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Rationale: Existing work suggests that patients with chronic obstructive pulmonary disease (pwCOPD) presented less frequently to the emergency department and were less likely to be hospitalized during the coronavirus disease (COVID-19) pandemic, but it is unclear if this was due to improved health and disease management or to increased barriers and/or avoidance of health care. Objectives: The objective of this study was to determine the impact of the pandemic on inpatient and outpatient healthcare use, disease incidence, and mortality rates in pwCOPD. Methods: A retrospective population-based analysis using linked administrative datasets from Alberta, Canada 18 months before and after March 12, 2020 was conducted to measure hospitalization, emergency department and outpatient visits, and COPD outpatient exacerbations during these time periods. Mortality data were also analyzed before versus after the pandemic, taking confirmed COVID-19 infection within 30 days into account. Subgroup analysis based on COPD exacerbation risk stratification was undertaken to determine if healthcare use differed based on exacerbation risk. Finally, sex-based analysis of healthcare use during the pandemic was also completed. Results: Hospitalization or emergency department visits and outpatient treatment for acute exacerbations of COPD dropped, whereas total outpatient COPD visits, including both virtual and in person, increased during the pandemic for pwCOPD. The mortality rate increased even after adjusting for COVID-19-associated deaths. Sex-based subgroup analysis showed a greater drop in acute care use for females, but the rise in mortality was seen for both sexes, with men experiencing a greater rate of mortality than women. Conclusions: Overall, pwCOPD accessed acute care resources less during the pandemic, which may have contributed to a rise in non-COVID-19 all-cause mortality.

Rationale & Objective: Formalized peer support is a promising approach for addressing the emotional and practical needs of people living with chronic kidney disease (CKD). We aimed to systematically identify and summarize peer support interventions studied in individuals with CKD with or without kidney replacement therapy (KRT)., Sources of Evidence: We searched electronic databases and grey literature sources in March 2023., Eligibility Criteria: Studies of any design were eligible if they reported sufficient detail on peer support interventions and outcomes for adults with CKD with or without KRT and/or their caregivers., Charting Methods: We extracted information on study and intervention characteristics and reported outcomes using established frameworks. We summarized quantitative data descriptively and qualitative data thematically. Our approach observed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews., Results: We included 77 studies describing 56 unique peer support interventions. Most reports were program evaluations (39%) or randomized controlled trials (27%) published after 2013. Two thirds of interventions focused on in-centre hemodialysis or mixed CKD populations, and three quarters were integrated within a kidney care clinic or program. Whereas most peer interactions centered on informational support, few programs offered focused support in areas such as transplant navigation or dialysis modality selection. Only one third of outcomes were assessed against a comparator group, with results suggesting improvements in psychological health with peer support., Limitations: Heterogeneity of included studies; lack of rigorous program evaluation., Conclusions: This review suggests recent growth in peer support programming with a variety of formats and delivery methods to address the diverse needs of people living with kidney disease. Notable gaps in peer support availability for transplant and home dialysis recipients and the lack of rigorous evaluations present opportunities to expand the reach and impact of peer support in the kidney care context., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: In Canada, regional evaluations of screening practices for chronic kidney disease (CKD) among people with diabetes highlight areas for improvement; however, national estimates are notably absent. Estimates of CKD incidence often discount the expected decline in estimated glomerular filtration rate (eGFR) associated with age; age-adaptive thresholds may help account for this. We describe the frequency of screening and diagnosis of CKD among adults with diabetes from a nationally representative primary care cohort., Methods: In this retrospective cohort study, we used electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network. We followed adult patients (≥18 years of age) with diabetes without CKD at baseline for 5 years starting in 2014. We determined the frequency of urine albumin-to-creatinine ratio (uACr) and/or eGFR testing over time. We