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Background The Cochrane Bias Methods Group recently developed the “Risk of Bias (ROB) in Non-randomized Studies of Interventions” (ROBINS-I) tool to assess ROB for non-randomized studies of interventions (NRSI). It is important to establish consistency in its application and interpretation across review teams. In addition, it is important to understand if specialized training and guidance will improve the reliability of the results of the assessments. Therefore, the objective of this cross-sectional study is to establish the inter-rater reliability (IRR), inter-consensus reliability (ICR), and concurrent validity of ROBINS-I. Furthermore, as this is a relatively new tool, it is important to understand the barriers to using this tool (e.g., time to conduct assessments and reach consensus—evaluator burden). Methods Reviewers from four participating centers will appraise the ROB of a sample of NRSI publications using the ROBINS-I tool in two stages. For IRR and ICR, two pairs of reviewers will assess the ROB for each NRSI publication. In the first stage, reviewers will assess the ROB without any formal guidance. In the second stage, reviewers will be provided customized training and guidance. At each stage, each pair of reviewers will resolve conflicts and arrive at a consensus. To calculate the IRR and ICR, we will use Gwet’s AC1 statistic. For concurrent validity, reviewers will appraise a sample of NRSI publications using both the New-castle Ottawa Scale (NOS) and ROBINS-I. We will analyze the concordance between the two tools for similar domains and for the overall judgments using Kendall’s tau coefficient. To measure the evaluator burden, we will assess the time taken to apply the ROBINS-I (without and with guidance), and the NOS. To assess the impact of customized training and guidance on the evaluator burden, we will use the generalized linear models. We will use Microsoft Excel and SAS 9.4 to manage and analyze study data, respectively. Discussion The quality of evidence from systematic reviews that include NRS depends partly on the study-level ROB assessments. The findings of this study will contribute to an improved understanding of the ROBINS-I tool and how best to use it.

ObjectivesTo identify, critically appraise and summarise evidence on the impact of employing primary healthcare professionals (PHCPs: family physicians/general practitioners (GPs), nurse practitioners (NP) and nurses with increased authority) in the emergency department (ED) triage, on patient flow outcomes.MethodsWe searched Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley) and CINAHL (EBSCO) (inception to January 2020). Our primary outcome was the time to provider initial assessment (PIA). Secondary outcomes included time to triage, proportion of patients leaving without being seen (LWBS), length of stay (ED LOS), proportion of patients leaving against medical advice (LAMA), number of repeat ED visits and patient satisfaction. Two independent reviewers selected studies, extracted data and assessed study quality using the National Institute for Health and Care Excellence quality assessment tool.ResultsFrom 23 973 records, 40 comparative studies including 10 randomised controlled trials (RCTs) and 13 pre–post studies were included. PHCP interventions were led by NP (n=14), GP (n=3) or nurses with increased authority (n=23) at triage. In all studies, PHCP-led intervention effectiveness was compared with the traditional nurse-led triage model. Median duration of the interventions was 6 months. Study quality was generally low (confounding bias); 7 RCTs were classified as moderate quality. Most studies reported that PHCP-led triage interventions decreased the PIA (13/14), ED LOS (29/30), proportion of patients LWBS (8/10), time to triage (3/3) and repeat ED visits (5/6), and increased the patient satisfaction (8/10). The proportion of patients LAMA did not differ between groups (3/3). Evidence from RCTs (n=8) as well as other study designs showed a significant decrease in ED LOS favouring the PHCP-led interventions.ConclusionsOverall, PHCP-led triage interventions improved ED patient flow metrics. There was a significant decrease in ED LOS irrespective of the study design, favouring the PHCP-led interventions. Evidence from well-designed high-quality RCTs is required prior to widespread implementation.PROSPERO registration numberCRD42020148053.

