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Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Purpose: The provision of healthcare is a substantial global contributor to greenhouse gas (GHG) emissions. Several medical specialties and national health systems have begun evaluating their carbon emission contributions. The aim of this review is to summarise and describe the carbon footprint resulting from the provision of adult, paediatric and neonatal critical care., Methods: A systematic search of Embase, Cochrane and Web of Science was performed in January 2023. Studies reporting any assessment of the carbon footprint of critical care were included. No language restrictions were applied. GHG emissions from life cycle assessments (LCA) were reported, in addition to waste, electricity and water use. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed., Results: In total, 13 studies assessing and describing the environmental impact of 36 adult or paediatric intensive care units (ICUs) were included. Two studies described full LCAs, seven reported waste only, two provided audits of unused medical supplies, one reported electricity use, and one study described a Material Flow Analysis. The estimated carbon emissions from critical care range between 88 kg CO 2 e/patient/day and 178 kg CO 2 e/patient/day. The two predominant sources of carbon emissions in critical care originate from electricity and gas use, as well as consumables. Waste production ranged from 1.1 to 13.7 kg/patient/day in the 6 studies where mean waste could be calculated., Conclusion: There is a significant carbon footprint that results from intensive care provision. Consumables and waste constitute important, measurable, and modifiable components of anthropogenic emissions. There remains uncertainty due to a lack of literature, several unstudied areas of carbon emissions from critical care units, and within measured areas, measurement and reporting of carbon emissions are inconsistent., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Clinical educators in geriatrics are often tasked with presenting a literature update at annual conferences and scientific meetings, which is a highly regarded continuing medical education (CME) activity. Preparation of an annual literature update cannot rely on bibliometric analysis due to time lag and poor correlation between bibliometrics and expert opinion on clinical relevance. The methodology of how top research articles of the year are selected and presented is not often reported., Methods: We conducted a scoping review for published reports of a curated selection of recent articles critically appraised for high impact to clinical practice in general geriatrics, published from 2010 to 2022., Results: Six annual literature updates were included for study. Three updates detailed their article sources, ranging from a survey of clinicians, consulting seven individual journals, searching up to four bibliographic databases, scanning social media outlets, and reviewing previous literature updates. One update reported a detailed method of article selection and consensus development. Critical appraisal of articles followed a structured reporting of clinical context, methods, results, and a statement of clinical implication or bottom line. Three of the six updates' results were disseminated in an annual conference update and did not evaluate learning outcomes of the audience. We mapped the results on a four-step framework of article search, selection, critical appraisal, and dissemination of knowledge., Conclusions: Educators in geriatrics consult numerous article sources spanning multiple journals, databases, social media, and peer suggestions to create an annual literature update. The methodology of article search and selection is inconsistently described. In this exciting area of CME, we encourage educators to develop a framework for conducting annual literature updates in geriatrics and expand its scholarship., (© 2024 The American Geriatrics Society.)

Background: Transgender individuals are discriminated against in health care environments and consistently experience poorer health outcomes than their cisgender counterparts. Enhancing physician training in transgender-specific health is critical to closing the transgender health gap., Methods: We conducted a scoping review to identify transgender health training objectives in Internal Medicine and Internal Medicine Subspecialty residency programmes in Canada and the United States. A systematic search was conducted from 1946 to 15 February 2022. Studies were eligible for inclusion if they were written in English, included transgender training objectives, and were aimed at resident physicians in Internal Medicine or Internal Medicine Subspecialty training programmes in Canada or the United States., Findings: We found 4048 papers, of which 11 were included for analysis. Transgender health training objectives were synthesised into five themes, including (1) terminology, physiology, and gender presentation, (2) gender-affirming care and communication, (3) hormonal and surgical management, (4) routine health management and maintenance, and (5) equity, diversity, and inclusion in clinical care. The majority of objectives pertained to equity, diversity, and inclusion in clinical care, namely, respectful communication and non-judgemental care of transgender patients., Discussion: Our findings provide a comprehensive overview of published transgender health objectives in Canada and the United States and highlight existing gaps in postgraduate medical education for Internal Medicine and Subspecialty programmes., Conclusions: We argue a need for standardisation of transgender-related residency training and suggest that postgraduate Internal Medicine programmes can utilise this review as a framework to begin enhancing transgender health education for their residents., (© 2023 The Authors. The Clinical Teacher published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was supported by funding from The Hospital for Sick Children Transplant and Regenerative Medicine Centre (TRMC). PPPR has been co-investigator on an investigator-led project funded by Pfizer that is unrelated to this study. JU reports being a past investigator for Sanofi/Regeneron, fees from Pfizer and AstraZeneca, all unrelated to vaccines. SKM has received honoraria for lectures from GlaxoSmithKline, was a member of ad hoc advisory boards for Pfizer, Sanofi Pasteur, and Merck and is a co-investigator on an investigator-led grant from Pfizer, all unrelated to this study. All authors have no conflict of interest relevant to this publication to declare. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Predicting recurrent venous thromboembolic events (VTEs) is challenging in clinical practice for both adults and children, but it is relevant for clinical management. Identifying laboratory risk factors for VTE recurrence may aid in clinical decision-making., Objective: The goal of this systematic review is to investigate the predictive role of FVIII, IX, or XI in recurrent VTE in adult and pediatric patients with a first VTE., Methods: A systematic review of the published literature was conducted in databases MEDLINE In-Process, Other Nonindexed Citations, MEDLINE Epub Ahead of Print, EMBASE Classic + EMBASE (OvidSP), and Cochrane (Wiley). We included observational and interventional studies that comprised adults or children with a first VTE, FVIII, FIX, and/or FXI and objectively confirmed VTE recurrence. The quality in prognosis studies tool was used to assess the risk of bias., Results: We identified 2177 unique studies, of which 19 were included (18 for adults and 1 for children). The risk of bias was overall low to moderate. The studies were heterogenous with regards to population (provoked/unprovoked primary VTE), exposure (type of assay and cut-off values), and statistical analysis results (measures of association and modeling strategy). In adults, contradictory evidence was found for FVIII and FXI as outcome predictors, while no research could establish if FIX predicts VTE recurrence. Data in pediatrics were limited. Given the extensive heterogeneity of the literature, a meta-analysis was not performed., Conclusions: Overall, there is contradictory evidence that FVIII, FIX, or FXI predict recurrent VTE in adults and children. Addressing heterogeneity is a relevant aspect to consider in future studies investigating prognostic factors for VTE recurrence., (© 2023 The Author(s).)