identified incident CKD diagnoses based on eGFR measurements using fixed-threshold and age-adaptive definitions and quantified the incidence proportion and rate., Results: We analyzed records from 37,604 patients with diabetes. Only 13% of patients had yearly eGFR and uACr testing for CKD, although roughly 60% had non-yearly use of both tests in 5 years. eGFR testing was performed more frequently than uACr testing (94.1% vs 76.6% having testing over follow-up). We found increased incidence proportions (14.6% vs 6.0%) and rates (33.1 vs 13.4 diagnoses per 1,000 person years) of CKD using the fixed-threshold compared with age-adaptive definition., Conclusions: Our study presents the first national understanding of screening practices for CKD among people with diabetes in Canada. Specifically, increased use of uACr testing should be encouraged for early detection of changes in kidney function., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gender-affirming estrogen therapy (GAET) is commonly used for feminization in transgender and nonbinary (TNB) individuals, yet the optimal rate of change (ROC) in estradiol levels for cardiovascular health is unclear. We examined the association between serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were systematically searched (inception-April 2023) for original articles reporting serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Data extraction was completed in duplicate following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Stratified random effect meta-analyses using serum estradiol ROC (serum estradiol baseline - serum estradiol follow-up /study duration) was used to assess longitudinal studies (low, 0 < ROC ≤ 1 pg/mL/mo; moderate, 1 < ROC ≤ 3 pg/mL/mo; high, ROC ≥ 3 pg/mL/mo). Thirty-five studies (13 cross-sectional, 19 cohort, and 3 trials) were included. Two studies collectively reported 50 cardiovascular-related deaths, and four collectively reported 23 adverse cardiovascular events. Nineteen studies reporting cardiovascular risk factors were meta-analyzed by ROC stratum (low = 5; moderate = 6; high = 8), demonstrating an association between moderate [0.40, 95% confidence interval (CI): 0.22, 0.59 kg/m 2 , I 2 = 28.2%] and high (0.46, 95% CI: 0.15, 0.78 kg/m 2 ; I 2 = 0.0%) serum estradiol ROC and increased body mass index. High (-6.67, 95% CI: -10.65, -2.68 mg/dL; I 2 = 0.0%) serum estradiol ROC was associated with decreased low-density lipoproteins. Low (-7.05, 95% CI: -10.40, -3.70 mmHg; I 2 = 0.0%) and moderate (-3.69, 95% CI: -4.93, -2.45 mmHg; I 2 = 0.0%) serum estradiol ROCs were associated with decreases in systolic blood pressure. In TNB adults using GAET, serum estradiol ROC may influence cardiovascular risk factors, which may have implications for clinical cardiovascular outcomes. NEW & NOTEWORTHY In this systematic review and meta-analysis of 35 studies involving 7,745 participants, high rates of serum estradiol change were associated with small increases in body mass index. Moderate to high rates of change were associated with decreases in low-density lipoprotein. Low rates of change were associated with small decreases in systolic blood pressure. Rate of serum estradiol change in adults using gender-affirming estrogen therapy may influence cardiovascular risk factors, though further research is warranted.

Aims: To compare processes of diabetes care by homeless status., Methods: A population-based propensity matched cohort study was conducted in Ontario, Canada. People with diabetes were identified in administrative healthcare data between April 2006 and March 2019. Those with a documented history of homelessness were matched to non-homeless controls. Data on processes of care measures included glucose monitoring tests, screening for microvascular complications, and physician follow-up. Differences in processes of care were compared by homeless status using proportions, risk ratios, and rate ratios., Results: Of the 1,076,437 people with diabetes, 5219 matched pairs were identified. Homelessness was associated with fewer tests for glycated hemoglobin (RR = 0.63; 95 %CI: 0.60-0.67), LDL cholesterol (RR = 0.80; 95 %CI: 0.78-0.82), serum creatinine (RR = 0.94; 95 %CI: 0.92-0.97), urine protein quantification (RR = 0.62; 95 %CI: 0.59-0.66), and eye examinations (RR = 0.74; 95 %CI: 0.71-0.77). People with a history of homelessness were less likely to use primary care for diabetes management (RR = 0.62; 95 %CI: 0.59-0.66) or specialist care (RR = 0.87; 95 %CI: 0.83-0.91) compared to non-homeless controls., Conclusions: Disparities in diabetes care are evident for people with a history of homelessness and contribute to excess morbidity in this population. These data provide an impetus for investment in tailored interventions to improve healthcare equity and prevent long-term complications., 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., (Copyright © 2024. Published by Elsevier B.V.)

