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Abstract Background To inform the development of a core outcome set (COS) for children and youth with mucopolysaccharidoses (MPS), we aimed to identify all outcomes and associated outcome measurement instruments that are reported in recent clinical trials and recommended as measurements in clinical management guidelines. Methods To identify English-language clinical trials and guidelines pertaining to MPS published between 2011 and mid-2021, we applied a comprehensive peer-reviewed search strategy to relevant databases and registers on May 16, 2021. Two reviewers independently screened retrieved citations and then full-text articles to determine eligibility for inclusion. From articles meeting inclusion criteria, we extracted details of the study design, population, intervention, and comparator, along with verbatim outcomes and associated outcome measurement instruments. Outcomes were organized into domains within five a priori core areas: life impact, pathophysiological manifestations, growth and development, resource use, and death. We conducted descriptive analyses at the study level, grouping articles arising from the same study. Results From 2593 unique citations, 73 articles from 61 unique studies were included in the review, pertaining to all MPS subtypes except for exceptionally rare subtypes. Eighty-four unique outcomes were reported across the studies, 33 (39%) of which were reported by three or fewer studies. Most outcomes (55; 65%) were in the pathophysiological manifestations core area, followed by life impact (17; 20%) and growth and development (10; 12%); one outcome each pertained to resource use and death. The most frequently reported outcomes were general adverse events (45; 74%), immune-related adverse events (39; 64%), and urinary glycosaminoglycans (38; 62%). Substantial variability existed in the reporting of outcome measurement instruments. Some differences in outcome reporting were observed by MPS subtype and publication year. Discussion Outcomes reported in clinical trials and guidelines for MPS in children and youth vary considerably and largely focus on pathophysiological manifestations. A COS is needed to standardize the selection and measurement of meaningful outcomes across future studies. We will present the outcomes identified in this review to knowledge users as part of a consensus process to select the most critical outcomes for inclusion in the COS. Trial Registration The protocol for this study was registered in PROSPERO (CRD42021267531) and in the COMET Database.

Introduction Home-based, virtually-supported care models may represent the most efficient and scalable approach to delivering prehabilitation services. However, virtual approaches to prehabilitation are understudied. This manuscript describes the protocol for an internal pilot randomised controlled trial of a virtually-delivered, multimodal prehabilitation intervention.Methods and analysis We will conduct a pragmatic, individual patient, internal pilot randomised controlled trial of home-based, virtually supported, multimodal prehabilitation compared with standard perioperative care in adults undergoing elective, inpatient thoracic, abdominal, pelvic and vascular surgery at five Canadian hospitals. Participants will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of 3–12 weeks of a home-based, multimodal (exercise, nutrition and psychosocial support) prehabilitation programme supported through an online platform. The primary feasibility outcomes and their progression targets are (1) monthly recruitment of>6 participants at each centre, (2) intervention adherence of>75%, (3) retention of>90% of participants at the patient-reported primary outcome point of 30-days after surgery and (4) elicitation of patient, clinician and researcher-identified barriers to our pragmatic trial. A sample size of 144 participants will be adequate to estimate recruitment, adherence and retention rates with acceptable precision. All participants will be followed to either death or up to 1 year. As an internal pilot, if no substantive changes to the trial or intervention design are required, pilot participant outcome data will migrate, unanalysed by allocation, to the future full-scale trial.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 4479) and our ethics review board (Protocol Approval #20230399–01T). Results will be disseminated through presentations at scientific conferences, peer-reviewed publications, partner organisations and engagement of social and traditional media.Trial registration number ClinicalTrials.gov identifier NCT06042491. Protocol, V.1.2, dated 6 June 2024.

Using digitized data from progression-free survival (PFS) and overall survival Kaplan–Meier curves, one can assess population survival kinetics through exponential decay nonlinear regression analyses. To demonstrate their utility, we analyzed PFS curves from published curative-intent trials of non-small cell lung cancer (NSCLC) adjuvant chemotherapy, adjuvant osimertinib in resected EGFR-mutant NSCLC (ADAURA trial), chemoradiotherapy for inoperable NSCLC, and limited small cell lung cancer (SCLC). These analyses permit assessment of log–linear curve shape and estimation of the proportion of patients cured, PFS half-lives for subpopulations destined to eventually relapse, and probability of eventual relapse in patients remaining progression-free at different time points. The proportion of patients potentially cured was 41% for adjuvant controls, 58% with adjuvant chemotherapy, 17% for ADAURA controls, not assessable with adjuvant osimertinib, 15% with chemoradiotherapy, and 12% for SCLC. Median PFS half-life for relapsing subpopulations was 11.9 months for adjuvant controls, 17.4 months with adjuvant chemotherapy, 24.4 months for ADAURA controls, not assessable with osimertinib, 9.3 months with chemoradiotherapy, and 10.7 months for SCLC. For those remaining relapse-free at 2 and 5 years, the cure probability was 74%/96% for adjuvant controls, 77%/93% with adjuvant chemotherapy, 51%/94% with chemoradiation, and 39%/87% with limited SCLC. Relatively easy population kinetic analyses add useful information.

Abstract Background Persons with inflammatory bowel diseases are at increased risk of developing colorectal cancer and require frequent colonoscopy surveillance. Guidelines recommend taking 30 to 40 non-targeted biopsies throughout the colorectum to detect “invisible” neoplasia in this setting, despite a lack of evidence supporting this practice. We sought to assess the utility of this practice through a randomized controlled trial. We first propose an internal pilot study to assess recruitment potential, protocol adherence and data capture to guide the full trial. Methods We have designed a multi-centre, parallel-group, non-inferiority randomized controlled trial to test the utility of non-targeted biopsies as an adjunct to colonoscopy surveillance for neoplasia detection in persons with inflammatory bowel disease involving the colorectum in routine clinical practice. Participants are randomized 1:1, stratified by study site, to either standard of care high-definition white-light colonoscopy with 32 to 40 non-targeted biopsies of non-neoplastic-appearing mucosa along with a sampling of abnormal-appearing mucosa (control group) or modified colonoscopy with targeted sampling alone (intervention group). The primary outcome for the full trial will be the proportion of persons with ≥ 1 neoplastic focus detected during colonoscopy. For the pilot phase, we will assess the feasibility of recruiting a minimum of 15% of the estimated sample size within 1 year, under identical conditions as the full trial, while maintaining ≥ 90–95% rate of protocol adherence and data capture. These participants will contribute data to the full trial. The trial is being conducted at 12 centres across Canada, with a total sample size of 1952 persons. Discussions The trial protocol has been approved by the ethics committees of all participating sites, and the pilot study has received funding through the Canadian Institutes of Health Research (PJT 159607). If feasibility metrics are met during the pilot phase, we will complete the full trial. The trial outcomes will contribute to update the practice guidelines in this area. Trial registration ClinicalTrials.gov, NCT04067778.

Abstract Background Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. Methods We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. Results Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). Conclusions A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. Trial Registration. Clinicaltrials.gov NCT02452762 Registered 25/05/2015.

Plain English summary Involving patients and families as partners in planning, conducting, and sharing results of health research, referred to as patient engagement, is becoming more common and recognized as important part of the research process. However, guidelines and examples of how to do this well are limited. In this article, we describe the development and features of the Ottawa Patient Engagement in Research Model at The Ottawa Hospital (TOH) and the Ottawa Hospital Research Institute (OHRI). Key pieces of the model include: a Patient and Family Engagement Program, which recruits, educates, and supports patients and families to engage in clinical care, decision making, and research; the Ottawa Methods Centre, which leads studies to understand the best methods to conduct research, and provides support to researchers for patient engagement; and the Office of Patient Engagement in Research Activities, which connects patients, researchers, clinicians, and other stakeholders. Early success of this model may be a result of shared priorities between TOH, OHRI and patients, the creation of a patient engagement policy, ongoing support provided to patients, family members and researchers, and creative methods for recruitment, tracking and evaluation procedures. Ongoing challenges and next steps include promoting diversity among patient partners, setting up a fair and transparent policy for compensating patient partners, and engaging patients across a variety of roles and research areas. This model represents a unique effort of patients, clinicians, researchers, and policymakers across disciplines and institutions to produce one strategy for meaningful teamwork with patients and families in health research.