Introduction: Long-term cardiovascular (CV) risk is a concern for differentiated thyroid cancer (DTC) survivors. Methods: We performed a systematic review and meta-analysis evaluating the risks of CV mortality and morbidity in DTC survivors compared with the general population. Respective meta-analyses were conducted for data that were adjusted for relevant confounders and crude data. We searched five electronic databases from inception to October 2021, supplemented with a hand search. Two reviewers independently screened citations, reviewed full text articles, extracted data, and critically appraised the studies, with discrepancies resolved by a third reviewer. The primary outcome was CV mortality. Secondary outcomes included atrial fibrillation, ischemic heart disease, stroke, and heart failure. We estimated the relative risk (RR) and confidence intervals [CI] of outcomes using random-effects models (adjusted for age and gender), compared with the general population. Results: We reviewed 3409 unique citations, 65 full text articles, and included 7 studies. CV mortality risk was significantly increased in DTC survivors in one study adjusted for confounders-adjusted RR (aRR) 3.35 ([CI 1.66-6.67]; 524 DTC, 1572 controls). The risk of CV morbidity in DTC survivors, adjusted for risk factors, was estimated as follows: atrial fibrillation-aRR 1.66 [CI 1.22-2.27] (3 studies, 4428 DTC, I 2  = 75%), ischemic heart disease-aRR 0.97 [CI 0.84-1.13] (2 studies, 3910 DTC, I 2  = 0%), stroke-aRR 1.14 [CI 0.84-1.55] (2 studies, 3910 DTC, I 2  = 69%), and heart failure-aRR 0.98 [CI 0.60-1.59] (2 studies, 3910 DTC, I 2  = 79%). In meta-analyses of unadjusted data, the risks of CV mortality were not significantly increased but the CV morbidity risks were similar to adjusted data. Conclusions: There is limited evidence suggesting that DTC survivors may be at an increased risk of CV death and atrial fibrillation (after adjustment for confounders). We did not observe a significantly increased risk of ischemic heart disease, stroke, or heart failure. Most analyses were subject to significant heterogeneity and further research, with careful attention to CV risk factors, is needed to clarify CV risk in DTC survivors. Registration: PROSPERO CRD42021244743.