Importance: People with kidney failure receiving maintenance dialysis visit the emergency department (ED) 3 times per year on average, which is 3- to 8-fold more often than the general population. Little is known about the factors that contribute to potentially preventable ED use in this population., Objective: To identify the clinical and sociodemographic factors associated with potentially preventable ED use among patients receiving maintenance dialysis., Design, Setting, and Participants: This cohort study used linked administrative health data within the Alberta Kidney Disease Network to identify adults aged 18 years or older receiving maintenance dialysis (ie, hemodialysis or peritoneal dialysis) between April 1, 2010, and March 31, 2019. Patients who had been receiving dialysis for more than 90 days were followed up from cohort entry (defined as dialysis start date plus 90 days) until death, outmigration from the province, receipt of a kidney transplant, or end of study follow-up. The Andersen behavioral model of health services was used as a conceptual framework to identify variables related to health care need, predisposing factors, and enabling factors. Data were analyzed in March 2024., Main Outcomes and Measures: Rates of all-cause ED encounters and potentially preventable ED use associated with 4 kidney disease-specific ambulatory care-sensitive conditions (hyperkalemia, heart failure, volume overload, and malignant hypertension) were calculated. Multivariable negative binomial regression models were used to examine the association between clinical and sociodemographic factors and rates of potentially preventable ED use., Results: The cohort included 4925 adults (mean [SD] age, 60.8 [15.5] years; 3071 males [62.4%]) with kidney failure receiving maintenance hemodialysis (3183 patients) or peritoneal dialysis (1742 patients) who were followed up for a mean (SD) of 2.5 (2.0) years. In all, 3877 patients had 34 029 all-cause ED encounters (3100 [95% CI, 2996-3206] encounters per 1000 person-years). Of these, 755 patients (19.5%) had 1351 potentially preventable ED encounters (114 [95% CI, 105-124] encounters per 1000 person-years). Compared with patients with a nonpreventable ED encounter, patients with a potentially preventable ED encounter were more likely to be in the lowest income quintile (38.8% vs 30.9%; P < .001); to experience heart failure (46.8% vs 39.9%; P = .001), depression (36.6% vs 32.5%; P = .03), and chronic pain (60.1% vs 54.9%; P = .01); and to have a longer duration of dialysis (3.6 vs 2.6 years; P < .001). In multivariable regression analyses, potentially preventable ED use was higher for younger adults (incidence rate ratio [IRR], 1.69 [95% CI, 1.33-2.15] for those aged 18 to 44 years) and patients with chronic pain (IRR, 1.35 [95% CI, 1.14-1.61]), greater material deprivation (IRR, 1.57 [95% CI, 1.16-2.12]), a history of hyperkalemia (IRR, 1.31 [95% CI, 1.09-1.58]), and historically high ED use (ie, ≥3 ED encounters in the prior year; IRR, 1.46 [95% CI, 1.23-1.73)., Conclusions and Relevance: In this study of adults receiving maintenance dialysis in Alberta, Canada, among those with ED use, 1 in 5 had a potentially preventable ED encounter; reasons for such encounters were associated with both psychosocial and medical factors. The findings underscore the need for strategies that address social determinants of health to avert potentially preventable ED use in this population.

