PPI., Methods and Analysis: The protocol describes a retrospective cohort study of all Ontario residents aged 66 years or older with atrial fibrillation and at least one pharmacy dispensation for a DOAC identified using linked administrative healthcare databases covering 2009-2020. Ontario drug benefit dispensation records will be used to ascertain PPI exposure during DOAC therapy. The primary outcome is a composite of clinically relevant bleeding, thrombotic events or all-cause death. A minimum of 520 patients in total with at least one of the components of the composite outcome are needed. Poisson regression with a generalised estimating equation model will be used to calculate the adjusted incidence rate difference, incidence rate ratios 95% CI, adjusting for propensity for PPI use using inverse probability of treatment weights., Ethics and Dissemination: This research is exempt from REB review under section 45 of Ontario's Personal Health Information Protection Act. We will report our findings in a peer-reviewed biomedical journal and present them at conferences. The study will provide useful evidence to optimise the coprescription of DOACs and PPIs in practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The Grades of Recommendations, Assessment, Development and Evaluation working group recently developed an innovative approach to interpreting results from network meta-analyses (NMA) through minimally and partially contextualised methods; however, the optimal method for presenting results for multiple outcomes using this approach remains uncertain. We; therefore, developed and iteratively modified a presentation method that effectively summarises NMA results of multiple outcomes for clinicians using this new interpretation approach., Design: Qualitative descriptive study., Setting: A steering group of seven individuals with experience in NMA and design validation studies developed two colour-coded presentation formats for evaluation. Through an iterative process, we assessed the validity of both formats to maximise their clarity and ease of interpretation., Participants: 26 participants including 20 clinicians who routinely provide patient care, 3 research staff/research methodologists and 3 residents., Main Outcome Measures: Two team members used qualitative content analysis to independently analyse transcripts of all interviews. The steering group reviewed the analyses and responded with serial modifications of the presentation format., Results: To ensure that readers could easily discern the benefits and safety of each included treatment across all assessed outcomes, participants primarily focused on simple information presentations, with intuitive organisational decisions and colour coding. Feedback ultimately resulted in two presentation versions, each preferred by a substantial group of participants, and development of a legend to facilitate interpretation., Conclusion: Iterative design validation facilitated the development of two novel formats for presenting minimally or partially contextualised NMA results for multiple outcomes. These presentation approaches appeal to audiences that include clinicians with limited familiarity with NMAs., Competing Interests: Competing interests: MB research grants from Pendopharm, Bioventus, and Acumed. All other authors have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Despite a lack of evidence demonstrating superiority to non-steroidal anti-inflammatory drugs, like ketorolac, that are associated with lower risk of harms, opioids remain the most prescribed analgesic for acute abdominal pain. In this pilot trial, we will assess the feasibility of a definitive trial comparing ketorolac with morphine in children with suspected appendicitis. We hypothesise that our study will be feasible based on a 40% consent rate., Methods and Analysis: A single-centre, non-inferiority, blinded (participant, clinician, investigators and outcome assessors), double-dummy randomised controlled trial of children aged 6-17 years presenting to a paediatric emergency department with ≤5 days of moderate to severe abdominal pain (≥5 on a Verbal Numerical Rating Scale) and are investigated for appendicitis. We will use variable randomised blocks of 4-6 and allocate participants in 1:1 ratio to receive either intravenous (IV) ketorolac 0.5 mg/kg+IV morphine placebo or IV morphine 0.1 mg/kg+IV ketorolac placebo. Analgesic co-intervention will be limited to acetaminophen (commonly used as first-line therapy). Participants in both groups will be allowed rescue therapy (morphine 0.5 mg/kg) within 60 min of our intervention. Our primary feasibility outcome is the proportion of eligible patients approached who provide informed consent and are enrolled in our trial. Our threshold for feasibility will be to achieve a ≥40% consent rate, and we will enrol 100 participants into our pilot trial., Ethics and Dissemination: Our study has received full approval by the Hamilton integrated Research Ethics Board. We will disseminate our study findings at national and international paediatric research conferences to garner interest and engage sites for a future multicentre definitive trial., Trial Registration: NCT04528563, Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Diabetes mellitus is the most common endocrine disorder in children, and the prevalence of paediatric type 1 and type 2 diabetes continue to rise globally. Diabetes clinical care programs pivoted to virtual care with the COVID-19 pandemic-driven social distancing measures. Yet, the impact of virtual care on health-related quality of life in children living with diabetes remains unclear. This protocol reports on the methods that will be implemented to conduct a systematic review to assess the health-related quality of life and metabolic health impacts of virtual diabetes care., Methods and Analysis: We will search MEDLINE, Embase, EMCare, PsycInfo, Web of Science, and the grey literature for eligible studies. We will screen title, abstract, and full-text papers for potential inclusion and assess the risk of bias and the overall confidence in the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis will be conducted if two studies report similar populations, study designs, methods, and outcomes.This systematic review will summarise the health-related quality of life outcomes for virtual diabetes care delivery models., Ethics and Dissemination: No ethics approval is required for this systematic review protocol as it does not include patient data. The