Abstract Background High blood pressure is the leading cause of cardiovascular disease worldwide. The prevalence of high blood pressure is steadily rising as the population grows amongst older adults with the ageing population. Therapeutical treatments are widely available to decrease blood pressures, in addition to many lifestyle options, such as dietary changes and exercise. There is a marked preference amongst patients, as reiterated by Hypertension Canada, for more research into non-therapeutic methods for controlling blood pressure or to reduce the burden of taking many pills to control high blood pressure. Indeed, effective options do exist, especially with diet, specifically decreasing sodium and increasing potassium intake. Current public health outreach primarily focusses on sodium intake, even though potassium intake remains low in the Western world. Excellent data exist in published research that increasing potassium intake, either via dietary modification or supplements, reduces blood pressure and reduces risk of cardiovascular outcomes such as stroke. However, the advice most often provided by medical professionals is to ‘eat more fruits and vegetables’ which has little impact on patient outcomes. Methods We propose to do a clinical trial in two stages with an adaptive trial design. In the first stage, participants with high blood pressure and proven low potassium intake (measured on the basis of a 24-h urine collection) will get individually tailored dietary advice, reinforced by weekly supportive phone/email support. At 4 weeks, if there has not been a measured increase in potassium intake, participants will be prescribed an additional potassium supplement. Testing will be conducted again at 8 weeks, to confirm the efficacy of the potassium supplement. Final measurements will be planned at 52 weeks to observe and measure the persistence of the effect of diet or additional supplement. Concurrent measurements of sodium intake, blood pressure, participant satisfaction, and safety measures will also be done. Discussion The results of the study will help determine the most effective method of increasing potassium intake, thus reducing blood pressure and need for blood pressure-lowering medicines, and at the same time potentially increasing participant satisfaction. The current guidelines recommend changes in diet, not a potassium supplement, to increase potassium intake; hence, the two-stage design will only add supplements if the most rigorous dietary advice does not work. Trial registration This study has been registered on ClinicalTrials.gov NCT03809884 . Registered on January 18, 2019

Introduction Deciding whether to stop or extend anticoagulant therapy indefinitely after completing at least 3 months of initial treatment for a first unprovoked venous thromboembolism (VTE) remains a challenge for clinicians, patients and policy makers. Guidelines suggest an indefinite duration of anticoagulant therapy in these patients, yet its benefits, harms and costs have not been formally assessed. The aim of this proposed modelling study is to assess the differences in clinical benefits, harms and costs of stopping versus continuing anticoagulant therapy indefinitely for a first unprovoked VTE.Methods and analysis We will develop a probabilistic Markov model, adopting a 1-month cycle length and a lifetime horizon, to estimate life-years, quality-adjusted life-years, costs and the incremental cost-effectiveness ratios for a simulated population of patients with a first unprovoked VTE who will receive indefinite duration of anticoagulant therapy versus a population who will not receive extended treatment after completing 3 months of initial anticoagulant therapy. The economic evaluation will adopt a third-party payer perspective relating to a Canadian publicly funded healthcare system. Estimates for the probability of relevant clinical events will be informed by systematic reviews and meta-analyses, while costs and utility values will be obtained from published Canadian sources. Stratified analyses based on sex, age and site of initial VTE will also be performed to identify subgroups of patients with a first unprovoked VTE in whom continuing anticoagulant therapy indefinitely might prove to be clinically beneficial and cost-effective over stopping treatment. We will also conduct sensitivity and scenario analyses to assess robustness of study findings to changes in individual or groups of key parameters.Ethics and dissemination Ethical approval is not applicable for this study. The results will be disseminated through presentations at relevant conferences and in a manuscript that will be submitted to a peer-reviewed journal.

Purpose: The optimal frequency for cardiac monitoring of left ventricular ejection fraction (LVEF) in patients receiving trastuzumab-based therapy for early breast cancer (EBC) is unknown. We conducted a randomized controlled trial comparing 3- versus 4-monthly cardiac monitoring. Patients and Method: Patients scheduled to receive trastuzumab-containing cancer therapy for EBC with normal (>53%) baseline LVEF were randomized to undergo LVEF assessments every 3 or 4 months. The primary outcome was the change in LVEF from baseline. Secondary outcomes included the rate of cardiac dysfunction (defined as a decrease in the LVEF of ≥10 percentage points, to a value

Introduction Prehabilitation is a high-priority intervention for patients, the public, clinicians and health systems. However, existing knowledge syntheses are generally low quality and do not provide insights regarding the relative efficacy of different prehabilitation components (eg, exercise, nutrition, psychosocial or cognitive interventions). The objective of the planned review is to evaluate the relative efficacy of different prehabilitation components to inform current care, implementation and future research.Methods and analysis We will perform a systematic review and component network meta-analysis (CNMA). We will use a peer-reviewed search strategy to identify all randomised trials of prehabilitation in adult surgical patients from Ovid Medline, Embase, the CINAHL, PsycINFO, Web of Science and the Cochrane Central Register of Controlled Trials, along with grey literature. All stages of the review and data extraction process will be performed in duplicate, following recommended best practices. To compare the relative efficacy of different prehabilitation components (prespecified as exercise, nutrition, psychosocial or cognitive interventions), we will use CNMA, an extension of network meta-analysis that allows estimation of the contributions to efficacy of each component of a multicomponent intervention through direct and indirect comparisons. We will use additive CNMA models for critical outcomes (postoperative complications, patient-reported recovery, physical recovery and length of stay); standard care will be the common reference condition. Pre-specified sensitivity and subgroup analyses will be conducted.Ethics and dissemination This review of published data does not require ethical review. Results will be disseminated via scientific conferences, peer-reviewed publications, social and traditional media and via our research network to target partners and organisations.

Category: Sports; Trauma Introduction/Purpose: Uncertainty exists regarding the best treatment for acute Achilles tendon ruptures. Simultaneous comparison of the multiple treatment options using traditional study designs is problematic; multiarm clinical trials often are logistically constrained to small sample sizes, and traditional meta-analyses are limited to comparisons of only two treatments that have been compared in head-to-head trials. Network meta-analyses allow for simultaneous comparison of all existing treatments utilizing both direct and indirect evidence. We performed a network meta-analysis of randomized controlled trials to answer the following questions: Considering open repair, minimally invasive surgery repair, functional rehabilitation, or primary immobilization for acute Achilles tendon ruptures, (1) which intervention is associated with the lowest risk of rerupture? (2) Which intervention is associated with the lowest risk of complications resulting in surgery? Methods: Five databases and grey literature sources were searched from inception to September 30, 2019. Included studies were RCTs comparing treatment of acute Achilles tendon ruptures using two or more of the following interventions: primary immobilization, functional rehabilitation, open surgical repair, or MIS repair. We excluded studies enrolling patients with chronic ruptures, reruptures, and preexisting Achilles tendinopathy as well as studies with more than 20% loss to follow-up or less than 6 months of follow-up. Nineteen RCTs (1316 patients) were included in the final analysis. The mean number of patients per study treatment arm was 35 +- 16, mean age was 41 +- 5 years, mean sex composition was 80% +- 10% males, and mean follow-up was 22 +- 12 months. The four treatment groups were compared for the main outcomes of rerupture and complications resulting in operation. The analysis was conducted using random-effects Bayesian network meta-analysis with vague priors. Results: Treatment with primary immobilization had a greater risk of rerupture than open surgery (odds ratio 4.06 [95% credible interval {CrI} 1.47 to 11.88]; p < 0.05). There were no other differences between treatments for risk of rerupture. Minimally invasive surgery was ranked first for fewest complications resulting in surgery and was associated with a lower risk of complications resulting in surgery than functional rehabilitation (OR 0.16 [95% CrI 0.02 to 0.90]; p < 0.05), open surgery (OR 0.22 [95% CrI 0.04 to 0.93]; p < 0.05), and primary immobilization (OR < 0.01 [95% CrI < 0.01 to 0.01]; p < 0.05). Risk of complications resulting in surgery was no different between primary immobilization and open surgery (OR 1.46 [95% CrI 0.35 to 5.36]). Data for patient-reported outcome scores and return to activity were inappropriate for pooling secondary to considerable clinical heterogeneity and imprecision associated with small sample sizes. Conclusion: Faced with acute Achilles tendon rupture, patients should be counseled that the risk of rerupture likely is no different across contemporary treatments. Considering the possibly lower risk of complications resulting in surgery associated with MIS repair, patients and surgeons must balance any benefit with the potential risks of MIS techniques. As treatments continue to evolve, consistent reporting of validated patient-reported outcome measures is critically important to facilitate analysis with existing RCT evidence. Infrequent but serious complications such as rerupture and deep infection should be further explored to determine whether meaningful differences exist in specific patient populations.