Rationale & Objective: Clinical guidelines define chronic kidney disease (CKD) as abnormalities of kidney structure or function for>3 months. Assessment of the duration criterion may be implemented in different ways, potentially impacting estimates of disease incidence or prevalence in the population, individual diagnosis, and treatment decisions, especially for more severe cases. We investigated differences in incidence and prognosis of CKD stage G4 identified by 1 of 4 algorithms., Study Design: Population-based cohort study in Alberta, Canada., Setting & Participants: Residents>18 years old with incident CKD stage G4 (eGFR 15-29mL/min/1.73m 2 ) diagnosed between April 1, 2015, and March 31, 2018, based on administrative and laboratory data., Exposure: Four outpatient eGFR-based algorithms, increasing in stringency, for defining cohorts with CKD G4 were evaluated: (1) a single test, (2) first eGFR<30mL/min/1.73m 2 and a second eGFR 15-29mL/min/1.73m 2 measured>90 days apart (2 tests), (3) ≥2 eGFR measurements of<30mL/min/1.73m 2 sustained for>90 days (qualifying period) and the last eGFR in the qualifying period of 15-29mL/min/1.73m 2 (relaxed sustained), and (4) ≥2 consecutive measurements of 15-29mL/min/1.73m 2 for>90 days (rigorous sustained)., Outcome: Time to the earliest of death, eGFR improvement (a sustained increase in eGFR to≥30mL/min/1.73m 2 for>90 days and>25% increase from the index eGFR), or kidney failure., Analytical Approach: For each of the 4 cohorts, incidence rates and event-specific cumulative incidence functions at 1 year from cohort entry were estimated., Results: The incidence rates of CKD G4 decreased as algorithms became more stringent, from 190.7 (single test) to 79.9 (rigorous sustained) per 100,000 person-years. The 2 cohorts based on sustained reductions in eGFR were of comparable size and 1-year event-specific probabilities. The 2 cohorts based on a single test and a 2-test sequence were larger and experienced higher probabilities of eGFR improvement., Limitations: A short follow-up period of 1 year and a predominantly White population., Conclusions: The use of more stringent algorithms for defining CKD G4 results in substantially lower estimates of disease incidence, the identification of a group with a lower probability of eGFR improvement, and a higher risk of kidney failure. These findings can inform implementation decisions of disease definitions in clinical reporting systems and research studies., Plain-Language Summary: Although guidelines recommend>3 months to define chronic kidney disease (CKD), the methods for defining specific stages, particularly G4 (eGFR 15-29mL/min/1.73m 2 ) when referral to nephrology services is recommended, have been implemented differently across studies and surveillance programs. We studied differences in incidence and prognosis of CKD G4 cohorts identified by 4 algorithms using administrative and outpatient laboratory databases in Alberta, Canada. We found that, compared with a single-test definition, more stringent definitions resulted in a lower disease incidence and identified a group with worse short-term kidney outcomes. These findings highlight the impact of the choice of algorithm used to define CKD G4 on disease burden estimates at the population level, on individual prognosis, and on treatment/referral decisions., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Continuity of care is broadly associated with better patient health outcomes. The relative contributions of continuity with an individual physician and with a practice, however, have not generally been distinguished. This retrospective observational study examined the impact of continuity of care for patients seen at their main clinic but by different family physicians., Methods: We analyzed linked health administrative data from 2015-2018 from Alberta, Canada to explore the association of physician and clinic continuity with rates of emergency department (ED) visits and hospitalizations across varying levels of patient complexity. Physician continuity was calculated using the known provider of care index and clinic continuity with an analogous measure. We developed zero-inflated negative binomial models to assess the association of each with all-cause ED visits and hospitalizations., Results: High physician continuity was associated with lower ED use across all levels of patient complexity and with fewer hospitalizations for highly complex patients. Broadly, no (0%) clinic continuity was associated with increased use and complete (100%) clinic continuity with decreased use, with the largest effect seen for the most complex patients. Levels of clinic continuity between 1% and 50% were generally associated with slightly higher use, and levels of 51% to 99% with slightly lower use., Conclusions: The best health care outcomes (measured by ED visits and hospitalizations) are associated with consistently seeing one's own primary family physician or seeing a clinic partner when that physician is unavailable. The effect of partial clinic continuity appears complex and requires additional research. These results provide some reassurance for part-time and shared practices, and guidance for primary care workforce policy makers., (© 2024 Annals of Family Medicine, Inc.)