Background: Injection-related pain and fear are common adverse reactions in children undergoing vaccination and influence vaccine acceptance. Despite the large body of literature on sources of vaccine non-compliance, there is no estimate of the prevalence of pain and fear as contributing factors. The objective was to estimate the prevalence of injection pain or fear of needles as barriers to childhood (i.e., 0-18 years) vaccination., Methods: Four databases were searched from inception for relevant English and French articles until August 2021. In addition, the references of recent systematic reviews and all articles included in the review were hand searched. Article screening and data extractions were performed in duplicate. Studies were included if they reported on injection-related pain or fear of needles in children (0-18 years) using a checklist/closed-ended question(s). Results were stratified by respondent (parents or children), type of pediatric population (general or under-vaccinated), and relative importance of barrier (pain or needle fear as primary reason or any reason for under-vaccination). Prevalence rates of pain or needle fear were combined using a random effects model. Quality of included studies was assessed using the Joanna Briggs Institute critical appraisal checklist for prevalence data. Quality across studies was assessed using GRADE., Results: There were 26 studies with 45 prevalence estimates published between 1995 and 2021. For parent reports (of children) and children self-reported reasons for non-compliance, prevalence rates of pain or needle fear ranged from 5 to 13% in a general population and 8 to 28% in an under-vaccinated population, with a substantial variation in the prevalence estimates. There was no difference between category of respondent or relative importance on pain or needle fear prevalence rate. A regression model demonstrated an overall prevalence rate of pain or needle fear as an obstacle to vaccination of 8% in the general population and 18.3% in the under-vaccinated population. All evidence was very low in quality., Conclusion: This is the first review to systematically quantify the prevalence and therefore, importance, of pain and needle fear as obstacles to vaccination in children around the world. Pain from injection or fear of needles were demonstrated to be sufficiently prevalent as barriers to vaccination in children to warrant attention. Addressing pain and fear has the potential to significantly improve vaccination acceptance., Competing Interests: Declaration of Competing Interest A. Taddio reports a University of Toronto Section 9 Trademark No. 924835 for CARD™. Authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite the availability of effective, safe, and feasible pain management strategies, infant pain remains undertreated. Parents can play a key role in advocating for or delivering pain management strategies if they are educated. To date, a quantitative synthesis of the effectiveness of parental education about pain management in the neonatal period has not been performed., Objective: To systematically review the effectiveness of parental education during the neonatal period on pain management in infancy., Methods: MEDLINE, EMBASE, PsycInfo, CINAHL, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs) and non-randomized trials (NRTs) that evaluated parental education with respect to pain management during the neonatal period in any setting from inception to February 2021. Screening of article titles and abstracts and data extraction were performed in duplicate. The risk of bias was assessed using the Cochrane Risk Bias Tool 2.0 and the Risk of Bias in Non-randomized Studies of Interventions for RCTs and NRTs, respectively. As per the GRADE methodology, critically important and important outcomes were identified. Critically important outcomes included utilization of pain management strategies and infant pain. Important outcomes included parental knowledge about pain mitigation strategies, parental attitudes, compliance with painful procedures, procedure outcomes, and safety. Data were combined and presented as relative risk (RR) or mean or standardized mean difference (MD or SMD) with 95% confidence interval (CI)., Results: Of the six studies eligible for inclusion, four studies were RCTs and two studies were NRTs. Written information and/or video were used to deliver parental education during the neonatal period in hospital settings in all studies. Four studies (two RCTs and two NRTs) reported on critically important outcomes. The risk of bias was low for the two RCTs and moderate to serious for the two NRTs. Utilization of pain management strategies was assessed for heel lance in the first 48 hours of life in two studies and for vaccine injection at 2 to 6 months of life in two studies. Higher utilization rate for pain management strategies was reported in the pain education group in three studies (RR 1.15, 95% CI 1.04, 1.26; N=2712). There was no difference in the mean number of pain management strategies used in one NRT tracking utilization tracking utilization as continuous data (MD 0.20, 95% CI -0.01, 0.41; N=178). Parent-reported infant pain scores were lower in the pain education group in one RCT (MD -0.16, 95% CI -0.27, -0.06; N=1615). The quality of evidence for the outcome of utilization of pain management strategies was very low while for the outcome of infant pain the quality of evidence was moderate. Five studies (3 RCTs and 2 NRTs) reported on important outcomes. The risk of bias was low for two RCTs and high for one RCT and moderate to serious for the two NRTs. Parental knowledge about pain management strategies (SMD 0.54, 95% CI 0.26, 0.82), parental confidence in their ability to manage pain (SMD 0.24, 95% CI 0.14, 0.34), parental satisfaction with education (MD 1.18, 95% CI 0.84, 1.52) and parental satisfaction with pain management (RR 1.05. 95% CI 1.01, 1.08) were increased in the pain education group. None of the included studies reported on procedural outcomes. No adverse events with the pain education nor the use of pain management interventions were reported in one study., Conclusions: Parental education in the neonatal period was effective in increasing utilization of pain management strategies during painful procedures. Reduction of pain in infants is based on one study of moderate quality. Furthermore, parental education increased parental knowledge about pain management strategies, confidence in their ability to manage infant pain, and satisfaction with the education and pain management. Parental pain education should be incorporated into postnatal care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: With the rise of artificial intelligence (AI) in ophthalmology, the need to define its diagnostic accuracy is increasingly important. The review aims to elucidate the diagnostic accuracy of AI algorithms in screening for all ophthalmic conditions in patient care settings that involve digital imaging modalities, using the reference standard of human graders., Methods: This is a systematic review and meta-analysis. A literature search will be conducted on Ovid MEDLINE, Ovid EMBASE, and Wiley Cochrane CENTRAL from January 1, 2000, to December 20, 2021. Studies will be selected via screening the titles and abstracts, followed by full-text screening. Articles that compare the results of AI-graded ophthalmic images with results from human graders as a reference standard will be included; articles that do not will be excluded. The systematic review software DistillerSR will be used to automate part of the screening process as an adjunct to human reviewers. After the full-text screening, data will be extracted from each study via the categories of study characteristics, patient information, AI methods, intervention, and outcomes. Risk of bias will be scored using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) by two trained independent reviewers. Disagreements at any step will be addressed by a third adjudicator. The study results will include summary receiver operating characteristic (sROC) curve plots as well as pooled sensitivity and specificity of artificial intelligence for detection of any ophthalmic conditions based on imaging modalities compared to the reference standard. Statistics will be calculated in the R statistical software., Discussion: This study will provide novel insights into the diagnostic accuracy of AI in new domains of ophthalmology that have not been previously studied. The protocol also outlines the use of an AI-based software to assist in article screening, which may serve as a reference for improving the efficiency and accuracy of future large systematic reviews., Trial Registration: PROSPERO, CRD42021274441., (© 2022. The Author(s).)