BackgroundPatients newly diagnosed with cancer represent a population at highest risk for stroke. The objective of this systematic review and meta-analysis was to estimate the incidence of stroke in the first year following a new diagnosis of cancer.MethodsWe searched MEDLINE and EMBASE from January 1980 to June 2021 for observational studies that enrolled adults with a new diagnosis of all cancers excluding non-melanoma skin cancer, and that reported the incidence of stroke at 1 year. PRISMA guidelines for meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. We used the Dersimonian and Laird random effects method to pool cumulative incidences after logit transformation, and reported pooled proportions as percentages. Statistical heterogeneity was assessed using the I2 statistic.ResultsA total of 12,083 studies were screened; 41 studies were included for analysis. Data from 2,552,121 subjects with cancer were analyzed. The cumulative incidence of total stroke at 1 year was 1.4% (95% CI 0.9–2.2%), while the pooled incidence of ischemic stroke was 1.3% (95% CI 1.0–1.8%) and 0.3% (95% CI 0.1–0.9%) for spontaneous intracerebral hemorrhage (ICH), with consistently high statistical heterogeneity (>99% I2).ConclusionThe estimated incidence of stroke during the first year after a new diagnosis of cancer is 1.4%, with a higher risk for ischemic stroke than ICH. Cancer patients should be educated on the risk of stroke at the time of diagnosis. Future studies should evaluate optimal primary prevention strategies in this high-risk group of patients.Systematic review registrationhttps://osf.io/ucwy9/.

Background: Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. Methods: EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. Results: 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = −6.7%, 95%CI = −13.5%–0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p

Abstract Background Achilles tendon ruptures are common injuries in an otherwise healthy, active population. Several treatment options exist, with both surgical and non-surgical options. Each treatment option has a unique set of risks and harms, which may present patients with decisional conflict. The aim of the proposed study is to develop, alpha test and field test a patient decision aid for patients presenting with acute Achilles tendon ruptures. Methods This is a three-stage study protocol. First, we will assemble a multi-disciplinary steering group including patients, clinicians, educators, and researchers to develop the patient decision aid prototype using the Ottawa Decision Support Framework. Second, we will perform a mixed-methods alpha test of the decision aid prototype with patients and clinicians experienced in acute Achilles tendon ruptures. Outcomes measured will include acceptability and usability of the patient decision aid measured using validated outcome scales and semi-structured interviews. A minimum of three rounds of feedback will be obtained. Results will be analyzed using descriptive statistics, reviewed by the steering group, to guide revisions to decision aid prototype at each round. The third stage will be field testing the revised decision aid prototype in usual clinical care. A pre-/post-study will be performed with patients with acute Achilles tendon ruptures. Patients will be recruited from the emergency department and complete the pre-consultation decision aid prior to a one-week follow up with their surgeon. The primary outcome of field testing will be feasibility of implementing the decision aid in the clinical setting and will be measured with recruitment and completion metrics. Secondary outcomes include acceptability of the decision aid, knowledge, preparedness for decision making, and decisional conflict, measured using validated outcome measures. Statistical analysis will be performed using descriptive analysis for primary outcomes and a student t-test and Wilcoxon Rank-Sum test for secondary outcomes. Discussion This comprehensive study protocol outlines the development, alpha testing, and field testing of a patient decision aid for patients with acute Achilles tendon rupture. Systematic and transparent development and testing of patient decision aids is critical to improve decision aid quality. Trial registration Not Applicable.

Abstract Cell‐based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard‐earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell‐based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence‐based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence‐based fashion.

Plain English summary In academia, authorship on a research publication is a central means to obtain credit for one’s contribution to a research project. In order to guide authorship decision making and facilitate transparent processes, the International Committee of Medical Journal Editors (ICMJE) has produced recommendations for authorship. These recommendations are widely adopted by hundreds of medical journals. However, there is no research on whether the ICJME’s recommendations for authorship appropriately recognize the distinct contributions of patient partners to research. This survey study asked Editors-in-Chief about their perceptions of patient partners as authors and on the suitability of the ICMJE authorship criteria. We find that a 30.8%of medical journal Editors-in-chief do not view the inclusion of patient partners as authors on manuscripts as appropriate. Editors-in-chief reported wide ranging views on whether the ICMJE criteria for authorship were appropriate for patient partners. The implication of this work is that there is a need for education and for consensus building within the biomedical community to establish processes that will facilitate patient partners equitable inclusion in research, including on research outputs like publications.

A cost–utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer’s perspective.

Abstract Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies—defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis—are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.

Abstract Background Novel therapies often fail to reach the bedside due to low trial recruitment rates. Prior to conducting one of the first chimeric antigen receptor (CAR) T cell therapy trials in Canada, we used the Theoretical Domains Framework, a novel tool for identifying barriers and enablers to behavior change, to identify physician-related barriers and enablers to screening and recruiting patients for an early phase immunotherapy trial. Methods We conducted interviews with hematologists across Canada and used a directed content analysis to identify relevant domains reflecting the key factors that may affect screening and recruitment. Results In total, we interviewed 15 hematologists. Physicians expressed “cautious hope”; while expressing safety, feasibility, and screening criteria concerns, 14 out of 15 hematologists intended to screen for the trial (domains: knowledge, goals, beliefs about consequences, intentions). Physicians underscored the “challenging contexts,” identifying resources, workload, forgetting, and patient wait times to receive CAR T cells as key practical barriers to screening (domains: environmental context and resources, memory, attention and decision-making, behavioral regulation). They also highlighted “variability in roles and procedures” that may lead to missed trial candidates (domain: social and professional role). Left unaddressed, these barriers may undermine trial recruitment. Conclusions This study is among the first to use the Theoretical Domains Framework from the physician perspective to identify recruitment challenges to early phase trials and demonstrates the value of this approach for identifying barriers to screening and recruitment that may not otherwise have been elicited. This approach can optimize trial procedures and may serve to inform future promising early phase cancer therapy trials. Trial registration ClinicalTrials.gov Identifier: NCT03765177 . Registered on December 5, 2018.

Background: The effectiveness of different acellular dermal matrices (ADM) used for implant-based reconstruction immediately following mastectomy is an important clinical question. A prospective randomized clinical trial was performed to evaluate the superiority of DermACELL over Alloderm-RTU in reducing drain duration. Methods: Patients undergoing mastectomy with subpectoral immediate and permanent implant-based breast reconstruction were randomized to Alloderm-RTU or DermACELL. The primary outcome was seroma formation, measured by the duration of postoperative drain placement. Secondary outcomes included: post drain removal seroma aspiration, infection, redbreast syndrome, wound dehiscence, loss of the implant, and unplanned return to the operating room. Results: 62 patients were randomized for 81 mastectomies (41 Alloderm-RTU, 40 DermACELL). Baseline characteristics were similar. There was no statistically significant difference in mean drain duration (p = 0.16), with a trend towards longer duration in the Alloderm-RTU group (1.6 days; 95%CI, 0.7 to 3.9). The overall rate of minor and major complications were statistically similar between the two groups; although patients with Alloderm-RTU had 3 times as many infections requiring antibiotics (7.9% vs. 2.5%) with a risk difference of 5.4 (95%CI −4.5 to 15.2), and twice as many unplanned returns to the operating room (15.8% vs. 7.5%) with a risk difference of 8.3 (95% CI −5.9 to 22.5) as DermACELL. Conclusion: This is the first prospective randomized clinical trial comparing the two most commonly used human-derived ADMs. There was no statistically significant difference in drain duration, minor, or major complications between DermACELL over Alloderm-RTU in immediate subpectoral permanent implant-based breast reconstruction post-mastectomy.