Delayed graft function (DGF) is a common post-operative complication with potential long-term sequelae for many kidney transplant recipients, and hemodynamic factors and fluid status play a role. Fixed perioperative fluid infusions are the standard of care, but more recent evidence in the non-transplant population has suggested benefit with goal-directed fluid strategies based on hemodynamic targets. We searched MEDLINE, EMBASE, Cochrane Controlled Trials Registry and Google Scholar through December 2022 for randomized controlled trials comparing risk of DGF between goal-directed and conventional fluid therapy in adults receiving a living or deceased donor kidney transplant. Effect estimates were reported with odds ratios (OR) and pooled using random effects meta-analysis. We identified 4 studies (205 participants) that met the inclusion criteria. The use of goal-directed fluid therapy had no significant effect on DGF (OR 1.37 95% CI, 0.34-5.6; p = 0.52; I 2  = 0.11). Subgroup analysis examining effects among deceased and living kidney donation did not reveal significant differences in the effects of fluid strategy on DGF between subgroups. Overall, the strength of the evidence for goal-directed versus conventional fluid therapy to reduce DGF was of low certainty. Our findings highlight the need for larger trials to determine the effect of goal-directed fluid therapy on this patient-centered outcome., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the Transplantation Reviews., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The risk of venous thromboembolism (VTE) is increased postpartum and contributes to important morbidity and mortality. While there have been advances in evaluating diagnostic algorithms for suspected VTE during pregnancy, there is limited data for postpartum individuals., Objective: We conducted a scoping review to describe and evaluate diagnostic strategies used to investigate suspected VTE in postpartum individuals., Methods: A comprehensive search strategy was conducted in Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (January 1, 2000-September 30, 2022) to identify original articles that reported on diagnostic strategies in postpartum individuals with suspected VTE. We extracted demographics, clinical decision rules used, D-dimer and imaging completed, including test performance and VTE outcomes., Results: A total of 13 studies conducted across 11 countries with separate postpartum data were included for 759 individuals with suspected PE (n = 634) or DVT (n = 125), including unpublished data (n = 251). Among those with suspected PE, computed tomography pulmonary angiography was conducted more commonly (n = 522) than ventilation-perfusion scans (n = 69), with PE positivity rates that ranged from 4 %-27.6 % and 0-50 % across studies, respectively. Among 131 postpartum individuals with suspected PE who had a D-dimer measured, only 4.6 % (6/131) had a negative D-dimer test. For postpartum individuals with suspected DVT, the most common diagnostic test was compression ultrasonography (positivity rate 12.2 %-18.6 %). There were limited retrospective data evaluating the clinical decision rules., Conclusions: There are heterogeneous approaches globally in the diagnosis of suspected postpartum VTE. Limited high-quality data available underscores the need for more robust evidence to inform clinical practice., Competing Interests: Declaration of competing interest Dr. Skeith holds unrelated research funding from CSL Behring and honoraria from Leo Pharma and Sanofi. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: Canadian guidelines recommend metformin as first-line therapy for incident uncomplicated type 2 diabetes and the vast majority of patients are treated accordingly. However, only 54% 65% remain on treatment after 1 year, with the highest discontinuation rates within the first 3 months. The purpose of this study was: (a) to identify individual and clinical factors associated with metformin discontinuation among patients with newly diagnosed uncomplicated type 2 diabetes in Alberta, Canada, and (b) describe glycated haemoglobin (HbA1c) trajectories in the first 12 months after initiation of pharmacotherapy, stratified by metformin usage pattern., Materials and Methods: We conducted a retrospective cohort study using linked administrative datasets from 2012 to 2017 to define a cohort of individuals with uncomplicated incident type 2 diabetes. Using logistic regression, we determined individual and clinical characteristics associated with metformin discontinuation. We categorized individuals based on