ObjectivesTo summarise the current evidence regarding interventions for accurate and timely cancer diagnosis among symptomatic individuals.DesignA scoping review following the Joanna Briggs Institute’s methodological framework for the conduct of scoping reviews and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist.Data sourcesMEDLINE (Ovid), CINAHL (EBSCOhost) and PsycINFO (Ovid) bibliographic databases, and websites of relevant organisations. Published and unpublished literature (grey literature) of any study type in the English language were searched for from January 2017 to January 2021.Eligibility and criteriaStudy participants were individuals of any age presenting at clinics with symptoms indicative of cancer. Interventions included practice guidelines, care pathways or other initiatives focused on achieving predefined benchmarks or targets for wait times, streamlined or rapid cancer diagnostic services, multidisciplinary teams and patient navigation strategies. Outcomes included accuracy and timeliness of cancer diagnosis.Data extraction and synthesisWe summarised findings graphically and descriptively.ResultsFrom 21 298 retrieved citations, 88 unique published articles and 16 unique unpublished documents (on 18 study reports), met the eligibility for inclusion. About half of the published literature and 83% of the unpublished literature were from the UK. Most of the studies were on interventions in patients with lung cancer. Rapid referral pathways and technology for supporting and streamlining the cancer diagnosis process were the most studied interventions. Interventions were mostly complex and organisation-specific. Common themes among the studies that concluded intervention was effective were multidisciplinary collaboration and the use of a nurse navigator.ConclusionsMultidisciplinary cooperation and involvement of a nurse navigator may be unique features to consider when designing, delivering and evaluating interventions focused on improving accurate and timely cancer diagnosis among symptomatic individuals. Future research should examine the effectiveness of the interventions identified through this review.

Background To better inform clinical practice, we summarized the findings from randomized controlled trials (RCTs) of antivirals for COVID-19. Methods We systematically searched for literature up to September 2020, and included English-language publications of RCTs among hospitalized COVID-19 patients. We conducted network meta-analysis combining results of both the direct and indirect comparisons of interventions. The efficacy outcomes were clinical progression, all-cause mortality, and viral clearance, and safety outcomes were diarrhea, nausea, and vomiting. We generated treatment rankings (best to worst) and summarized rank probabilities using rankogram. Results We included 15 RCTs (14,418 patients) from 7,237 retrieved citations. There was no evidence for efficacy of the assessed antivirals compared with placebo/no treatment or with another antiviral for all efficacy outcomes. Lopinavir (400 mg)/ritonavir (100 mg) significantly increased diarrhea, nausea, and vomiting compared with placebo/no treatment and other antivirals, and was ranked worst for these outcomes, while triazavirin (250 mg), baloxavir marboxil (80 mg), and remdesivir (100 mg – 10 days) ranked best, respectively. Conclusions and relevance The available evidence does not support the use of any antiviral drugs for COVID-19. Cautious interpretations of the findings are, however, advised considering the paucity of the evidence. More RCTs are needed for a stronger evidence base.

ObjectivesTo conduct a scoping review to identify and summarise the existing literature on interventions involving primary healthcare professionals to manage emergency department (ED) overcrowding.DesignA scoping review.Data sourcesA comprehensive database search of Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley) and CINAHL (EBSCO) databases was conducted (inception until January 2020) using peer-reviewed search strategies, complemented by a search of grey literature sources.Eligibility criteriaInterventions and strategies involving primary healthcare professionals (PHCPs: general practitioners (GPs), nurse practitioners (NPs) or nurses with expanded role) to manage ED overcrowding.MethodsWe engaged and collaborated, with 13 patient partners during the design and conduct stages of this review. We conducted this review using the JBI guidelines. Two reviewers independently selected studies and extracted data. We conducted descriptive analysis of the included studies (frequencies and percentages).ResultsFrom 23 947 records identified, we included 268 studies published between 1981 and 2020. The majority (58%) of studies were conducted in North America and were predominantly cohort studies (42%). The reported interventions were either ‘within ED’ (48%) interventions (eg, PHCP-led ED triage or fast track) or ‘outside ED’ interventions (52%) (eg, after-hours GP clinic and GP cooperatives). PHCPs involved in the interventions were: GP (32%), NP (26%), nurses with expanded role (16%) and combinations of the PHCPs (42%). The ‘within ED’ and ‘outside ED’ interventions reported outcomes on patient flow and ED utilisation, respectively.ConclusionsWe identified many interventions involving PHCPs that predominantly reported a positive impact on ED utilisation/patient flow metrics. Future research needs to focus on conducting well-designed randomized controlled trials (RCTs) and systematic reviews to evaluate the effectiveness of specific interventions involving PHCPs to critically appraise and summarise evidence on this topic.