Abstract Background As systematic reviews’ limited coverage of the medical literature necessitates decision-making based on unsystematic review, we investigated a possible advantage of systematic review (aside from dataset size and systematic analysis): does systematic review avoid potential bias in sampling primary studies from high impact factor journals? If randomized controlled trials (RCTs) reported in higher-impact journals present different treatment benefits than RCTs reported in lower-impact journals, readers who focus on higher-impact journals for their rapid literature reviews may introduce bias which could be mitigated by complete, systematic sampling. Methods We randomly sampled Cochrane Library (20 July 2005) treatment reviews that measured mortality as a binary outcome, published in English or French, with at least five RCTs with one or more deaths. Our domain-based assessment of risk of bias included funding source, randomness of allocation sequence, blinding, and allocation concealment. The primary analysis employed logistic regression by a generalized linear model with a generalized estimating equation to estimate the association between various factors and publication in a journal with a high journal impact factor (JIF). Results From the 29 included systematic reviews, 189 RCTs contributed data. However, in the primary analyses comparing RCT results within meta-analyses, there was no statistically significant association: unadjusted odds of greater than 50% mortality protection in high-JIF (> 5) journals were 1.4 (95% CI 0.42, 4.4) and adjusted, 2.5 (95% CI 0.6, 10). Elements of study quality were weakly, inconsistently, and not statistically significantly correlated with journal impact factor. Conclusions Journal impact factor may have little to no association with study results, or methodological quality, but the evidence is very uncertain.

Abstract Objective To systematically review the evidence to evaluate oncologic outcomes for patients with early stage buccal squamous cell carcinoma treated with surgery versus surgery and adjuvant radiation therapy. Data sources Ovid MedLine, EMBASE, Google Scholar, PubMed. Review methods The primary purpose was to perform a systematic review to determine the published literature comparing oncologic outcomes of patients with early stage (Stages I&II) buccal mucosal squamous cell carcinoma, treated with surgical resection alone versus surgery plus adjuvant radiation therapy. Oncologic outcomes of interest were overall survival, locoregional recurrence, and disease specific survival. The secondary aim was to perform a meta-analysis to quantitively compare and summarize the data on oncologic outcomes between treatments. Results A total of 1457 studies were screened and five retrospective cohort studies (n = 733 patients) were eligible for quantitative analysis. Overall study quality was moderate to high. Pooled relative risk ratios using a fixed effects model did not reveal any statistically significant difference in overall survival (p = 0.70) or locoregional recurrence rates (p = 0.72) in Stage I and II disease. Conclusions These results demonstrate there is sparse evidence comparing oncologic outcomes for early stage buccal squamous cell carcinoma treated with surgery alone versus surgery and adjuvant radiation therapy. Our findings based on a limited body of evidence suggest no obvious benefit in the addition of adjuvant radiation therapy, however robust randomized trials are warranted to reach firm conclusions.

Abstract Background and Aims Optimal management of cancer treatment‐induced hypomagnesemia (hMg) is not known. We assessed the feasibility of using a novel pragmatic clinical trials model to compare two commonly used oral Mg replacement strategies. Methods Patients with grade 1 to 3 hMg while receiving either platinum‐based chemotherapy or epidermal growth factor receptor inhibitors (EGFRI) were randomized to oral magnesium oxide (MgOx) or oral magnesium citrate (MgCit). The trial methodology utilized the integrated consent model. Feasibility would be successful if; accrual rate was ≥5 patients a month and if measures of patient and physician engagement, were > 50%. Secondary endpoints included; comparison of Mg levels, cardiac arrhythmias, and rates of treatment delay/hospitalizations. Results From July 2016 to December 2017, an average of 1 patient a month was accrued. All 15 eligible and approached patients consented to participate in the study (100% engagement) and 7/15 were randomized to MgOx and 8/15 to MgCit. The percentage of physicians who approached patients for the study was 4 of 6 (66.6% engagement). The mean slope of change in Mg (mmol/L/day) was 0.0022 (95% CI: −0.0001 to 0.0044) for MgOx and 0.0006 (95% CI, −0.0012 to 0.0024) for MgCit (P = .2123). Three patients (20%) required IV magnesium while on the study (2 MgCit and 1 MgOx). Grade 1 diarrhea occurred in 3 patients in the MgCit arm. Conclusion Despite oral magnesium tolerability and meeting most of its feasibility endpoints, this study did not meet its target accrual rate. Alternative designs would be necessary for a definitive efficacy study.

Background: We present the 2-year results of a randomised trial comparing 4- versus 12-weekly bone-targeting agents (BTAs) in patients with bone metastases from breast or castration-resistant prostate cancer (CRPC). Patients and Methods: Patients with bone metastases from breast or CRPC, who were going to start or were already receiving BTAs, were randomised to 4- or 12-weekly BTA treatment for 2 years. The endpoints were: symptomatic skeletal events (SSE) rates, time to SSEs, toxicity and cost-effectiveness. Results: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). After 2 years, the cumulative incidence rate (95% CI) of SSEs was 32.7% (24.6% to 41.1%) and 28.1% (20.3% to 36.4%) for the 4- and 12-weekly intervention groups respectively. The hazard ratio for time to first SSE was 0.96 (95% CI = 0.63 to 1.47). However, in a post hoc analysis, those patients who had an on-study SSE, there was a small non-statistical increased risk of subsequent SSEs among patients on the 12-weekly dosing arm (HR = 1.14; 95% CI – 0.90–1.44). BTA-related toxicity rates were similar between study arms. A cost-utility analysis showed that 12-weekly BTA is cost-effective from a public payer’s perspective. Conclusion: These results in addition to those previously reported for de-escalating zoledronate, would support that de-escalation of commonly used BTAs is a reasonable and economically valid treatment option. While not statistically significant, the increase in subsequent SSEs in the 12-weekly arm requires further exploration.

Abstract Objective Angioplasty is a fundamental treatment for atherosclerotic disease and may be performed as the sole therapy in small vessel disease. However, the ideal duration of balloon inflation has not yet been identified. Our study investigated whether prolonged inflation of at least 1-min duration, when compared with brief inflation, affects residual stenosis after arterial angioplasty. Data sources and methods Two independent reviewers conducted a systematic review of EMBASE, MEDLINE, CENTRAL, trial registries and grey literature, using pre-specified search syntax. Data abstraction and quantitative analysis was performed independently, according to pre-specified criteria. The primary outcome was residual stenosis after initial angioplasty, in addition to other pre-specific clinical and radiographic outcomes. All analyses were stratified by coronary, cerebrovascular, and peripheral territory. The study protocol is published and registered on PROSPERO (CRD42018092702). Results Six relevant articles were identified, of which one investigated peripheral vascular angioplasty and five investigated coronary artery angioplasty, encompassing 1496 procedures. The studies were at moderate risk of bias. Minimal heterogeneity within coronary studies allowed for subgroup meta-analysis. Prolonged inflation was significantly associated with lower risk of residual stenosis post-inflation in the pooled coronary trials (RR 1.76 [95% CI 1.46–2.12], I2 = 0%, p

Abstract Background Development of fistula-in-ano following incision and drainage (I&D) of anorectal abscesses occurs in over 30% of patients. It is associated with significant patient morbidity and societal cost. The use of antibiotics following drainage is controversial, with randomized controlled trials reporting opposing conclusions regarding their influence on the rate of fistula formation. Given the significant burden associated with their development, it is imperative to determine strategies to minimize their occurrence. The objective of this review is to summarize the available evidence on the role of antibiotics following I&D of anorectal abscesses on fistula formation. Secondary objectives include determining if antibiotics are associated with morbidity, repeat presentation to the emergency department, and requirement for reoperation. Methods/design MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials, http://apps.who.int/trialsearch, and clinicaltrials.gov will be searched to identify published and ongoing unpublished interventional and observational studies evaluating the role of antibiotics post I&D on the incidence of fistula formation. There will be no restriction on language, date, or journal. Title and abstracts as well as full texts will be screened in duplicate based on inclusion and exclusion criteria. The Cochrane Risk of Bias tool and ROBINS-I will be used to assess risk of bias in randomized and non-randomized studies, respectively. Our primary outcome is the incidence of fistula formation; secondary outcomes include morbidity, representation to ED, and reoperation. Study heterogeneity will be calculated with Cochran’s Q test, P value, and I 2 index. SASS (version 9.4) will be used for meta-analysis. Discussion This is the first study to review the available evidence on adjuvant antibiotics and incidence of fistula formation following I&D of anorectal abscesses. Systematic review registration PROSPERO CRD42018092044