Background: While the high burden of illness caused by seasonal influenza in children and the elderly is well recognize, less is known about the burden in adults 50-64 years of age. The lack of data for this age group is a key challenge in evaluating the cost-effectiveness of immunization programs. We aimed to assess influenza-associated hospitalization and mortality rates and case fatality rates for hospitalized cases among adults aged 50-64 years., Methods: This rapid review was conducted according to the PRISMA; we searched MEDLINE, EMBASE, Cochrane, Web of Science, and grey literature for articles and reports published since 2010. Studies reporting rates of hospitalization and/or mortality associated with laboratory-confirmed influenza among adults 50-64 or 45-64 years of age for the 2010-11 through 2019-20 seasons were included., Results: Twenty studies from 13 countries were reviewed. Reported rates of hospitalization associated with laboratory-confirmed influenza were 5.7 to 112.8 per 100,000. Rates tended to be higher in the 2015-2019 compared with the 2010-2014 seasons and were higher in studies reporting data from high-income versus low and middle-income countries. Mortality rates were reported in only one study, with rates ranging from 0.8 to 3.5 per 100,000 in four different seasons. The case fatality rate among those hospitalized with influenza, as reported by population-based studies, ranged from 1.3% to 5.6%., Conclusions: Seasonal influenza imposes a significant burden of morbidity on adults 50-64 years of age but with high heterogeneity across seasons and geographic regions. Ongoing surveillance is required to improve estimates of burden to better inform influenza vaccination and other public health policies., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Living Donor Liver Transplantation(LDLT) in acute liver failure(ALF) patients has been limited by concerns regarding donor safety, consent process and recipient outcomes. Our objective was to conduct a systematic review(SR) and meta-analysis to address the concerns about subpar LDLT outcomes in patients with ALF., Methods: We retrieved a total of 5965 literature references in our SR. United Network for Organ Sharing (UNOS) database was queried for patients over the age of 18, who underwent LDLT for "status 1" or "status 1A" listing., Results: Of 427 articles reviewed, 3 studies comprising 2574 patients (192 underwent LDLT and 2382 DDLT), were included in the meta-analysis. One, 3,5-year patient and graft survival demonstrated no difference between LDLT and DDLT group: 1-year patient survival OR1.51; 95%CI [0.58,1.90]; 1-year graft survival OR 1.19; 95%CI [0.65-2.18]; 3-year patient survival OR 0.97;95%CI [0.52-1.88]; 3-year graft survival OR 1.21 95%CI [0.67-2.16]; 5-year patient survival 0.9; 95%CI [0.37-2.20]; 5-year graft survival OR 1.30; 95%CI [0.57-2.97]. UNOS database search returned only 3 patients that underwent LDLT for ALF compared to 1562 with DDLT, precluding comparison., Conclusion: One, 3, and 5-year patient and graft survival following LDLT vs DDLT transplantation were not statistically significantly different; however, due to limited number of studies further studies are warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Living donor liver transplantation (LDLT) emerged in the 1980s as a viable alternative to scarce cadaveric organs for pediatric patients. However, pediatric waitlist mortality remains high. Long-term outcomes of living and deceased donor liver transplantation (DDLT) are inconsistently described in the literature. Our aim was to systematically review the safety and efficacy of LDLT after 1 year of transplantation among pediatric patients with all causes of liver failure. We searched the MEDLINE, Medline-in-Process, MEDLINE Epub Ahead of Print, Embase + Embase Classic (OvidSP), and Cochrane (Wiley) from February 1, 1947 to February 26, 2020, without language restrictions. The primary outcomes were patient and graft survival beyond 1 year following transplantation. A meta-analysis of unadjusted and adjusted odds and hazard ratios was performed using a random-effects model. A total of 24 studies with 3677 patients who underwent LDLT and 9098 patients who underwent DDLT were included for analysis. In patients with chronic or combined chronic liver failure and acute liver failure (ALF), 1-year (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.53-0.88), 3-year (OR, 0.73; 95% CI, 0.61-0.89), 5-year (OR, 0.71; 95% CI, 0.57-0.89), and 10-year (OR, 0.42; 95% CI, 0.18-1.00) patient and 1-year (OR, 0.50; 95% CI, 0.35-0.70), 3-year (OR, 0.55; 95% CI, 0.37-0.83), 5-year (OR, 0.5; 95% CI, 0.32-0.76), and 10-year (OR, 0.26; 95% CI, 0.14-0.49) graft survival were consistently better in LDLT recipients compared with those in DDLT recipients. In patients with ALF, no difference was seen between the 2 groups except for 5-year patient survival (OR, 0.60; 95% CI, 0.38-0.95), which favored LDLT. Sensitivity analysis by era showed improved survival in the most recent cohort of patients, consistent with the well-described learning curve for the LDLT technique. LDLT provides superior patient and graft survival outcomes relative to DDLT in pediatric patients with chronic liver failure and ALF. More resources may be needed to develop infrastructures and health care systems to support living liver donation., (© 2021 American Association for the Study of Liver Diseases.)

Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37-70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4-100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time.Prospero registration CRD42019094101., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To assess the sensitivity and specificity of automated movement recognition in predicting motor impairment in high-risk infants., Method: We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus databases and identified additional studies from the references of relevant studies. We included studies that evaluated automated movement recognition in high-risk infants to predict motor impairment, including cerebral palsy (CP) and non-CP motor impairments. Two authors independently assessed studies for inclusion, extracted data, and assessed methodological quality using the Quality Assessment of Diagnostic Accuracy Studies-2. Meta-analyses were performed using hierarchical summary receiver operating characteristic models., Results: Of 6536 articles, 13 articles assessing 59 movement variables in 1248 infants under 5 months corrected age were included. Of these, 143 infants had CP. The overall sensitivity and specificity for motor impairment were 0.73 (95% confidence interval [CI] 0.68-0.77) and 0.70 (95% CI 0.65-0.75) respectively. Comparatively, clinical General Movements Assessment (GMA) was found to have sensitivity and specificity of 98% (95% CI 74-100) and 91% (95% CI 83-93) respectively. Sensor-based technologies had higher specificity (0.88, 95% CI 0.80-0.93)., Interpretation: Automated movement recognition technology remains inferior to clinical GMA. The strength of this study is its meta-analysis to summarize performance, although generalizability of these results is limited by study heterogeneity., (© 2021 Mac Keith Press.)