systematic review will be published in a peer-reviewed journal and presented at international conferences., Prospero Registration Number: CRD42021235646., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Major depressive disorder (MDD or depression) is prevalent among adults aged 65 years and older. The effectiveness and safety of interventions used to treat depression is often assessed through randomised controlled trials (RCTs). However, heterogeneity in the selection, measurement and reporting of outcomes in RCTs renders comparisons between trial results, interpretability and generalisability of findings challenging. There is presently no core outcome set (COS) for use in RCTs that assess interventions for older adults with MDD. We will conduct a methodological review of the literature for outcomes reported in trials for adults 65 years and older with depression to assess the heterogeneity of outcome measures., Methods and Analysis: RCTs evaluating pharmacotherapy, psychotherapy, or any other treatment intervention for older adults with MDD published in the last 10 years will be located using electronic database searches (MEDLINE, Embase, PsycINFO and the Cochrane Central Register of Controlled Trials). Reviewers will conduct title and abstract screening, full-text screening and data extraction of trials eligible for inclusion independently and in duplicate. Outcomes will be synthesised and mapped to core outcome-domain frameworks. We will summarise characteristics associated with trials and outcomes., Ethics and Dissemination: We hope that findings from our methodological review will reduce variability in outcome selection, measurement and reporting and facilitate the development of a COS for older adults with MDD. Our review will also inform evidence synthesis efforts in identifying the best treatment practices for this clinical population. Ethics approval is not required, as this study is a literature review., Prospero Registration Number: CRD42021244753., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The aetiology of sleep disruptions is unknown, but hormonal fluctuations during the menstrual cycle, pregnancy and menopause have been shown to potentially affect how well a woman sleeps. The aim of this systematic review was to investigate whether hormonal contraceptives are associated with a decreased quality of sleep and increased sleep duration in women of reproductive age., Methods: This review will analyse data from randomised controlled trials or non-randomised comparative studies investigating the association between hormonal contraceptives and sleep outcomes among women of reproductive age. Reviews addressing the same research question with similar eligibility criteria will be included. A literature search will be performed using the MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases from inception to 7 March 2021. The Cochrane Collaboration's Risk of Bias for Randomised Trials V.2.0 and The Risk of Bias for Non-randomised Studies of Interventions tool will be used to assess risk of bias for each outcome in eligible studies. Two reviewers will independently assess eligibility of studies and risk of bias and extract the data. All extracted data will be presented in tables and narrative form. For sleep measures investigated by two or more studies with low heterogeneity, we will conduct random-effects meta-analysis to estimate the magnitude of the overall effect of hormonal contraceptives. If studies included in this systematic review form a connected network, a network meta-analysis will be conducted to estimate the comparative effect of different contraceptives. The Grading of Recommendations, Assessment, Development, and Evaluation approach will be used to summarise the quality of evidence. Our protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols 2015 guidelines., Ethics and Dissemination: Ethics approval is not required as data were sourced from previously reported studies. The findings of this review will be published in a peer-reviewed journal and presented at relevant conferences., Prospero Registration Number: CRD42020199958., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The COVID-19 pandemic has driven unprecedented social and economic reform in efforts to curb the impact of disease. Governments worldwide have legislated non-essential service shutdowns and adapted essential service provision in order to minimise face-to-face contact. We anticipate major consequences resulting from such policies, with marginalised populations expected to bear the greatest burden of such measures, especially those with substance use disorders (SUDs)., Methods and Analysis: We aim to conduct (1) a scoping review to summarise the available evidence evaluating the impact of the COVID-19 pandemic on patients with SUDs, and (2) an evidence map to visually plot and categorise the current available evidence evaluating the impact of COVID-19 on patients with SUDs to identify gaps in addressing high-risk populations., Ethics and Dissemination: Ethics approval is not required for this scoping review as we plan to review publicly available data. This is part of a multistep project, whereby we intend to use the findings generated from this review in combination with data from an ongoing prospective cohort study our team is leading, encompassing over 2000 patients with SUDs receiving medication-assisted therapy in Ontario prior to and during the COVID-19 pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Streptococcal pharyngitis, which commonly occurs in children, should be treated with antibiotics. Clinical prediction rules to differentiate streptococcal pharyngitis from viral infection are not recommended in children. Rapid point-of-care (POC) antigen tests have limited sensitivity and so are not often used in Canadian paediatric emergency departments (EDs). Standard paediatric practice is to rely on laboratory-based testing, which often results in a delay before the results can be communicated to the patient; this may impede appropriate prescribing, decrease caregiver satisfaction and delay recovery. The objective of this study is to determine whether a novel rapid molecular POC assay for streptococcal pharyngitis leads to more appropriate antibiotic use in children seeking care in a paediatric ED than standard laboratory-based testing., Methods and Analysis: A randomised, superiority, open-label, trial with two parallel groups. Children presenting to a tertiary paediatric ED at least 3 years of age who have a throat