Abstract Background and purpose Cerebral venous thrombosis causes disability from venous infarct and hemorrhage and potential mortality. Anticoagulation improves survival and disability outcomes, yet direct oral anticoagulants are currently not indicated in cerebral venous thrombosis due to lack of evidence, despite being on the market for nearly a decade. This systematic review will collate evidence of reported safety and efficacy of direct oral anticoagulant therapy in cerebral venous thrombosis. Methods A search strategy was developed with a research librarian and registered on a protocol database (PROSPERO CRD42017078398). All published studies from MEDLINE and EMBASE up to February 2019 containing patients diagnosed with cerebral venous thrombosis who were treated with a direct oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban) will be included. A risk of bias analysis will be performed to evaluate quality of studies overall. Discussion Current guidelines in the treatment of cerebral vein thrombosis dating back to 2011 from the American Heart Association/American Stroke Association endorse the utility of anticoagulation for the treatment of cerebral vein thrombosis; however, they did not support the use of direct oral anticoagulants. Updated guidelines from the European Stroke Organization, endorsed by the European Academy of Neurology in 2017, also refute utilization of direct oral anticoagulants due to a lack of evidence. There have been nearly 10 years of experience with direct oral anticoagulants in the treatment of venous thrombosis and prevention of stroke in patients with atrial fibrillation, with purported efficacy and safety in comparison with heparins and vitamin K antagonists. Our goal is to undertake a systematic review to assess the effectiveness and safety of direct oral anticoagulants in patients with cerebral vein thrombosis to help guide clinical decision-making for patients unable to take heparins or vitamin K antagonists and to direct future studies to contribute further to an area of certain evidence-based needs. Systematic review registration PROSPERO CRD42017078398

Abstract Background Inadequate and poor quality outcome reporting in clinical trials is a well-documented problem that impedes the ability of researchers to evaluate, replicate, synthesize, and build upon study findings and impacts evidence-based decision-making by patients, clinicians, and policy-makers. To facilitate harmonized and transparent reporting of outcomes in trial protocols and published reports, the Instrument for reporting Planned Endpoints in Clinical Trials (InsPECT) is being developed. The final product will provide unique InsPECT extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines. Methods The InsPECT SPIRIT and CONSORT extensions will be developed in accordance with the methodological framework created by the EQUATOR (Enhancing the Quality and Transparency of Health Research Quality) Network for reporting guideline development. Development will consist of (1) the creation of an initial list of candidate outcome reporting items synthesized from expert consultations and a scoping review of existing guidance for reporting outcomes in trial protocols and reports; (2) a three-round international Delphi study to identify additional candidate items and assess candidate item importance on a 9-point Likert scale, completed by stakeholders such as trial report and protocol authors, systematic review authors, biostatisticians and epidemiologists, reporting guideline developers, clinicians, journal editors, and research ethics board representatives; and (3) an in-person expert consensus meeting to finalize the set of essential outcome reporting items for trial protocols and reports, respectively. The consensus meeting discussions will be independently facilitated and informed by the empirical evidence identified in the primary literature and through the opinions (aggregate rankings and comments) collected via the Delphi study. An integrated knowledge translation approach will be used throughout InsPECT development to facilitate implementation and dissemination, in addition to standard post-development activities. Discussion InsPECT will provide evidence-informed and consensus-based standards focused on outcome reporting in clinical trials that can be applied across diverse disease areas, study populations, and outcomes. InsPECT will support the standardization of trial outcome reporting, which will maximize trial usability, reduce bias, foster trial replication, improve trial design and execution, and ultimately reduce research waste and help improve patient outcomes.

Abstract Background Pulmonary arterial hypertension (PAH) is a rare disease characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary arterial pressures leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. The objective of this systematic review was to compare the efficacy of regenerative cell therapies in preclinical models of PAH. Methods A systematic search strategy was developed and executed. We included preclinical animal studies using regenerative cell therapy in experimental models of PAH. Primary outcomes were right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). The secondary outcome was right ventricle/left ventricle + septum weight ratio (RV/LV+S). Pooled effect sizes were undertaken using random effects inverse variance models. Risk of bias and publication bias were assessed. Results The systematic search yielded 1285 studies, of which 44 met eligibility criteria. Treatment with regenerative cell therapy was associated with decreased RVSP (SMD − 2.10; 95% CI − 2.59 to − 1.60), mPAP (SMD − 2.16; 95% CI − 2.97 to − 1.35), and RV/LV+S (SMD − 1.31, 95% CI − 1.64 to − 0.97). Subgroup analysis demonstrated that cell modification resulted in greater reduction in RVSP. The effects on RVSP and mPAP remained statistically significant even after adjustment for publication bias. The majority of studies had an unclear risk of bias. Conclusions Preclinical studies of regenerative cell therapy demonstrated efficacy in animal models of PAH; however, future studies should consider incorporating design elements to reduce the risk of bias. Systematic review registration Suen CM, Zhai A, Lalu MM, Welsh C, Levac BM, Fergusson D, McIntyre L and Stewart DJ. Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol. Syst Rev. 2016;5:89. Trial registration CAMARADES-NC3Rs Preclinical Systematic Review & Meta-analysis Facility (SyRF). http://syrf.org.uk/protocols/. Syst Rev 5:89, 2016

Abstract Background Angioplasty is a fundamental treatment for atherosclerotic disease in the cardiac, cerebrovascular, and peripheral vascular beds. However, the optimal duration of balloon inflation has not been identified. Our study will investigate whether prolonged angioplasty balloon inflation of at least 1 min duration, when compared with brief inflation, affects residual stenosis after arterial angioplasty. Methods In compliance with PRISMA, two independent reviewers will conduct a systematic review of EMBASE, MEDLINE, CENTRAL, trial registries, grey literature, and ancestry and citation search. Data abstraction, quantitative, and quantitative meta-analysis will be performed according to pre-specified criteria. The primary outcome is residual stenosis immediately after initial angioplasty; however, secondary outcomes will include multiple short and long term pre-specific clinical and radiographic outcomes. Risk of bias, subgroup analyses, and sensitivity analyses are planned. Discussion Despite the ubiquitous use of angioplasty in atherosclerotic disease and multiple trials investigating the ideal balloon inflation duration, there are no systematic reviews evaluating prolonged angioplasty balloon inflation. Currently synthesized evidence is insufficient to confidently direct clinical decision-making, and the current variation in operator preference of balloon angioplasty duration suggests ongoing clinical equipoise. Given the known availability of current primary evidence, our study intends to synthesize the evidence and guide future clinical decision making and investigation. Systematic review registration PROSPERO CRD42018092702

Abstract Background Achilles tendon ruptures are a common injury and are increasing in incidence. Several management strategies exist for both non-operative and operative care, with each strategy offering unique risks and benefits. Traditional pairwise meta-analyses have been performed to compare management strategies; however, all treatment options have never been integrated in a single analysis. Network meta-analysis (NMA) is a generalization of pairwise meta-analysis, which allows for the comparison of multiple interventions based on all available direct and indirect evidence. The objectives of this review are to synthesize the evidence on the management options for acute Achilles tendon rupture and identify which treatment gives the best functional outcomes. Methods A systematic review with NMA is planned. An electronic literature search will be performed in conjunction with an experienced information specialist in MEDLINE, EMBASE, CINAHL, PEDro, and the Cochrane Central Register of Controlled Trials. We will include randomized controlled trials with a minimum 6-month follow-up. Two independent reviewers will screen citations for eligibility, extract study data, and perform risk of bias assessments. The primary outcome will be disease-specific functional outcome scores (AOFAS, Leppilahti, modified Leppilahti) at 1 year. Secondary outcomes will include complications (re-rupture, sural nerve injury, wound complications, deep infection, secondary surgeries), strength, range of motion, return to work, return to sport, and quality-of-life measures (including the SF-36 questionnaire). Traditional pairwise meta-analyses will be performed for all direct comparisons where evidence is available, and NMAs will subsequently be performed where possible to compare all management strategies. Discussion The data generated from this review will provide health-care providers with a clear evidence synthesis of all Achilles tendon rupture management strategies. Additionally, these data will be incorporated into the development of a patient decision aid to assist patients and clinicians in making a preference-based decision when faced with an Achilles tendon rupture. Systematic review registration PROSPERO CRD42018093033.