Increasing rates of antimicrobial-resistant organisms have focused attention on sink drainage systems as reservoirs for hospital-acquired Gammaproteobacteria colonization and infection. We aimed to assess the quality of evidence for transmission from this reservoir. We searched 8 databases and identified 52 studies implicating sink drainage systems in acute care hospitals as a reservoir for Gammaproteobacterial colonization/infection. We used a causality tool to summarize the quality of evidence. Included studies provided evidence of co-occurrence of contaminated sink drainage systems and colonization/infection, temporal sequencing compatible with sink drainage reservoirs, some steps in potential causal pathways, and relatedness between bacteria from sink drainage systems and patients. Some studies provided convincing evidence of reduced risk of organism acquisition following interventions. No single study provided convincing evidence across all causality domains, and the attributable fraction of infections related to sink drainage systems remains unknown. These results may help to guide conduct and reporting in future studies., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Obesity is a known risk factor for stroke, but its impact on functional recovery is less clear. Understanding the effect of obesity on functional recovery during inpatient rehabilitation will aid clinicians in patient counselling and help administrators with program planning., Objective: To determine if obesity affects the functional outcomes of adults undergoing inpatient stroke rehabilitation., Methods: MEDLINE, Embase, CINAHL, and Cochrane databases were searched using the subject headings and text word terms for stroke, rehabilitation, and obesity. Two independent reviewers screened the articles against pre-defined eligibility criteria and extracted the data. Outcomes of interest included FIM, mRS, Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, and Barthel Index., Results: Seven studies from five countries with a total of 3070 participants were included. There was significant heterogeneity among the studies in the BMI cut-off points and functional outcome measures used. Two studies found a positive association between obesity and functional outcome, two studies found no association, and three studies reported a negative relationship., Conclusions: No conclusions could be drawn regarding whether the functional outcome of adults undergoing inpatient stroke rehabilitation differ between individuals with and without obesity.

Objectives: Metformin has been associated with improved survival outcomes in various malignancies. However, studies in kidney cancer are conflicting. We performed a systematic review and meta-analysis to evaluate the association between metformin and kidney cancer survival., Materials and Methods: We searched Medline and EMBASE databases from inception to June 2017 to identify studies evaluating the association between metformin use and kidney cancer survival outcomes. We evaluated risk of bias with the Newcastle-Ottawa scale. We pooled hazard ratios (HRs) for recurrence-free, progression-free, cancer-specific, and overall survival using random effects models, and explored heterogeneity with metaregression. We evaluated publication bias through Begg's and Egger's tests, and the trim and fill procedure., Results: We identified 9 studies meeting inclusion criteria, collectively involving 7426 patients. Five studies were at low risk of bias. The direction of association for metformin use was toward benefit for recurrence-free survival (HR, 0.99; 95% confidence interval [CI], 0.36-2.74), progression-free survival (pooled HR, 0.84; 95% CI, 0.66-1.07), cancer-specific (pooled HR, 0.72; 95% CI, 0.48-1.09), and overall survival (pooled HR, 0.73; 95% CI, 0.50-1.09), though none reached statistical significance. Metaregression found no study-level characteristic to be associated with the effect size, and there was no strong evidence of publication bias for any outcome., Conclusions: There is no evidence of a statistically significant association between metformin use and any survival outcome in kidney cancer. We discuss the potential for bias in chemoprevention studies and provide recommendations to reduce bias in future studies evaluating metformin in kidney cancer.

Rationale: Trials investigating use of lower tidal volumes and inspiratory pressures for patients with acute respiratory distress syndrome (ARDS) have shown mixed results., Objectives: To compare clinical outcomes of mechanical ventilation strategies that limit tidal volumes and inspiratory pressures (LTV) to strategies with tidal volumes of 10 to 15 ml/kg among patients with ARDS., Methods: This is a systematic review and meta-analysis of clinical trials investigating LTV mechanical ventilation strategies. We used random effects models to evaluate the effect of LTV on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation. Our primary analysis excluded trials for which the LTV strategy was combined with the additional strategy of higher positive end-expiratory pressure (PEEP), but these trials were included in a stratified sensitivity analysis. We performed metaregression of tidal volume gradient achieved between intervention and control groups on mortality effect estimates. We used Grading of Recommendations Assessment, Development, and Evaluation methodology to determine the quality of evidence., Results: Seven randomized trials involving 1,481 patients met eligibility criteria for this review. Mortality was not significantly lower for patients receiving an LTV strategy (33.6%) as compared with control strategies (40.4%) (relative risk [RR], 0.87; 95% confidence interval [CI], 0.70-1.08; heterogeneity statistic I 2  = 46%), nor did an LTV strategy significantly decrease barotrauma or ventilator-free days when compared with a lower PEEP strategy. Quality of evidence for clinical outcomes was downgraded for imprecision. Metaregression showed a significant inverse association between larger tidal volume gradient between LTV and control groups and log odds ratios for mortality (β, -0.1587; P = 0.0022). Sensitivity analysis including trials that protocolized an LTV/high PEEP cointervention showed lower mortality associated with LTV (nine trials and 1,629 patients; RR, 0.80; 95% CI, 0.66-0.98; I 2  = 46%). Compared with trials not using a high PEEP cointervention, trials using a strategy of LTV combined with high PEEP showed a greater mortality benefit (RR, 0.58; 95% CI, 0.41-0.82; P for interaction = 0.05)., Conclusions: The trend toward lower mortality with LTV ventilation in the primary analysis and the significant relationship between the degree of tidal volume reduction and the mortality effect together suggest, but do not prove, that LTV ventilation improves mortality among critically ill adults with ARDS.