swab ordered for diagnosis of streptococcal pharyngitis will be eligible; those who have taken antibiotics within 72 hours prior to presentation and those with additional active infections will be excluded. The primary study outcome will be appropriate antibiotic treatment at 3-5 days postenrolment. Secondary outcomes include time to symptom resolution, caregiver satisfaction, caregiver/child absenteeism, number of subsequent healthcare visits, clinician satisfaction and incremental cost-effectiveness of POC testing. A total of 352 participants will be needed., Ethics and Dissemination: All study documentation has been approved by the Hamilton Integrated Research Ethics board and informed consent will be obtained from all participants. Data from this trial will be presented at major conferences and published in peer-reviewed publications to facilitate collaborations with networks of clinicians experienced in the dissemination of clinical guidelines., Trial Registration Number: NCT04247243., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the efficacy and harms of adding medical cannabis to prescription opioids among people living with chronic pain., Design: Systematic review., Data Sources: CENTRAL, EMBASE and MEDLINE., Main Outcomes and Measures: Opioid dose reduction, pain relief, sleep disturbance, physical and emotional functioning and adverse events., Study Selection Criteria and Methods: We included studies that enrolled patients with chronic pain receiving prescription opioids and explored the impact of adding medical cannabis. We used Grading of Recommendations Assessment, Development and Evaluation to assess the certainty of evidence for each outcome., Results: Eligible studies included five randomised trials (all enrolling chronic cancer-pain patients) and 12 observational studies. All randomised trials instructed participants to maintain their opioid dose, which resulted in a very low certainty evidence that adding cannabis has little or no impact on opioid use (weighted mean difference (WMD) -3.4 milligram morphine equivalent (MME); 95% CI (CI) -12.7 to 5.8). Randomised trials provided high certainty evidence that cannabis addition had little or no effect on pain relief (WMD -0.18 cm; 95% CI -0.38 to 0.02; on a 10 cm Visual Analogue Scale (VAS) for pain) or sleep disturbance (WMD -0.22 cm; 95% CI -0.4 to -0.06; on a 10 cm VAS for sleep disturbance; minimally important difference is 1 cm) among chronic cancer pain patients. Addition of cannabis likely increases nausea (relative risk (RR) 1.43; 95% CI 1.04 to 1.96; risk difference (RD) 4%, 95% CI 0% to 7%) and vomiting (RR 1.5; 95% CI 1.01 to 2.24; RD 3%; 95% CI 0% to 6%) (both moderate certainty) and may have no effect on constipation (RR 0.85; 95% CI 0.54 to 1.35; RD -1%; 95% CI -4% to 2%) (low certainty). Eight observational studies provided very low certainty evidence that adding cannabis reduced opioid use (WMD -22.5 MME; 95% CI -43.06 to -1.97)., Conclusion: Opioid-sparing effects of medical cannabis for chronic pain remain uncertain due to very low certainty evidence. PROSPERO registration number CRD42018091098., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Social isolation and loneliness in older adults are significant public health issues. Various interventions such as exercise programmes or social activities are used in the management of social isolation and loneliness in older adults. Network meta-analysis (NMA) provides effect estimates for all comparisons by considering the relative efficacy of multiple intervention alternatives. Therefore, this study will determine the comparative efficacy of intervention to alleviate social isolation and loneliness of older adults in community dwelling by comparing direct and indirect interventions through systematic review and NMA., Methods and Analysis: We will include all relevant randomised controlled trials for interventions of social isolation and loneliness in older adults written in English without any limitation of publication date through electronic databases: MEDLINE via OVID, EMBASE, Cochrane Central Registry of Controlled Trials (CENTRAL), PsycINFO and CINAHL. Independent teams of reviewers will screen trial eligibility, collect data, identify duplication and assess risk of bias, by using the Cochrane revised risk of bias tool. The interventions for the management of social isolation and loneliness will be included. The primary outcome is social isolation. The secondary outcomes are loneliness and health-related quality of life. We will conduct an NMA through a Bayesian hierarchical model, by testing assumption (ie, transitivity) for NMA. We will also estimate the ranking probabilities for all interventions at each possible rank for each intervention. For estimation of each intervention efficacy, we will assess the certainty and credibility using the Grading of Recommendations Assessment, Development and Evaluation approach., Ethics and Dissemination: Ethics approval will not be obtained for this systematic review as it will be conducted with published papers. The review results will be presented at a field-specific conference and published in a relevant peer-reviewed journal., Prospero Registration Number: CRD42020155789., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Prespecified progression criteria can inform the decision to progress from an external randomised pilot trial to a definitive randomised controlled trial. We assessed the characteristics of progression criteria reported in external randomised pilot trial protocols and results publications, including whether progression criteria were specified a priori and mentioned in prepublication peer reviewer reports., Study Design: Methodological review., Methods: We searched four journals through PubMed: British Medical Journal Open , Pilot and Feasibility Studies , Trials and Public Library of Science One . Eligible publications reported external randomised pilot trial protocols or results, were published between January 2018 and December 2019 and reported progression criteria. We double data extracted 25% of the included publications. Here we report the progression criteria characteristics., Results: We included 160 publications (123 protocols and 37 completed trials). Recruitment and retention were the most frequent indicators contributing to progression criteria. Progression criteria were mostly reported as distinct thresholds (eg, achieving a specific target; 133/160, 83%). Less than a third of the planned and completed pilot trials that