Background: Adjuvant zoledronate is widely used in patients with early stage breast cancer (EBC), but its optimal duration and dosing interval is still unknown. While a single-dose of zoledronate can improve bone density for many years, a proper evaluation of its effects on breast cancer-related outcomes would require a large trial. In this pilot study we evaluated the feasibility of performing such a trial. Methods: Eligible patients with EBC were randomised to receive either one dose of zoledronate or 7 doses (6-monthly dosing for 3 years). Feasibility was assessed by a combination of primary outcomes including: activation of at least 6 Ontario sites within a year, active participation (i.e. approaching eligible patients for study participation) of at least half of the medical oncologists, and enrolment of at least 100 patients across all sites within 9 months of the sixth site being activated. Results: All 6 sites were activated within 1 year and of 47 medical oncologists, 27 (57%) approached patients. Between November 2018 and April 2020, 211 eligible patients were randomised, 106 (50.2%) to a single dose of zoledronate and 105 (49.8%) to 6-monthly dosing. Baseline characteristics of randomised patients included; median age 59 (range 36–88), ER and/or PR positive (85%), Her2 positive (23%), menopausal status (premenopausal [19%], perimenopausal [6.7%] and postmenopausal [74%]) and 74% received neo/adjuvant chemotherapy. Conclusions: All study feasibility endpoints were met in this trial comparing alternative schedules for adjuvant zoledronate. We will now seek funding for performing a larger efficacy trial.Trial registration: NCT03664687.

IntroductionThere is an increased risk of stroke in patients with cancer-this risk is particularly heightened around the time of cancer diagnosis, although no studies have systematically quantified this risk in the literature. Patients newly diagnosed with cancer without prior stroke represent a highly susceptible population in whom there is a window of opportunity to study and implement primary prevention strategies. Therefore, the objective of this systematic review and meta-analysis is to identify the cumulative incidence of ischemic and hemorrhagic strokes during the first year after a diagnosis of cancer.Methods and analysisMEDLINE, EMBASE, and PubMed will be searched with the assistance from a medical information specialist, from 1980 until present. Eligible studies will include observational studies that have enrolled adult patients newly diagnosed with cancer and report outcomes of stroke during the first year of cancer diagnosis. We will exclude all randomized and non-randomized interventional studies. Data on participant characteristics, study design, baseline characteristics, and outcome characteristics will be extracted. Study quality will be assessed using the Newcastle-Ottawa Scale for cohort studies, and heterogeneity will be assessed using the I2 statistic. Pooled cumulative incidence will be calculated for ischemic and hemorrhagic strokes separately using a random-effects model.Ethics and disseminationNo formal research ethics approval is necessary as primary data collection will not be done. We will disseminate our findings through scientific conference presentations, peer-reviewed publications, and social media/the press. The findings from this review will inform clinicians and patients regarding the risk of stroke in patients newly diagnosed with cancer by quantifying the cumulative incidence of each subtype of stroke during the first year after a diagnosis of cancer. This represents a window of opportunity to implement prevention strategies in a susceptible population.Registration id with open science frameworkosf.io/ucwy9.

Background and purposeRecovery after intracerebral haemorrhage (ICH) is often slower than ischemic stroke. Despite this, ICH research often quantifies recovery using the same outcome measures obtained at the same timepoints as ischemic stroke. The primary objective of this scoping review is to map the existing literature to determine when and how outcomes are being measured in prospective studies of recovery after ICH.MethodsWe searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science from inception to November 2019, for prospective studies that included patients with ICH. Two investigators independently screened the studies and extracted data around timing and type of outcome assessment.ResultsAmong the 9761 manuscripts reviewed, 395 met inclusion criteria, of which 276 were observational studies and 129 were interventional studies that enrolled 66274 patients. Mortality was assessed in 93% of studies. Functional outcomes were assessed in 85% of studies. The most frequently used functional assessment tool was the modified Rankin Scale (mRS) (60%), followed by the National Institute of Health Stroke Severity Scale (22%) and Barthel Index (21%). The most frequent timepoint at which mortality was assessed was 90 days (41%), followed by 180 days (18%) and 365 days (12%), with 2% beyond 1 year. The most frequent timepoint used for assessing mRS was 90 days (62%), followed by 180 days (21%) and 365 days (17%).ConclusionWhile most prospective ICH studies report mortality and functional outcomes only at 90 days, a significant proportion do so at 1 year and beyond. Our results support the feasibility of collecting long-term outcome data to optimally assess recovery in ICH.

Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012–2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2·48, 95% Confidence Interval (CI) = 1·27–4·86; I2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/embolic events, death, or malignancy (RR = 1·16, 0·99, 1·14, 0·78, 0·93; 95% CI = 0·70–1·91, 0·81–1·21, 0·67–1·95, 0·65–0·94, 0·60–1·45; I2 = 0%, 0%, 0%, 0%, 0%). No included trials were ended prematurely due to safety concerns. Interpretations: MSC therapy continues to exhibit a favourable safety profile. Future trials should continue to strengthen study rigor, reporting of MSC characterization, and adverse events. Funding: Stem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund Keywords: Mesenchymal stem cells, Safety, Adverse events, Systematic review

IntroductionTo summarize and compare the effectiveness of pharmacological thromboprophylaxis to pneumatic compression devices (PCD) for the prevention of venous thromboembolism in patients with acute intracerebral hemorrhage.MethodsMEDLINE, PUBMED, EMBASE, and CENTRAL were systematically searched to identify randomized and non-randomized studies that compared each intervention directly to each other or against a common control (hydration, anti-platelet agents, stockings) in adults with acute spontaneous intracerebral hemorrhage. Two investigators independently screened the studies, extracted data, and appraised risk of bias. Studies with a high risk of bias were excluded from our final analysis. The primary outcome was the occurrence of venous thromboembolism (proximal deep vein thrombosis or pulmonary embolism) in the first 30 days.Results8,739 articles were screened; four articles, all randomized control trials, met eligibility criteria. Bayesian network meta-analysis was performed to calculate risk estimates using both fixed and random effects analyses. 607 patients were included in the network analysis. PCD were associated with a significant decrease in venous thromboembolism compared to control (OR: 0.43, 95% Credible Limits [CrI]: 0.23-0.80). We did not find evidence of statistically significant differences between pharmacological thromboprophylaxis and control (OR: 0.93, 95% CrI: 0.19-4.37) or between PCD and pharmacological thromboprophylaxis (OR: 0.47, 95% CrI: 0.09-2.54).ConclusionPCDs are superior to control interventions, but meaningful comparisons with pharmacotherapy are not possible due to a lack of data. This requires further exploration via large pragmatic clinical trials.Trial registrationPROSPERO: CRD42018090960.

Abstract Background Current guidelines identify the choice of fluid resuscitation as important in minimizing the incidence of secondary brain injury from cerebral edema. It is widely accepted that isotonic crystalloid resuscitation fluids, specifically normal saline (NS), are optimal for resuscitation and that other relatively hypotonic fluids, such as Ringer’s lactate (RL), should be avoided in this patient population. The aim of this review is to systematically compare the use of relatively hypotonic versus isotonic crystalloid resuscitation fluids in clinical and pre-clinical models of acute brain injury and their effect on outcomes. In recognition of the potential need for a network meta-analysis (NMA), we have also included all other relevant crystalloid resuscitation fluids as interventions of relevance to potentially inform indirect comparisons. Methods Systematic searches of MEDLINE, Embase, and Web of Science BIOSIS Previews® will be used to identify eligible clinical and pre-clinical studies, which included studies examining acute brain injury (human and in vivo animal brain injury models) within the first 7 days of therapy. The intervention of interest is the intravenous use of relatively hypotonic crystalloid resuscitation fluids (e.g., Ringer’s lactate, Hartmann’s or Plasma Lyte® fluids). The main comparator of interest is an isotonic crystalloid resuscitation fluid, specifically normal saline (0.9%). Other crystalloid resuscitation fluids (e.g., hypertonic saline (3–23.4%)) will also be included as an additional intervention of interest. The primary outcome measures of interest are intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Secondary outcomes include the effect of resuscitation on cerebral edema, brain and serum osmolarity, and electrolyte concentrations and clinical outcomes including modified Rankin Scale (mRS), (extended) Glasgow Outcome Scale (GOS/eGOS), and mortality. Separate meta-analyses will be conducted to quantify the effects of the different fluid resuscitation on acute brain injury outcomes in clinical and pre-clinical populations. Network meta-analyses to compare interventions will also be performed to compare the effects of different interventions. Discussion This systematic review will comprehensively summarize the difference in treatment efficacy of various crystalloid resuscitation fluids in acute brain injury. This review is essential to underscore the evidence, or lack thereof, present in the literature to date to support current preference-driven practice and to direct future study. Systematic review registration PROSPERO #CRD42016042960

Abstract Background Breast cancer and its treatment can have many physical and psychological effects on affected women. Women’s personal goals may provide insight into their priorities and motivations in the context of breast cancer. Incorporating personal goal-setting into support and care interventions may have an effect on psychological well-being. This protocol describes our scoping review methods, the aim of which is to examine and map the existing evidence on personal goal-setting among women with a breast cancer diagnosis. Methods Our scoping review will search for published, full-length articles, where personal goal-setting is a major component of the study, and the study population is females with breast cancer. MEDLINE, PsycInfo, CINAHL, EMBASE, the Cochrane Library, and AMED databases will be searched. Two independent reviewers will conduct all screening and extract data. Descriptive information about the studies, participants, any interventions, measurement tools, outcomes, and results will be reported. Discussion The results from this review will chart the literature, contributing to optimizing the incorporation of personal goal-setting approaches into effective interventions for the care and support of women with breast cancer.