Rationale: Higher positive end-expiratory pressure (PEEP) levels may reduce atelectrauma, but increase over-distention lung injury. Whether higher PEEP improves clinical outcomes among patients with acute respiratory distress syndrome (ARDS) is unclear., Objectives: To compare clinical outcomes of mechanical ventilation strategies using higher PEEP levels versus lower PEEP strategies in patients with ARDS., Methods: We performed a systematic review and meta-analysis of clinical trials investigating mechanical ventilation strategies using higher versus lower PEEP levels. We used random effects models to evaluate the effect of higher PEEP on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation., Results: We identified eight randomized trials comparing higher versus lower PEEP strategies, enrolling 2,728 patients with ARDS. Patients were 55 (±16) (mean ± SD) years old and 61% were men. Mean PEEP in the higher PEEP groups was 15.1 (±3.6) cm H 2 O as compared with 9.1 (±2.7) cm H 2 O in the lower PEEP groups. Primary analysis excluding two trials that did not use lower Vt ventilation in the lower PEEP control groups did not demonstrate significantly reduced mortality for patients receiving higher PEEP as compared with a lower PEEP (six trials; 2,580 patients; relative risk, 0.91; 95% confidence interval [CI] = 0.80-1.03). A higher PEEP strategy also did not significantly decrease barotrauma, new organ failure, or ventilator-free days when compared with a lower PEEP strategy (moderate-level evidence). Quality of evidence for primary analyses was downgraded for precision, as CIs of outcomes included estimates that would result in divergent recommendations for use of higher PEEP. Secondary analysis, including trials that did not use low Vt in low-PEEP control groups, showed significant mortality reduction for high-PEEP strategies (eight trials; 2,728 patients; relative risk, 0.84; 95% CI = 0.71-0.99), with greater mortality benefit observed for high PEEP in trials that did not use lower Vts in the low-PEEP control group (P = 0.02). Analyses stratifying by use of recruitment maneuvers (P for interaction = 0.69), or use of physiological targets to set PEEP versus PEEP/Fi O 2 tables (P for interaction = 0.13), did not show significant effect modification., Conclusions: Use of higher PEEP is unlikely to improve clinical outcomes among unselected patients with ARDS.

Rationale: The application of prone positioning for acute respiratory distress syndrome (ARDS) has evolved, with recent trials focusing on patients with more severe ARDS, and applying prone ventilation for more prolonged periods., Objectives: This review evaluates the effect of prone positioning on 28-day mortality (primary outcome) compared with conventional mechanical ventilation in the supine position for adults with ARDS., Methods: We updated the literature search from a systematic review published in 2010, searching MEDLINE, EMBASE, and CENTRAL (through to August 2016). We included randomized, controlled trials (RCTs) comparing prone to supine positioning in mechanically ventilated adults with ARDS, and conducted sensitivity analyses to explore the effects of duration of prone ventilation, concurrent lung-protective ventilation and ARDS severity. Secondary outcomes included Pa O 2 /Fi O 2 ratio on Day 4 and an evaluation of adverse events. Meta-analyses used random effects models. Methodologic quality of the RCTs was evaluated using the Cochrane risk of bias instrument, and methodologic quality of the overall body of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines., Results: Eight RCTs fulfilled entry criteria, and included 2,129 patients (1,093 [51%] proned). Meta-analysis revealed no difference in mortality (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.68-1.04), but subgroup analyses found lower mortality with 12 hours or greater duration prone (five trials; RR, 0.74; 95% CI, 0.56-0.99) and for patients with moderate to severe ARDS (five trials; RR, 0.74; 95% CI, 0.56-0.99). Pa O 2 /Fi O 2 ratio on Day 4 for all patients was significantly higher in the prone positioning group (mean difference, 23.5; 95% CI, 12.4-34.5). Prone positioning was associated with higher rates of endotracheal tube obstruction and pressure sores. Risk of bias was low across the trials., Conclusions: Prone positioning is likely to reduce mortality among patients with severe ARDS when applied for at least 12 hours daily.

Rationale: In patients with acute respiratory distress syndrome (ARDS), lung recruitment maneuvers (LRMs) may prevent ventilator-induced lung injury and improve survival., Objectives: To summarize the current evidence in support of the use of LRMs in adult patients with ARDS and to inform the recently published American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline on mechanical ventilation in ARDS., Methods: We conducted a systematic review and meta-analysis of randomized trials comparing mechanical ventilation strategies with and without LRMs. Eligible trials were identified from among previously published systematic reviews and an updated literature search. Data on 28-day mortality, oxygenation, adverse events, and use of rescue therapy were collected, and results were pooled using random effects models weighted by inverse variance. Strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology., Results: We screened 430 citations and previous systematic reviews and found six trials eligible for inclusion (n = 1,423 patients in total). The type of LRM varied widely between trials, and five of the trials involved a cointervention with a higher positive end-expiratory pressure (PEEP) ventilation strategy. Risk of bias was deemed high in one trial. In the primary analysis, the only trial without a cointervention showed that LRMs were associated with reduced mortality (one trial; risk ratio [RR], 0.62; 95% confidence interval [CI], 0.39-0.98; evidence grade = low). Meta-analysis of all six trials also suggested a significant mortality reduction (six trials; RR, 0.81; 95% CI, 0.69-0.95; evidence grade = moderate), and the use of a higher PEEP cointervention did not significantly modify the mortality effect (P = 0.27 for heterogeneity). LRMs were also associated with improved oxygenation after 24 hours (six trials; mean increase, 52 mm Hg; 95% CI, 23-81 mm Hg) and less frequent requirement for rescue therapy (three trials; RR, 0.65; 95% CI, 0.45-0.94). LRMs were not associated with an increased rate of barotrauma (four trials; RR, 0.84; 95% CI, 0.46-1.55). The rate of hemodynamic compromise was not significantly increased with LRMs (three trials; RR, 1.30; 95% CI, 0.92-1.78)., Conclusions: Randomized trials suggest that LRMs in combination with a higher PEEP ventilation strategy reduce mortality, but confidence in this finding is limited. Further trials are required to confirm benefit from LRMs in adults with ARDS.