included qualitative research reported how these findings would contribute towards progression criteria (34/108, 31%). The publications seldom stated who established the progression criteria (12/160, 7.5%) or provided rationale or justification for progression criteria (44/160, 28%). Most completed pilot trials reported the intention to proceed to a definitive trial (30/37, 81%), but less than half strictly met all of their progression criteria (17/37, 46%). Prepublication peer reviewer reports were available for 153/160 publications (96%). Peer reviewer reports for 86/153 (56%) publications mentioned progression criteria, with peer reviewers of 35 publications commenting that progression criteria appeared not to be specified., Conclusions: Many external randomised pilot trial publications did not adequately report or propose prespecified progression criteria to inform whether to proceed to a future definitive randomised controlled trial., Competing Interests: Competing interests: KM, SEd, CB, MJC, GL, LT, SEl and SH contribute to a Pilot and Feasibility Studies working group. GL and LT are editors in chief of the Pilot and Feasibility Studies journal. SEl, MJC and CB are editors of the Pilot and Feasibility Studies journal., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Randomised controlled trials conducted using cohorts and routinely collected data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. A Consolidated Standards of Reporting Trials (CONSORT) statement extension for trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE) has been developed with the goal of improving reporting quality. This article describes the processes and methods used to develop the extension and decisions made to arrive at the final checklist., Methods: The development process involved five stages: (1) identification of the need for a reporting guideline and project launch; (2) conduct of a scoping review to identify possible modifications to CONSORT 2010 checklist items and possible new extension items; (3) a three-round modified Delphi study involving key stakeholders to gather feedback on the checklist; (4) a consensus meeting to finalise items to be included in the extension, followed by stakeholder piloting of the checklist; and (5) publication, dissemination and implementation of the final checklist., Results: 27 items were initially developed and rated in Delphi round 1, 13 items were rated in round 2 and 11 items were rated in round 3. Response rates for the Delphi study were 92 of 125 (74%) invited participants in round 1, 77 of 92 (84%) round 1 completers in round 2 and 62 of 77 (81%) round 2 completers in round 3. Twenty-seven members of the project team representing a variety of stakeholder groups attended the in-person consensus meeting. The final checklist includes five new items and eight modified items. The extension Explanation & Elaboration document further clarifies aspects that are important to report., Conclusion: Uptake of CONSORT-ROUTINE and accompanying Explanation & Elaboration document will improve conduct of trials, as well as the transparency and completeness of reporting of trials conducted using cohorts and routinely collected data., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Youth with brain-based disabilities (BBDs), as well as their parents/caregivers, often feel ill-prepared for the transfer from paediatric to adult healthcare services. To address this pressing issue, we developed the MyREADY Transition TM BBD App, a patient-facing e-health intervention. The primary aim of this randomised controlled trial (RCT) was to determine whether the App will result in greater transition readiness compared with usual care for youth with BBD. Secondary aims included exploring the contextual experiences of youth using the App, as well as the interactive processes of youth, their parents/caregivers and healthcare providers around use of the intervention., Methods and Analysis: We aimed to randomise 264 youth with BBD between 15 and 17 years of age, to receive existing services/usual care (control group) or to receive usual care along with the App (intervention group). Our recruitment strategy includes remote and virtual options in response to the current requirements for physical distancing due to the COVID-19 pandemic. We will use an embedded experimental model design which involves embedding a qualitative study within a RCT. The Transition Readiness Assessment Questionnaire will be administered as the primary outcome measure. Analysis of covariance will be used to compare change in the two groups on the primary outcome measure; analysis will be intention-to-treat. Interviews will be conducted with subsets of youth in the intervention group, as well as parents/caregivers and healthcare providers., Ethics and Dissemination: The study has been approved by the research ethics board of each participating site in four different regions in Canada. We will leverage our patient and family partnerships to find novel dissemination strategies. Study findings will be shared with the academic and stakeholder community, including dissemination of teaching and training tools through patient associations, and patient and family advocacy groups., Trial Registration Number: NCT03852550., Competing Interests: Competing interests: JWG and AJM received research grants from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research. JWG holds the Scotiabank Chair in Child Health Research. AK and RR were paid in part for their work as consultants. BG, LN, SS, NM and AV-D-L were paid for their work as project staff members. LT was paid in part for his work as statistical consultant., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Vaping behaviour has increased in popularity and is particularly important to examine how it effects health outcomes in vulnerable populations, including those with opioid use disorder (OUD). With polysubstance use including cigarette and cannabis use being highly prevalent in the OUD population and cannabis/nicotine increasingly being consumed by vaping, vaping may have an important contribution to health outcomes in these individuals. The primary objective of this review is to systematically assess the literature related to patients with OUD and the effects vaping has shown on their physical and mental health., Method and Analysis: A systematic search of databases including MEDLINE, Embase, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Cochrane Clinical Trials Registry, the National Institutes for