patterns of metformin use and then used mean HbA1c measurements over a 12-month follow-up period to determine glycaemic trajectories for each pattern., Results: Characteristics associated with metformin discontinuation were younger age, lower baseline HbA1c and having fewer comorbidities. Sex, income and location (urban/rural) were not significantly associated with metformin discontinuation. Individuals who continued metformin with higher adherence and individuals who discontinued metformin entirely had lowest HbA1c values at 12 months from treatment initiation. Those who changed therapy or had additional therapies added had higher HbA1c values at 12 months., Conclusion: Identifying characteristics associated with discontinuation of metformin and individuals' medication usage patterns provide an opportunity for targeted interventions to support patients' glycaemic management., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: The objective of this study was to explore the longitudinal relationship between anxiety and depressive symptoms and migraine outcomes in children and adolescents., Background: Children and adolescents with migraine experience more anxiety and depressive symptoms than their peers without migraine, but it is unknown if these symptoms are associated with differential migraine outcomes., Methods: In this prospective clinical cohort study, children and adolescents aged 8.0-18.0 years with migraine completed headache questionnaires and validated measures of anxiety and depressive symptoms (Patient-Reported Outcomes Measurement Information System) at an initial consultation and at their first follow-up visit with a neurologist. Changes in monthly headache frequency and changes in migraine-related disability (Pediatric Migraine Disability Assessment) were tracked at each time point. The relationships between these migraine outcomes and anxiety and depressive symptoms were estimated using models controlling for sex, age, headache frequency, and treatment type., Results: There were 123 consenting participants. In models adjusted for age, sex, baseline disability score, and treatment type, baseline anxiety and depressive symptom levels were not significantly associated with change in headache frequency (for anxiety symptoms: β = -0.05, 95% confidence interval [CI] = -0.268 to 0.166, p = 0.639; for depressive symptoms: β = 0.14, 95% CI = -0.079 to 0.359, p = 0.209). Similarly, in models adjusted for age, sex, baseline headache frequency, and treatment type, the change in disability was not associated with baseline anxiety (β = -0.45, 95% CI = -1.69 to 0.78, p = 0.470), nor with baseline depressive symptom scores (β = 0.16, 95% CI = -1.07 to 1.40, p = 0.796). In post hoc exploratory analyses (N = 84 with anxiety and N = 82 with depressive symptom data at both visits), there were also no significant associations between change in mental health symptoms and change in headache frequency (for anxiety symptoms: β = -0.084, 95% CI = -0.246 to 0.078, p = 0.306; for depressive symptoms: β = -0.013, 95% CI = -0.164 to 0.138, p = 0.865). Similarly, the change in disability scores between visits was not related to the change in anxiety (β = 0.85, 95% CI = -0.095 to 1.78, p = 0.077) nor depressive symptom scores (β = 0.32, 95% CI = -0.51 to 1.15, p = 0.446)., Conclusion: Baseline anxiety and depressive symptom levels were not associated with longitudinal migraine outcomes and neither were longitudinal changes in anxiety and depressive symptom levels; this contradicts popular clinical belief that mental health symptoms predict or consistently change in tandem with migraine outcomes., (© 2024 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: There are no consensus definitions for evaluating kidney function recovery after acute kidney injury (AKI) and acute kidney disease (AKD), nor is it clear how recovery varies across populations and clinical subsets. We present a federated analysis of four population-based cohorts from Canada, Denmark and Scotland, 2011-18., Methods: We identified incident AKD defined by serum creatinine changes within 48 h, 7 days and 90 days based on KDIGO AKI and AKD criteria. Separately, we applied changes up to 365 days to address widely used e-alert implementations that extend beyond the KDIGO AKI and AKD timeframes. Kidney recovery was based on resolution of AKD and a subsequent creatinine measurement below 1.2× baseline. We evaluated transitions between non-recovery, recovery and death up to 1 year; within age, sex and comorbidity subgroups; between subset AKD definitions; and across cohorts., Results: There were 