Rationale: By minimizing tidal lung strain and maintaining alveolar recruitment, high-frequency oscillatory ventilation (HFOV) may protect against ventilator-induced lung injury., Objectives: To summarize the current evidence in support of the use of HFOV in adult patients with acute respiratory distress syndrome., Methods: We conducted a systematic review and meta-analysis of randomized trials comparing mortality rates with the use of HFOV versus conventional mechanical ventilation for adult patients with acute respiratory distress syndrome. Eligible trials were identified from previously published systematic reviews and an updated literature search. Data on 28-day mortality, oxygenation, adverse events, and use of rescue therapies were collected; effects were pooled using random effects models weighted by inverse variance. Strength of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology., Results: Six trials were eligible for inclusion (total n = 1,715 patients). Four trials mandated lung-protective ventilation in the control group and one trial applied a higher positive end-expiratory pressure (PEEP) ventilation strategy in the control group. None of the trials were judged to be at high risk of bias, though all were unblinded. In trials that did not systematically employ any cointerventions with HFOV and that targeted low tidal volumes in the patients randomized to conventional ventilation (primary analysis), HFOV had no significant effect on mortality (three trials; risk ratio [RR], 1.14; 95% confidence interval [CI], 0.88 to 1.48; evidence grade = high). Pooled analysis of all six trials also did not suggest a significant mortality reduction (RR, 0.94; 95% CI, 0.71 to 1.24; evidence grade = low). The single trial that employed a conventional ventilation strategy with both lower tidal volumes and higher PEEP as control reported higher mortality in patients receiving HFOV (RR, 1.41; 95% CI, 1.12 to 1.79). HFOV was not associated with improved oxygenation after 24 hours (five trials; mean increase of 10 mm Hg; 95% CI, -16 to 37 mm Hg). Rates of barotrauma were not different between HFOV and conventional ventilation, although significant benefit or harm could not be excluded (RR, 1.15; 95% CI, 0.61 to 2.17)., Conclusions: Published randomized trials suggest that HFOV is not associated with a mortality benefit, and may even be harmful in comparison to ventilation with low tidal volumes and higher levels of PEEP.

Background: This document provides evidence-based clinical practice guidelines on the use of mechanical ventilation in adult patients with acute respiratory distress syndrome (ARDS)., Methods: A multidisciplinary panel conducted systematic reviews and metaanalyses of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations., Results: For all patients with ARDS, the recommendation is strong for mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure < 30 cm H 2 O) (moderate confidence in effect estimates). For patients with severe ARDS, the recommendation is strong for prone positioning for more than 12 h/d (moderate confidence in effect estimates). For patients with moderate or severe ARDS, the recommendation is strong against routine use of high-frequency oscillatory ventilation (high confidence in effect estimates) and conditional for higher positive end-expiratory pressure (moderate confidence in effect estimates) and recruitment maneuvers (low confidence in effect estimates). Additional evidence is necessary to make a definitive recommendation for or against the use of extracorporeal membrane oxygenation in patients with severe ARDS., Conclusions: The panel formulated and provided the rationale for recommendations on selected ventilatory interventions for adult patients with ARDS. Clinicians managing patients with ARDS should personalize decisions for their patients, particularly regarding the conditional recommendations in this guideline.

Background: Statin use has been associated with improved survival outcomes in various malignancies. Randomized controlled trials are currently underway evaluating their utility as adjunctive cancer therapies. However, studies evaluating the association between statin use and outcomes in kidney cancer yield conflicting results., Methods: We searched MEDLINE and EMBASE to identify studies evaluating the association between statin use and kidney cancer survival outcomes. We evaluated risk of bias with the Newcastle-Ottawa Scale. We pooled hazard ratios for recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival using random-effects models. We evaluated publication bias through Begg's and Egger's tests, and the trim and fill procedure., Results: We identified 12 studies meeting inclusion criteria and summarized data from 18,105 patients. No study was considered to be at high risk of bias. Statin use was not significantly associated with recurrence-free survival (pooled HR 0.97, 95% CI 0.89-1.06) or progression-free survival (pooled HR 0.92, 95% CI 0.51-1.65); however, statin use was associated with marked improvements in cancer-specific survival (pooled HR 0.67, 95% CI 0.47-0.94) and overall survival (pooled HR 0.74, 95% CI 0.63-0.88). There was no strong evidence of publication bias for any outcome., Conclusions: Our results demonstrate that statin use among patients with kidney cancer is associated with significantly improved cancer-specific and overall survival. Further studies are needed to confirm the therapeutic role of statins in kidney cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This systematic review aims to identify existing social risk screening instruments applicable to hospitalized children (primary) and evaluate their content validity and methodological quality (secondary). Individual questions were abstracted and sorted by social risk theme. Content validity was evaluated by 13 hospital-based social workers. Methodological quality was assessed using the 108-item Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist. A total of 1070 citations were evaluated and 146 articles were reviewed, which identified 44 unique instruments. No instrument was applicable to social risk in hospitalized children. Sixty-one percent of instruments focused on a single social risk theme and only 18% of instruments covered more than 5 themes. The 2 instruments with the highest combination of social worker endorsement and COSMIN scores each addressed only 1 social risk theme relevant to hospitalized children. A broad, content valid and methodologically strong social risk screening instrument for hospitalized children was not identified.