Health Clinical Trials Registry and the WHO International Clinical Trials Registry Platform from inception to 31 December 2020 will be conducted. Identified citations will be screened by two reviewers to determine eligibility at the title and abstract level, and then at the full text and data extraction phases. Any disagreements in inclusion will be resolved through unblinded discussion by these reviewers, with any remaining disagreements being resolved by a third reviewer. Data collection from eligible studies will be conducted according to the data extraction form tested prior to abstraction. Included studies will be examined for quality and bias and will be meta-analysed where applicable. This protocol is reported in keeping with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines., Ethics and Dissemination: The results for this review will be disseminated through publications in peer-reviewed journals, posters and presentations at scientific conferences. Additionally, we are collaborating with the Canadian Addiction Treatment Centre clinics to help disseminate the findings for this review. As this is a systematic review, no ethics approval is needed., Review Registration Number: CRD42020178441., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Existing methods of measuring effectiveness of pharmacological treatment for opioid use disorder (OUD) are highly variable. Therefore, understanding patients' treatment goals is an integral part of patient-centred care. Our objective is to explore whether patients' treatment goals align with a frequently used clinical outcome, opioid abstinence., Design: Triangulation mixed-methods design., Setting and Participants: We collected prospective data from 2030 participants who were receiving methadone or buprenorphine-naloxone treatment for a diagnosis of OUD in order to meet study inclusion criteria. Participants were recruited from 45 centrally-managed outpatient opioid agonist therapy clinics in Ontario, Canada. At study entry, we asked, 'What are your goals in treatment?' and used NVivo software to identify common themes., Primary Outcome Measure: Urine drug screens (UDS) were collected for 3 months post-study enrolment in order to identify abstinence versus ongoing opioid use (mean number of UDS over 3 months=12.6, SD=5.3). We used logistic regression to examine the association between treatment goals and opioid abstinence., Results: Participants had a mean age of 39.2 years (SD=10.7), 44% were women and median duration in treatment was 2.6 years (IQR 5.2). Six overarching goals were identified from patient responses, including 'stop or taper off of treatment' (68%), 'stay or get clean' (37%) and 'live a normal life' (14%). Participants reporting the goal 'stay or get clean' had lower odds of abstinence at 3 months than those who did not report this goal (OR=0.73, 95% CI 0.59 to 0.91, p=0.005). Although the majority of patients wanted to taper off or stop medication, this goal was not associated with opioid abstinence, nor were any of their other goals., Conclusions: Patient goals in OUD treatment do not appear to be associated with programme measures of outcome (ie, abstinence from opioids). Future studies are needed to examine outcomes related to patient-reported treatment goals found in our study; pain management, employment, and stopping/tapering treatment should all be explored., Competing Interests: Competing interests: Dr David C. Marsh reports Salary income as Chief Medical Director, Canadian Addiction Treatment Centres and as Associate Dean Research, Innovation and International Relations, Northern Ontario School of Medicine., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Methodological studies (ie, studies that evaluate the design, conduct, analysis or reporting of other studies in health research) address various facets of health research including, for instance, data collection techniques, differences in approaches to analyses, reporting quality, adherence to guidelines or publication bias. As a result, methodological studies can help to identify knowledge gaps in the methodology of health research and strategies for improvement in research practices. Differences in methodological study names and a lack of reporting guidance contribute to lack of comparability across studies and difficulties in identifying relevant previous methodological studies. This paper outlines the methods we will use to develop an evidence-based tool-the MethodologIcal STudy reportIng Checklist-to harmonise naming conventions and improve the reporting of methodological studies., Methods and Analysis: We will search for methodological studies in the Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Embase, MEDLINE, Web of Science, check reference lists and contact experts in the field. We will extract and summarise data on the study names, design and reporting features of the included methodological studies. Consensus on study terms and recommended reporting items will be achieved via video conference meetings with a panel of experts including researchers who have published methodological studies., Ethics and Dissemination: The consensus study has been exempt from ethics review by the Hamilton Integrated Research Ethics Board. The results of the review and the reporting guideline will be disseminated in stakeholder meetings, conferences, peer-reviewed publications, in requests to journal editors (to endorse or make the guideline a requirement for authors), and on the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and reporting guideline websites., Registration: We have registered the development of the reporting guideline with the EQUATOR Network and publicly posted this project on the Open Science Framework (www.osf.io/9hgbq)., Competing Interests: Competing interests: ‘Yes, there are competing interests for one or more authors and I have provided a Competing Interests statement in my manuscript and in the box below’., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate the cost-effectiveness of the Community Paramedicine at Clinic (CP@clinic) programme compared with usual care in seniors residing in subsidised housing., Design: A cost-utility analysis was conducted within a large pragmatic cluster randomised controlled trial (RCT). Subsidised housing buildings were matched by sociodemographics and location (rural/urban), and allocated to intervention (CP@clinic for 1 year) or control (usual care) via computer-assisted paired randomisation., Setting: Thirty-two subsidised seniors' housing