In view of many unanswered clinical questions regarding treatment of COVID-19 with remdesivir, we systematically identified, critically appraised and summarized the findings from randomized controlled trials (RCTs) of remdesivir for COVID-19. We searched relevant databases/websites (up to September 2020) and selected English-language RCT publications of remdesivir for COVID-19. We conducted meta-analysis using an inverse variance, random-effects model in addition to trial sequential analysis (TSA) for the efficacy outcomes: all-cause mortality, viral burden and clinical progression. Safety outcomes were diarrhoea, nausea, and vomiting. We calculated the relative risk (RR) and 95% confidence interval (CI) for all outcomes. Statistical heterogeneity was calculated using the I2 statistic. We included five RCTs (7540 participants) from 7237 citations. Most (80%) were of an unclear to high risk of bias. There was no evidence of a significant improvement with remdesivir (100 mg, 10 days) regarding all-cause mortality (RR 0.94, CI 0.82–1.07; I2 = 0%; 4 RCTs; 7143 patients), clinical progression (RR 1.08, CI 0.99–1.18; I2 = 70.4%; 3 RCTs; 1692 patients), or diarrhoea (RR 0.82, CI 0.40–1.66; I2 = 0%; 2 RCTs; 630 patients). Nausea occurred more often with remdesivir (RR 2.77, CI 1.28–6.03; I2 = 0%; 2 RCTs; 630 patients). TSA showed that the required information size was not reached for firm conclusions to be drawn. There is insufficient evidence to support the use of remdesivir for treatment of COVID-19. More high-quality RCTs are needed for a stronger evidence. Until then, remdesivir should remain an experimental drug for COVID-19.

Background Implementation strategies are vital for the uptake of evidence to improve health, healthcare delivery, and decision-making. Medical or mental emergencies may be life-threatening, especially in children, due to their unique physiological needs when presenting in the emergency departments (EDs). Thus, practice change in EDs attending to children requires evidence-informed considerations regarding the best approaches to implementing research evidence. We aimed to identify and map the characteristics of implementation strategies used in the emergency management of children. Methods We conducted a scoping review using Arksey and O’Malley’s framework. We searched four databases [Medline (Ovid), Embase (Ovid), Cochrane Central (Wiley) and CINAHL (Ebsco)] from inception to May 2019, for implementation studies in children (≤21 years) in emergency settings. Two pairs of reviewers independently selected studies for inclusion and extracted the data. We performed a descriptive analysis of the included studies. Results We included 87 studies from a total of 9,607 retrieved citations. Most of the studies were before and after study design (n = 68, 61%) conducted in North America (n = 63, 70%); less than one-tenth of the included studies (n = 7, 8%) were randomized controlled trials (RCTs). About one-third of the included studies used a single strategy to improve the uptake of research evidence. Dissemination strategies were more commonly utilized (n = 77, 89%) compared to other implementation strategies; process (n = 47, 54%), integration (n = 49, 56%), and capacity building and scale-up strategies (n = 13, 15%). Studies that adopted capacity building and scale-up as part of the strategies were most effective (100%) compared to dissemination (90%), process (88%) and integration (85%). Conclusions Studies on implementation strategies in emergency management of children have mostly been non-randomized studies. This review suggests that ‘dissemination’ is the most common strategy used, and ‘capacity building and scale-up’ are the most effective strategies. Higher-quality evidence from randomized-controlled trials is needed to accurately assess the effectiveness of implementation strategies in emergency management of children.