Abstract Background The “Age of Blood in Children in Pediatric Intensive Care Unit” (ABC PICU) study is a randomized controlled trial (RCT) that aims to determine if red blood cell (RBC) unit storage age affects outcomes in critically ill children. While RBCs can be stored for up to 42 days in additive solutions, their efficacy and safety after long-term storage have been challenged. Preclinical and clinical observational evidence suggests loss of efficacy and lack of safety of older RBC units, especially in more vulnerable populations such as critically ill children. Because there is a belief that shorter storage will improve outcomes, some physicians and institutions systematically transfuse fresh RBCs to children. Conversely, the standard practice of blood banks is to deliver the oldest available RBC unit (first-in, first-out policy) in order to decrease wastage. Methods/design The ABC PICU study, is a double-blind superiority trial comparing the development of “New or Progressive Multiple Organ Dysfunction Syndrome” (NPMODS) in 1538 critically ill children randomized to either transfusion with RBCs stored for ≤ 7 days or to standard-issue RBCs (oldest in inventory). Patients are being recruited from 52 centers in the US, Canada, France, Italy, and Israel. Discussion The ABC PICU study should have significant implications for blood procurement services. A relative risk reduction of 33% is postulated in the short-storage arm. If a difference is found, this will indicate that fresher RBCs do improve outcomes in the pediatric intensive care unit population and would justify that use in critically ill children. If no difference is found, this will reassure clinicians and transfusion medicine specialists regarding the safety of the current system of allocating the oldest RBC unit in inventory and will discourage clinicians from preferentially requesting fresher blood for critically ill children. Trial registration ClinicalTrials.gov, ID: NCT01977547. Registered on 6 November 2013.

Abstract Background Whether a restrictive strategy for red blood cell (RBC) transfusion is applied to patients with aneurysmal subarachnoid hemorrhage (aSAH) is unclear. To inform the design and conduct of a future clinical trial, we sought to describe transfusion practices, hemoglobin (Hb) triggers, and predictors of RBC transfusion in patients with aSAH. Methods This is a retrospective cohort study of all consecutively admitted adult patients with aSAH at four tertiary care centers from January 1, 2012, to December 31, 2013. Patients were identified from hospital administrative discharge records and existing local aSAH databases. Data collection by trained abstractors included demographic data, aSAH characteristics, Hb and transfusion data, other major aSAH cointerventions, and outcomes using a pretested case report form with standardized procedures. Descriptive statistics were used to summarize data, and regression models were used to identify associations between anemia, transfusion, and other relevant predictors and outcome. Results A total of 527 patients met inclusion eligibility. Mean (±SD) age was 57 ± 13 years, and 357 patients (67.7%) were female. The median modified Fisher grade was 4 (IQR 3–4). Mean nadir Hb was 98 ± 20 g/L and occurred on median admission day 4 (IQR 2–11). RBC transfusion occurred in 100 patients (19.0%). Transfusion rates varied across centers (12.1–27.4%, p = 0.02). Patients received a median of 1 RBC unit (IQR 1–2) per transfusion episode and a median total of 2 units (IQR 1–4). Median pretransfusion Hb for first transfusion was 79 g/L (IQR 74–93) and did not vary substantially across centers (78–82 g/L, p = 0.37). Of patients with nadir Hb

Plain English summary With the growing movement to engage patients in research, questions are being asked about who is engaging patients and how they are being engaged. Internationally, research groups are supporting and funding patient-oriented research studies that engage patients in the identification of research priorities and the design, conduct and uptake of research. As we move forward, we need to know what meaningful patient engagement looks like, how it benefits research and clinical practice, and what are the barriers to patient engagement? We conducted a review of the published literature looking for trials that report engaging patients in the research. We included both randomized controlled trials and non-randomized comparative trials. We looked at these trials for important study characteristics, including how patients were engaged, to better understand the practices used in trials. Importantly, we also discuss the number of trials reporting patient engagement practices relative to all published trials. We found that very few trials report any patient engagement activities even though it is widely supported by many major funding organizations. The findings of our work will advance patient-oriented research by showing how patients can be engaged and by stressing that patient engagement practices need to be better reported. Abstract Background Patient-Oriented Research (POR) is research informed by patients and is centred on what is of importance to them. A fundamental component of POR is that patients are included as an integral part of the research process from conception to dissemination and implementation, and by extension, across the research continuum from basic research to pragmatic trials [J Comp Eff Res 2012, 1:181–94, JAMA 2012, 307:1587–8]. Since POR’s inception, questions have been raised as to how best to achieve this goal. We conducted a systematic review of randomized controlled trials and non-randomized comparative trials that report engaging patients in their research. Our main goal was to describe the characteristics of published trials engaging patients in research, and to identify the extent of patient engagement activities reported in these trials. Methods The MEDLINE®, EMBASE®, Cinahl, PsycINFO, Cochrane Methodology Registry, and Pubmed were searched from May 2011 to June 16th, 2016. Title, abstract and full text screening of all reports were conducted independently by two reviewers. Data were extracted from included trials by one reviewer and verified by a second. All trials that report patient engagement for the purposes of research were included. Results Of the 9490 citations retrieved, 2777 were reviewed at full text, of which 23 trials were included. Out of the 23 trials, 17 were randomized control trials, and six were non-randomized comparative trials. The majority of these trials (83%, 19/23) originated in the United States and United Kingdom. The trials engaged a range of 2-24 patients/ community representatives per study. Engagement of children and minorities occurred in 13% (3/23) and 26% (6/23) of trials; respectively. Engagement was identified in the development of the research question, the selection of study outcomes, and the dissemination and implementation of results. Conclusions The prevalence of patient engagement in patient-oriented interventional research is very poor with 23 trials reporting activities engaging patients. Research dedicated to determining the best practice for meaningful engagement is still needed, but adequate reporting measures also need to be defined.

Abstract Background Contrast-induced acute kidney injury (CI-AKI) is defined as worsening of renal function after the administration of iodinated contrast material. In patients with cardiovascular disease, kidney disease, and/or diabetes, renin-angiotensin system blockers, non-steroidal anti-inflammatory drugs, diuretics, and metformin can increase the risk of CI-AKI when undergoing contrast imaging. Despite CI-AKI being the leading iatrogenic cause of acute kidney injury, there is a lack of sufficient scientific evidence supporting which drugs should be stopped, when they should be stopped, and when they should be resumed. The purpose of this systematic review is to assess (1) the effect of withholding medication before contrast procedures on the risk of CI-AKI and other clinical outcomes and (2) the incidence of adverse events occurring after withholding these drugs prior to contrast procedures. This protocol has been registered with PROSPERO, https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016033178. Methods An information specialist will assist in searching MEDLINE, Embase, and the Cochrane Library databases to identify randomized controlled trials, observational studies, case reports, and case series. Relevant abstracts from professional society meetings and web-based registries of clinical trials will also be included. Studies included will compare patients aged ≥ 18 years instructed to continue taking the drugs of interest and those advised to stop taking them before undergoing contrast procedures. If these drugs are not withheld prior to contrast procedures, the studies must compare patients who are administered these drugs and those who are not before undergoing contrast procedures. Two reviewers will independently screen the titles and abstracts of the studies obtained from the search using pre-defined inclusion criteria and will then extract data from the full texts of selected studies. The quality of the studies will be assessed by two independent reviewers using the Cochrane Risk of Bias 2.0 tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. Discussion This systematic review will provide a synthesis of current evidence on the discontinuation of drugs prior to contrast procedures and its effect on CI-AKI and other clinical outcomes. These findings will provide clinicians with guidelines and serve as a strong research base for future studies in this field. Systematic review registration PROSPERO CRD42016033178