buildings in Ontario., Participants: Building residents 55 years and older., Intervention: CP@clinic is a weekly community paramedic-led, chronic disease prevention and health promotion programme in the building common areas. CP@clinic is free to residents and includes risk assessments, referrals to resources, and reports back to family physicians., Outcome Measures: Quality-adjusted life years (QALYs) gained, measured with EQ-5D-3L. QALYs were estimated using area-under-the curve over the 1-year intervention, controlling for preintervention utility scores and building pairings. Programme cost data were collected before and during implementation. Costs associated with emergency medical services (EMS) use were estimated. An incremental cost effectiveness ratio (ICER) based on incremental costs and health outcomes between groups was calculated. Probabilistic sensitivity analysis using bootstrapping was performed., Results: The RCT included 1461 residents; 146 and 125 seniors completed the EQ-5D-3L in intervention and control buildings, respectively. There was a significant adjusted mean QALY gain of 0.03 (95% CI 0.01 to 0.05) for the intervention group. Total programme cost for implementing in five communities was $C128 462 and the reduction in EMS calls avoided an estimated $C256 583. The ICER was $C2933/QALY (bootstrapped mean ICER with Fieller's 95% CI was $4850 ($2246 to $12 396)) but could be even more cost effective after accounting for the EMS call reduction., Conclusion: The CP@clinic ICER was well below the commonly used Canadian cost-utility threshold of $C50 000. CP@clinic scale-up across subsidised housing is feasible and could result in better health-related quality-of-life and reduced EMS use in low-income seniors., Trial Registration Number: Clinicaltrials.gov, NCT02152891., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: High-cost users (HCUs) account for a small proportion of the population but use a disproportionately large share of healthcare resources. Although HCUs exist in all healthcare types, acute care is the most expensive type of service and the most significant contributor to expenditures among HCUs. This study aims to determine demographic, socioeconomic and clinical factors associated with being HCUs in adult patients (≥18 years) receiving acute care in Canada., Methods and Analysis: This is a population-based analysis using a national linked dataset. Adult patients who had at least one interaction with acute care facilities each year from 2011 to 2014 were captured in the dataset, and those living in institutions or other collective residences were not covered. The primary outcome is HCU of acute care (yes/no), which is defined as whether a patient is within the top 10% of the highest acute care cost users in his/her province. Multilevel logistic regression will be used to identify factors associated with HCU and to examine the provincial variations of these identified risk factors. Sensitivity analyses investigating the influences of different high user definitions and missing data on the study results will also be performed., Ethics and Dissemination: All researchers will follow the codes and rules set by Statistics Canada and the Research Data Centre and give priority to the confidentiality of the data during and after this study. The study findings will be published in peer-review journals and disseminated at academic conferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This protocol is describing a multicentre, single-blind randomised controlled trial. The objective is to compare the efficacy of MyndMove therapy versus conventional therapy (CT) in improving upper extremity function in individuals with C4-C7 traumatic, incomplete spinal cord injury (SCI). It is being conducted in two US and two Canadian SCI rehabilitation centres., Methods and Analysis: Sixty people aged 18 years or older with a C4-C7 incomplete (AIS B-D) SCI between 4 months and 8 years postinjury are randomised to receive 40 sessions of MyndMove neuromodulation therapy or CT within a 14-week period of time. Therapy sessions are 1 hour in duration with a dose of 3-5 sessions per week. Assessments occur prior to randomisation, after 20 sessions, after 40 sessions and 10 weeks after the last session. The primary outcome measure is the efficacy of MyndMove therapy versus CT in improving upper extremity function as measured by Spinal Cord Independence Measure III: Self-Care subscore after 40 sessions. Secondary outcomes include: (1) improvements in the SCIM mobility subscore; (2) upper limb functions measured by Graded Redefined Assessment of Strength, Sensibility and Prehension and (3) Toronto Rehab Institute Hand Function Test; (4) To assess safety as measured by serious and non-serious adverse events recorded for participants in both groups of the study population over the duration of the study; (5) to compare the change in quality of life as measured by the Spinal Cord Injury-Quality of Life; and (6) to evaluate the impact on healthcare resource utilisation., Ethics and Dissemination: All ethical approvals were obtained prior to enrolling any participants. Dissemination of the results of the study will be made at peer-reviewed academic meetings and through peer-reviewed medical journals TRIAL REGISTRATION NUMBER: NCT03439319., Competing Interests: Competing interests: MyndTec Inc is the contracting organisation of this study and through funding provided by US Army Medical Research and Materiel Command, researchers are reimbursed for doing this study. All investigators have an interest in completing the study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We sought to map the evidence and identify interventions that increase initiation of antiretroviral therapy, adherence to antiretroviral therapy and retention in care for people living with HIV at high risk for poor engagement in care., Methods: We conducted an overview of systematic reviews and sought for evidence on vulnerable populations (men who have sex with men (MSM), African, Caribbean and Black (ACB) people, sex workers (SWs), people who inject drugs (PWID) and indigenous people). We searched PubMed, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Web of Science and the Cochrane Library in November 2018. We screened, extracted data and assessed methodological quality in duplicate and present a narrative synthesis., Results: We identified 2420 records of which only 98 systematic reviews were eligible. Overall, 65/98 (66.3%) were at low risk of bias. Systematic