464 868 incident cases, median age 67-75 years. At 1 year, results were consistent across cohorts, with pooled mortalities for creatinine changes within 48 h, 7 days, 90 days and 365 days (and 95% confidence interval) of 40% (34%-45%), 40% (34%-46%), 37% (31%-42%) and 22% (16%-29%) respectively, and non-recovery of kidney function of 19% (15%-23%), 30% (24%-35%), 25% (21%-29%) and 37% (30%-43%), respectively. Recovery by 14 and 90 days was frequently not sustained at 1 year. Older males and those with heart failure or cancer were more likely to die than to experience sustained non-recovery, whereas the converse was true for younger females and those with diabetes., Conclusion: Consistently across multiple cohorts, based on 1-year mortality and non-recovery, KDIGO AKD (up to 90 days) is at least prognostically similar to KDIGO AKI (7 days), and covers more people. Outcomes associated with AKD vary by age, sex and comorbidities such that older males are more likely to die, and younger females are less likely to recover., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Context: Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, but the comparative outcomes of targeted treatment remain unclear., Objective: To compare the clinical outcomes in patients treated for primary aldosteronism over time., Methods: Medline and EMBASE were searched. Original studies reporting the incidence of mortality, major adverse cardiovascular outcomes (MACE), progression to chronic kidney disease, or diabetes following adrenalectomy vs medical therapy were selected. Two reviewers independently abstracted data and assessed study quality. Standard meta-analyses were conducted using random-effects models to estimate relative differences. Time to benefit meta-analyses were conducted by fitting Weibull survival curves to estimate absolute risk differences and pooled using random-effects models., Results: 15 541 patients (16 studies) with PA were included. Surgery was consistently associated with an overall lower risk of death (hazard ratio [HR] 0.34, 95% CI 0.22-0.54) and MACE (HR 0.55, 95% CI 0.36-0.84) compared with medical therapy. Surgery was associated with a significantly lower risk of hospitalization for heart failure (HR 0.48 95% CI 0.34-0.70) and progression to chronic kidney disease (HR 0.62 95% CI 0.39-0.98), and nonsignificant reductions in myocardial infarction and stroke. In absolute terms, 200 patients would need to be treated with surgery instead of medical therapy to prevent 1 death after 12.3 (95% CI 3.1-48.7) months., Conclusion: Surgery is associated with lower all-cause mortality and MACE than medical therapy for PA. For most patients, the long-term surgical benefits outweigh the short-term perioperative risks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Pediatric hand fractures are common and routinely referred to surgeons, yet most heal well without surgical intervention. This trend inspired the development of the Calgary Kids' Hand Rule (CKHR), a clinical prediction rule designed to predict "complex" fractures that require surgical referral. The CKHR was adapted into a checklist whereby the presence of any 1 of 6 clinically or radiologically identifiable fracture characteristics predicts a complex fracture. The aim of this study was to assess the accuracy of the CKHR in a prospective sample of children with hand fractures. Methods: Physicians were asked to complete the CKHR checklist when referring pediatric patients (< 18 years) to hand surgeons at a Canadian pediatric hospital (April 2019-September 2020). Completed checklists represented predicted outcomes and were compared to observed outcomes (determined via chart review). Predictive accuracy (primary outcome) was evaluated based on sensitivity and specificity. Secondary outcomes were interrater reliability between referring physicians and surgeons, and survey assessment of CKHR user satisfaction. Results: In total 365 fractures were included, with only 16 requiring surgical intervention. Overall performance of the CKHR was good with 84% sensitivity and 71% specificity. Percent agreement between referring physicians and surgeons ranged from 84.1% to 96.3% on individual predictors, with 78.1% agreement on the presence of any predictors. Survey results showed general user satisfaction but also identified areas for improvement. Conclusion: This study posits the CKHR as an accurate and clinically useful prediction rule and highlights the importance of education for its effective use and eventual scale and spread., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2022 The Author(s).)