Purpose: We identified studies that described use of any patient-reported outcome scale for hearing loss or tinnitus among children and adolescents and young adults (AYAs) with cancer or hematopoietic stem cell transplantation (HSCT) recipients., Method: In this systematic review, we performed electronic searches of OvidSP MEDLINE, EMBASE, and PsycINFO to August 2015. We included studies if they used any patient-reported scale of hearing loss or tinnitus among children and AYAs with cancer or HSCT recipients. Only English language publications were included. Two reviewers identified studies and abstracted data., Results: There were 953 studies screened; 6 met eligibility criteria. All studies administered hearing patient-reported outcomes only once, after therapy completion. None of the studies described the psychometric properties of the hearing-specific component. Three instruments (among 6 studies) were used: Health Utilities Index (Barr et al., 2000; Fu et al., 2006; Kennedy et al., 2014), Hearing Measurement Scales (Einar-Jon et al., 2011; Einarsson et al., 2011), and the Tinnitus Questionnaire for Auditory Brainstem Implant (Soussi & Otto, 1994). All had limitations, precluding routine use for hearing assessment in this population., Conclusions: We identified few studies that included hearing patient-reported measures for children and AYA cancer and HSCT patients. None are ideal to take forward into future studies. Future work should focus on the creation of a new psychometrically sound instrument for hearing outcomes in this population.

Aim: Thiopurine S-methyltransferase (TPMT) testing is used in patients receiving thiopurines to identify enzyme deficiencies and risk for adverse drug reactions. It is uncertain whether genotyping is superior to phenotyping. The objectives were to conduct a systematic review of TPMT-test performance studies., Materials & Methods: Electronic and grey literature sources were searched for studies reporting test performance compared with a reference standard. Sixty-six eligible studies were appraised for quality., Results: Thirty phenotype-genotype and six phenotype-phenotype comparisons were of high quality. The calculated sensitivity and specificity for genotyping to identify a homozygous mutation ranged from 0.0-100.0% and from 97.8-100.0%, respectively., Conclusion: Clinical decision-makers require high-quality evidence of clinical validity and clinical utility of TPMT genotyping to ensure appropriate use in patients.

Needle fear typically begins in childhood and represents an important health-related issue across the lifespan. Individuals who are highly fearful of needles frequently avoid health care. Although guidance exists for managing needle pain and fear during procedures, the most highly fearful may refuse or abstain from such procedures. The purpose of a clinical practice guideline (CPG) is to provide actionable instruction on the management of a particular health concern; this guidance emerges from a systematic process. Using evidence from a rigorous systematic review interpreted by an expert panel, this CPG provides recommendations on exposure-based interventions for high levels of needle fear in children and adults. The AGREE-II, GRADE, and Cochrane methodologies were used. Exposure-based interventions were included. The included evidence was very low quality on average. Strong recommendations include the following. In vivo (live/in person) exposure-based therapy is recommended (vs. no treatment) for children seven years and older and adults with high levels of needle fear. Non-in vivo (imaginal, computer-based) exposure (vs. no treatment) is recommended for individuals (over seven years of age) who are unwilling to undergo in vivo exposure. Although there were no included trials which examined children < 7 years, exposure-based interventions are discussed as good clinical practice. Implementation considerations are discussed and clinical tools are provided. Utilization of these recommended practices may lead to improved health outcomes due to better health care compliance. Research on the understanding and treatment of high levels of needle fear is urgently needed; specific recommendations are provided.

Background: The aim of this paper is twofold: (1) to describe the fundamental differences between formative and reflective measurement models, and (2) to review the options proposed in the literature to obtain overall instrument summary scores, with a particular focus on formative models., Methods: An extensive literature search was conducted using the following databases: MEDLINE, EMBASE, PsycINFO, CINAHL and ABI/INFORM, using "formative" and "reflective" as text words; relevant articles' reference lists were hand searched., Results: Reflective models are most frequently scored by means of simple summation, which is consistent with the theory underlying these models. However, our review suggests that formative models might be better summarized using weighted combinations of indicators, since each indicator captures unique features of the underlying construct. For this purpose, indicator weights have been obtained using choice-based, statistical, researcher-based, and combined approaches., Conclusion: Whereas simple summation is a theoretically justified scoring system for reflective measurement models, formative measures likely benefit from the use of weighted scores that preserve the contribution of each of the aspects of the construct.

Background: A knowledge synthesis was undertaken to inform the development of a revised and expanded clinical practice guideline about managing vaccination pain in children to include the management of pain across the lifespan and the management of fear in individuals with high levels of needle fear. This manuscript describes the methodological details of the knowledge synthesis and presents the list of included clinical questions, critical and important outcomes, search strategy, and search strategy results., Methods: The Grading of Assessments, Recommendations, Development and Evaluation (GRADE) and Cochrane methodologies provided the general framework. The project team voted on clinical questions for inclusion and critically important and important outcomes. A broad search strategy was used to identify relevant randomized-controlled trials and quasi-randomized-controlled trials. Quality of research evidence was assessed using the Cochrane risk of bias tool and quality across studies was assessed using GRADE. Multiple measures of the same construct within studies (eg, observer-rated and parent-rated infant distress) were combined before pooling. The standardized mean difference and 95% confidence intervals (CI) or relative risk and 95% CI was used to express the effects of an intervention., Results: Altogether, 55 clinical questions were selected for inclusion in the knowledge synthesis; 49 pertained to pain management during vaccine injections and 6 pertained to fear management in individuals with high levels of needle fear. Pain, fear, and distress were typically prioritized as critically important outcomes across clinical questions. The search strategy identified 136 relevant studies., Conclusions: This manuscript describes the methodological details of a knowledge synthesis about pain management during vaccination and fear management in individuals with high levels of needle fear. Subsequent manuscripts in this series will present the results for the included questions.