reviews focused on ACB (66/98; 67.3%), MSM (32/98; 32.7%), PWID (6/98; 6.1%), SWs and prisoners (both 4/98; 4.1%). Interventions were: mixed (37/98; 37.8%), digital (22/98; 22.4%), behavioural or educational (9/98; 9.2%), peer or community based (8/98; 8.2%), health system (7/98; 7.1%), medication modification (6/98; 6.1%), economic (4/98; 4.1%), pharmacy based (3/98; 3.1%) or task-shifting (2/98; 2.0%). Most of the reviews concluded that the interventions effective (69/98; 70.4%), 17.3% (17/98) were neutral or were indeterminate 12.2% (12/98). Knowledge gaps were the types of participants included in primary studies (vulnerable populations not included), poor research quality of primary studies and poorly tailored interventions (not designed for vulnerable populations). Digital, mixed and peer/community-based interventions were reported to be effective across the continuum of care., Conclusions: Interventions along the care cascade are mostly focused on adherence and do not sufficiently address all vulnerable populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Oral anticoagulants (OACs) are widely prescribed in older adults. High OAC-related adverse event rates in the early period following hospital discharge argue for an analysis to identify predictors. Our objective is to identify and validate clinical and continuity of care variables among seniors discharged from hospital on an OAC, which are independently associated with OAC-related adverse events within 30 days., Methods and Analysis: We propose a population-based retrospective cohort study of all adults aged 66 years or older who were discharged from hospital on an OAC from September 2010 to March 2015 in Ontario, Canada. The primary outcome is a composite of the first hospitalisation or emergency department visit for a haemorrhage or thromboembolic event or mortality within 30 days of hospital discharge. A Cox proportional hazards model will be used to determine the association between the composite outcome and a set of prespecified covariates. A split sample method will be adopted to validate the variables associated with OAC-related adverse events., Ethics and Dissemination: The use of data in this project was authorised under section 45 of Ontario's Personal Health Information Protection Act, which does not require review by a research ethics board. Results will be disseminated via peer-reviewed publications and presentations at conferences and will determine intervention targets to improve OAC management in upcoming randomised trials., Trial Registration Number: ClinicalTrials.gov Identifier: NCT02777047; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The current COVID-19 pandemic has resulted in high rates of infection and death, as well as widespread social disruption and a reduction in access to healthcare services and support. There is growing concern over how the pandemic, as well as measures put in place to curb the pandemic, will impact people with mental disorders. We aim to study the effect of pandemics and epidemics on mental health outcomes for people with premorbid mental disorders., Methods and Analysis: With our predefined search strategy, we will search five databases for studies reporting on mental health outcomes in people with pre-existing mental disorders during pandemic and epidemic settings. Search dates are planned as follows: 5 May 2020 and 23 July 2020. The following databases will be searched: MEDLINE/PubMed, CINAHL, PsycINFO, MedRxiv and EMBASE. Data will be screened and extracted in duplicate by two independent reviewers. Studies involving non-clinical populations or patients diagnosed with a mental disorder during a pandemic/epidemic will be excluded. We will include data collected from all pandemics and epidemics throughout history, including the present COVID-19 pandemic. If possible, study findings will be combined in meta-analyses, and subgroup analyses will be performed. We hope that this review will shed light on the impact of pandemics and epidemics on those with pre-existing mental disorders. Knowledge generated may inform future intervention studies as well as healthcare policies. Given the potential implications of the current pandemic measures (ie, disruption of healthcare services) on mental health, we will also compile a list of existing mental health resources., Ethics and Dissemination: No ethical approval is required for this protocol and proposed systematic review as we will only use data from previously published papers that have themselves received ethics clearance and used proper informed consent procedures., Systematic Review Registration: PROSPERO registration number: CRD42020179611., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Suicidal behaviour remains a major public health challenge worldwide. Several countries have developed national suicide guidelines aimed at raising awareness of and preventing deaths by suicide. One of the interventions often mentioned in these national guidelines is the involvement of family members as a protective factor in suicide prevention. However, the level or type of family involvement required to reduce suicidal behaviour is not well understood. Thus, in this systematic review, we seek to determine the effectiveness of family-based interventions as a suicide prevention tool, by comparing suicide mortality rates between countries whose national suicide prevention guidelines include family-based interventions and those whose do not., Methods and Analysis: MEDLINE, EMBASE, PsycINFO, Web of Science and WHO MiNDbank databases as well as grey literature such as National Guideline Clearinghouse will be searched. National guidelines for suicide prevention published within the last 20 years (between 1999 and 2019) will be included. Results will be analysed using thematic and qualitative analyses., Ethics and Dissemination: The findings of the study will help improve the efficacy of national suicide prevention strategies. Findings will be disseminated using easily accessible summary reports and resources to primary end users., Prospero Registration Number: This protocol has been registered on PROSPERO (CRD42019130195)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile -associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU., Methods and Analysis: The objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer's perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital 'hoteling' costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach., Ethics and Dissemination: Study approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals., Trial Registration Number: NCT01782755; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Pilot/feasibility studies assess the feasibility of conducting a larger study. Although researchers ought to communicate the feasibility objectives to their participants, many research ethics guidelines do not comment on how informed consent applies to pilot studies. It is unclear whether researchers and research ethics boards clearly communicate the purpose of pilot studies to participants consenting.The primary objective of this study is to assess whether pilot/feasibility studies submitted for ethics approval to a research ethics board transparently communicate the purpose of the study to participants through their informed consent practice. A highly transparent consent practice entails the consent documents communicate: (1) the term 'pilot' or 'feasibility' in the title; (2) the definition of a pilot/feasibility study; (3) the primary objectives of the study are to assess feasibility; (4) the specific feasibility objectives; and (5) the criteria for the study to successfully lead to the main study. The secondary objectives are to assess whether there is a difference between submitted and revised versions of the consent documents (revisions are made to obtain research ethics approval), to determine factors associated with transparent consent practices and to assess the consistency with which pilot and feasibility studies assess feasibility outcomes as their primary objectives., Methods and Analysis: This is a retrospective review of informed consent information for pilot/feasibility studies submitted to the Hamilton integrated Research Ethics Board, Canada. We will look at submitted and revised consent documents for pilot/feasibility studies submitted over a 14-year period. We will use descriptive statistics to summarise data, reporting results as percentages with 95% CIs, and conduct logistic regression to determine characteristics associated with transparent consent practices., Ethics and Dissemination: The study protocol was approved by the Hamilton integrated Research Ethics Board, and the results of this study will be submitted for publication in a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Despite the increasing number of drugs and various guidelines on the management of type 2 diabetes mellitus (T2DM), several patients continue with the disease uncontrolled. There are several non-pharmacological treatments available for managing T2DM, but various of them have never been compared directly to determine the best strategies., Objective: This study will evaluate the comparative effects of non-pharmacological strategies in the management of T2DM in primary care or community settings., Methods and Analysis: We will perform a systematic review and network meta-analysis (NMA), and will include randomised controlled trials if one of the following interventions were applied in adult patients with T2DM: nutritional therapy, physical activity, psychological interventions, social interventions, multidisciplinary lifestyle interventions, diabetes self-management education and support (DSMES), technology-enabled DSMES, interventions delivered only either by pharmacists or by nurses, self-blood glucose monitoring in non-insulin-treated T2DM, health coaching, benchmarking and usual care. The primary outcome will be glycaemic control (glycated haemoglobin (HbA1c) (%)), and the secondary outcomes will be weight loss, quality of life, patient satisfaction, frequency of cardiovascular events and deaths, number of patients in each group with HbA1c <7, adverse events and medication adherence. We have developed search strategies for Embase, Medline, Latin American and Caribbean Health Sciences Literature, Cochrane Central Register of Controlled Trials, Trip database, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature Australasian Medical Index and Chinese Biomedical Literature Database. Four reviewers will assess the studies for their eligibility and their risk of bias in pairs and independently. An NMA will be performed using a Bayesian hierarchical model, and the treatment hierarchy will be obtained using the surface under the cumulative ranking curve. To determine our confidence in an overall treatment ranking from the NMA, we will follow the Grading of Recommendations Assessment, Development and Evaluation approach., Ethics and Dissemination: As no primary data collection will be undertaken, no formal ethical assessment is required. We plan to present the results of this systematic review in a peer-reviewed scientific journal, conferences and the popular press., Prospero Registration Number: CRD42019127856., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Chronic Myeloid Leukaemia (CML) constitutes 15% of new adult leukaemia cases as well as 2%-3% of leukaemia in children under 15% and 9% of leukaemias in adolescents 15-19 years of age annually. The introduction of Tyrosine Kinase Inhibitors (TKI) therapy has dramatically improved survival in these patients, yet the off-target effects of this treatment may have long-term health impacts on CML survivors. The risk of adverse health outcomes is especially important in children, where TKI exposure may occur during critical windows of growth and puberty, and patients require treatment for prolonged periods of time. The aim of this systematic review protocol is to report on the methods used to conduct a systematic review to investigate the endometabolic and bone health effects of TKI therapy in CML., Methods and Analysis: Searches will be conducted in the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception on August 1st, 2019. Searches may be updated while performing the systematic review to ensure new evidence is included if applicable. Grey literature search will include ClinicalTrials.gov and ProQuest Dissertations and Theses A&I. We will perform a meta-analysis if there are at least two studies reporting similar populations, interventions, methods and tracking the same outcome measures. The studies should also have similar age and sex distributions., Ethics and Dissemination: As this is a systematic review protocol, it does not include patient data; therefore, Research Ethics Board approval is not indicated. The systematic review will be published in a peer-reviewed journal and presented at international conferences., Prospero Registration Number: CRD42018091175., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)