Background A new tool, “risk of bias (ROB) instrument for non-randomized studies of exposures (ROB-NRSE),” was recently developed. It is important to establish consistency in its application and interpretation across review teams. In addition, it is important to understand if specialized training and guidance will improve the reliability in the results of the assessments. Therefore, the objective of this cross-sectional study is to establish the inter-rater reliability (IRR), inter-consensus reliability (ICR), and concurrent validity of the new ROB-NRSE tool. Furthermore, as this is a relatively new tool, it is important to understand the barriers to using this tool (e.g., time to conduct assessments and reach consensus—evaluator burden). Methods Reviewers from four participating centers will apprise the ROB of a sample of NRSE publications using ROB-NRSE tool in two stages. For IRR and ICR, two pairs of reviewers will assess the ROB for each NRSE publication. In the first stage, reviewers will assess the ROB without any formal guidance. In the second stage, reviewers will be provided customized training and guidance. At each stage, each pair of reviewers will resolve conflicts and arrive at a consensus. To calculate the IRR and ICR, we will use Gwet’s AC1 statistic. For concurrent validity, reviewers will appraise a sample of NRSE publications using both the Newcastle-Ottawa Scale (NOS) and ROB-NRSE tool. We will analyze the concordance between the two tools for similar domains and for the overall judgments using Kendall’s tau coefficient. To measure evaluator burden, we will assess the time taken to apply ROB-NRSE tool (without and with guidance), and the NOS. To assess the impact of customized training and guidance on the evaluator burden, we will use the generalized linear models. We will use Microsoft Excel and SAS 9.4, to manage and analyze study data, respectively. Discussion The quality of evidence from systematic reviews that include NRSE depends partly on the study-level ROB assessments. The findings of this study will contribute to an improved understanding of ROB-NRSE and how best to use it.

BACKGROUND Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference −0.37 kg/m 2 ; 95% confidence interval [CI] −1.10 to 0.36; I 2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I 2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749

ObjectivesTo provide a comprehensive systematic overview of current evidence from pooled analyses/meta-analyses and systematic reviews (PMASRs) pertaining to dairy consumption and incident cancer and/or all-cause or cancer-specific mortality.DesignOverview of reviews.SettingCommunity setting.ParticipantsThe unit of analysis is PMASRs. A total of 42 PMASRs was included in this overview of reviews.Interventions/exposuresAny dairy product consumption (eg, milk, yogurt, etc).Primary and secondary outcomes measuresPrimary outcome measure is development of any type of cancer. Secondary outcome measures are all-cause mortality and cancer-specific mortality.ResultsFrom 9693 citations identified, we included 42 PMASRs (52 study reports) published between 1991 and 2017. Thirty-one (74%) of these was pooled analyses/meta analyses, and only 11 (26%) were systematic reviews and meta-analyses. There was a wide variability in the type of study designs included within the other PMASRs, thus contributing to variable and, in instances, divergent estimates of cancer risk for several cancer subtypes. For example, only one systematic review and meta-analysis exclusively included prospective study designs. Most PMASRs were of low to moderate quality based on the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scores. The median AMSTAR score was 5 (IQR 2–7). Our overview identified conflicting evidence from PMASRs on association between dairy consumption and incident cancers or mortality. Heterogeneity in summary estimates reflected the inclusion of variable study designs and overall low methodological quality of individual PMASRs.ConclusionsThe association between dairy consumption and cancer risk has been explored in PMASRs with a variety of study designs and of low to moderate quality. To fully characterise valid associations between dairy consumption and risk of cancer and/or mortality rigorously conducted, PMASRs including only high-quality prospective study designs are required.Trial registration numberCRD42017078463.