Abstract Background Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. Methods/design The VITdAL-PICU pilot study is designed as a multicenter placebo-controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D

Abstract Background Vitamin D deficiency (VDD) has been hypothesized not only to be common but also to represent a potentially modifiable risk factor for greater illness severity and clinical outcome during critical illness. The objective of this systematic review was to determine the frequency of VDD in pediatric critical illness and its association with clinical outcomes. Methods MEDLINE, Embase, and CENTRAL were searched through December 12, 2016, with no date or language restrictions. The primary objective was to estimate the prevalence of VDD in the pediatric intensive care unit (PICU) and compare vitamin D status with healthy control populations. Secondary objectives were to evaluate whether VDD is associated with mortality, increased illness severity, PICU interventions, and patient clinical course. Random effects meta-analysis was used to calculate pooled VDD event rate, compare levels with those of control subjects, and evaluate for associations between VDD and clinical outcome. Results Among 2700 citations, 17 studies meeting study eligibility were identified. The studies reported a total of 2783 critically ill children and had a median sample size of 120 (range 12–511). The majority of studies used a 25-hydroxyvitamin D [25(OH)D] level less than 50 nmol/L to define VDD, and the pooled VDD prevalence was 54.8 (95% CI 45.4–63.9). Average 25(OH)D levels were significantly lower in PICU patients than in healthy control subjects (pooled difference −17.3 nmol/L, 95% CI −14.0 to −20.6). In a meta-analysis calculation, we found that VDD was associated with increased mortality (OR 1.62, 95% CI 1.11–2.36), illness severity, and need for PICU interventions. Conclusions Approximately 50% of critically ill children have VDD at the time of PICU admission, defined as a blood total 25(OH)D concentration under 50 nmol/L. VDD was further determined to be associated with greater illness severity, multiple organ dysfunction, and mortality in the PICU setting. Clinical trials are required to determine if optimization of vitamin D status improves patient outcome. Trial registration PROSPERO, CRD42016026617 . Registered on 11 January 2016.

Abstract Background Despite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial. Methods/design A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling. Discussion This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design.

Purpose: Despite widespread use of fluorouracil, epirubicin, cyclophosphamide, docetaxel (FEC-D) chemotherapy in breast cancer, the optimal strategy for primary febrile neutropenia (FN) prophylaxis remains unknown. A systematic review was therefore performed. Methods: Embase, Ovid MEDLINE, PubMed, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, and conference proceedings were searched from 1946 to April 2016 for trials that reported the effectiveness of primary FN prophylaxis with FEC-D chemotherapy. Outcome measures were incidence of FN; treatment-related hospitalizations; chemotherapy dose delays, reductions, and discontinuations; and adverse events from prophylaxis. Results: Of 2,205 identified citations, eight studies (n = 1,250) met our eligibility criteria. Three additional studies (n = 293) were identified from a prior systematic review. Three randomized controlled trials (n = 576), one phase IV single-arm trial (n = 69), one prospective observational study (n = 37), and six retrospective studies (n = 861) were identified. Agents investigated were pegfilgrastim (n = 108), filgrastim (n = 1,119), and ciprofloxacin (n = 89). The heterogeneity of studies meant that a narrative synthesis of results was performed. Median FN rates for patients who received FEC-D with and without primary prophylaxis were 10.1% (interquartile range [IQR], 3.9% to 22.6%) and 23.9% (IQR, 9.2% to 27.3%), respectively. In the absence of primary prophylaxis, FN was more common during docetaxel than during FEC. Data from six studies showed a median rate of dose reductions and delays of 6.1% (IQR, 3.1% to 14.3%) and 19.3% (IQR, 10.5% to 32.8%), respectively, that occurred as a consequence of FN. Toxicity from prophylaxis itself was rarely reported. Conclusion: Primary FN prophylaxis is effective in patients who receive FEC-D chemotherapy. The paucity of prospective data makes optimal recommendations about the choice and timing of prophylaxis challenging.

Background: Kidney transplantation is the optimal treatment for patients with end-stage renal disease; however, long-term outcomes remain suboptimal. Objective: The objectives of our study were to examine the variation in survival rates and determine whether center volume and case mix are associated with transplant outcomes and explain the variation across kidney transplant centers in Ontario, Canada. Design: This was a population-based cohort study using health care administrative databases. Setting: A total of 5 transplant centers across Ontario, Canada. Patients: We included adults (≥18 years) undergoing primary, solitary kidney transplantation between January 1, 2000 to December 31, 2013. Measurements: The co-primary outcomes were death-censored graft loss and total mortality. Methods: Multivariable Cox proportional hazards regression was used to assess potential associations and describe variation, using hazard ratios (HRs) with 95% confidence intervals (CIs) for each center relative to the average across all centers. Results: The study cohort included 5037 patients followed for a median of 5.3 years, interquartile range (2.7-8.6). In multivariable models, recipient age, body mass index, Charlson Index, time on dialysis, donor type, and age were found to be significantly associated with death-censored graft loss, and recipient age and sex, Charlson Index, time on dialysis, donor age, and time era of transplant were associated with total mortality. There was statistically significant variation across centers observed for death-censored graft loss ( P = .04) with HRs ranging from 0.72 to 1.22. However, neither adjusting for case mix nor center volume meaningfully changed the HRs reflecting each center-specific effect. There was a tendency toward reduced risk of graft loss (HR, per additional 25 patients, 0.90 [95% CI, 0.78-1.04]) in centers with higher volumes. For total mortality, there was statistically significant variation across centers with HRs ranging from 0.82 to 1.13 ( P = .04); however, neither adjusting for case mix or center volume meaningfully changed the HRs. Center volume was not significantly associated with total mortality (HR, per additional 25 patients, 1.04 [95% CI, 0.90-1.20]). Limitations: This study was limited by the small number of centers included. Conclusions: Outcomes differ across the 5 transplant centers in Ontario. We did not find any strong support for our hypotheses that case mix or center volume is responsible for these differences.

Abstract Background Critically ill patients frequently experience severe agitation placing them at risk of harm. Physical restraint is common in intensive care units (ICUs) for clinician concerns about safety. However, physical restraint may not prevent medical device removal and has been associated with negative physical and psychological consequences. While professional society guidelines, legislation, and accreditation standards recommend physical restraint minimization, guidelines for critically ill patients are over a decade old, with recommendations that are non-specific. Our systematic review will synthesize evidence on physical restraint in critically ill adults with the primary objective of identifying effective minimization strategies. Methods Two authors will independently search from inception to July 2016 the following: Ovid MEDLINE, CINAHL, Embase, Web of Science, Cochrane Library, PROSPERO, Joanna Briggs Institute, grey literature, professional society websites, and the International Clinical Trials Registry Platform. We will include quantitative and qualitative study designs, clinical practice guidelines, policy documents, and professional society recommendations relevant to physical restraint of critically ill adults. Authors will independently perform data extraction in duplicate and complete risk of bias and quality assessment using recommended tools. We will assess evidence quality for quantitative studies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and for qualitative studies using the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) guidelines. Outcomes of interest include (1) efficacy/effectiveness of physical restraint minimization strategies; (2) adverse events (unintentional device removal, psychological impact, physical injury) and associated benefits including harm prevention; (3) ICU outcomes (ventilation duration, length of stay, and mortality); (4) prevalence, incidence, patterns of use including patient and treatment characteristics and chemical restraint; (5) barriers and facilitators to minimization; (6) patient, family, and healthcare professional perspectives; (7) professional society-endorsed recommendations; and (8) evidence gaps and research priorities. Discussion We will use our systematic review findings to produce updated guidelines on physical restraint use for critically ill adults and to develop a professional society-endorsed position statement. This will foster patient and clinician safety by providing clinicians, administrators, and policy makers with a tool to promote minimal and safe use of physical restraint for critically ill adults. Systematic review registration PROSPERO CRD42015027860

Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias – as in clinical medicine and healthcare – or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work. Keywords: Methodological quality, Reporting quality, Risk of bias, Scoping review, Toxicity studies