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure and death in patients with chronic kidney disease (CKD) but are underused. We evaluated the number of patients with CKD in Australia that would be eligible for treatment and estimated the number of cardiorenal and kidney failure events that could be averted with improved uptake of SGLT2 inhibitors., Methods: This cross-sectional observational study leveraged nationally representative primary care data from 392 Australian general practices (MedicineInsight) between 1 January 2020 and 31 December 2021. We identified patients that would have met inclusion criteria of key SGLT2 inhibitor trials and applied these data to age and sex-stratified estimates of CKD prevalence for the Australian population (using national census data), estimating the number of preventable events using trial event rates. Key outcomes included cardiorenal events (CKD progression, kidney failure, or death due to cardiovascular or kidney disease) and kidney failure., Findings: In MedicineInsight, 44.2% of adults with CKD would have met CKD eligibility criteria for an SGLT2 inhibitor; baseline use was 4.1%. Applying these data to the Australian population, 230,246 patients with CKD would have been eligible for treatment with an SGLT2 inhibitor. Optimal implementation of SGLT2 inhibitors (75% uptake) could reduce cardiorenal and kidney failure events annually in Australia by 3644 (95% CI 3526-3764) and 1312 (95% CI 1242-1385), respectively., Interpretation: Improved uptake of SGLT2 inhibitors for patients with CKD in Australia has the potential to prevent large numbers of patients experiencing CKD progression or dying due to cardiovascular or kidney disease. Identifying strategies to increase the uptake of SGLT2 inhibitors is critical to realising the population-level benefits of this drug class., Funding: University of New South Wales Scientia Program and Boehringer IngelheimEli Lilly Alliance., Competing Interests: The Renal Division of The George Institute for Global Health has received sponsorship funding provided by Boehringer Ingelheim and Eli Lilly Alliance, and is supported by the University of New South Wales Scientia Program. The design, analysis, interpretation or writing of this manuscript was performed independent of all funding bodies. All study authors assumed final responsibility for all aspects of the study, including the decision to submit the manuscript for publication. BLN has received fees for travel support, advisory boards, scientific presentations and steering committee roles from AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Janssen, and Medscape with all honoraria paid to The George Institute for Global Health. He serves as Secretariat of the SGLT2 Meta-Analysis Cardio-Renal Trialists Consortium and is a member of the Caring for Australians and New Zealanders with Kidney Impairment (CARI) living guidelines on SGLT2 inhibitors. MJ is responsible for research projects that have received unrestricted research funding from Boehringer Ingelheim and Eli Lilly Alliance. SK has received consultancy fees from Chinook and Dimerix Pharmaceuticals. This study was supported by an unrestricted research grant from Boehringer Ingelheim. SVB has served on advisory board of Bayer, AstraZeneca, GSK and Vifor Pharma; received speakers fees from Bayer, AstraZeneca, Pfizer and Vifor Pharma, and non-financial research support from Bayer with all fees paid to his institution. MJJ is supported by an NHMRC Investigator Grant; is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and MSD; has received fees for Advisory, Steering Committee and/or Scientific Presentations from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, MSD, Occuryx, Roche and Vifor; with any consultancy, honoraria or travel support paid to her institution. VP has received fees for advisory boards, steering committee roles, or scientific presentations from AbbVie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Tricida, and Vitae. MW has received consultancy fees from Amgen and Freeline., (© 2023 The Author(s).)

Background: Early interventions in CKD have been shown to improve health outcomes; however, gaps in access to nephrology care remain common. Nurse practitioners can improve access to care; however, the quality and outcomes of nurse practitioner care for CKD are uncertain., Methods: In this propensity score-matched cohort study, patients with CKD meeting criteria for nurse practitioner care were matched 1:1 on their propensity scores for ( 1 ) nurse practitioner care versus primary care alone and ( 2 ) nurse practitioner versus nephrologist care. Processes of care were measured within 1 year after cohort entry, and clinical outcomes were measured over 5 years of follow-up and compared between propensity score-matched groups., Results: A total of 961 (99%) patients from the nurse practitioner clinic were matched on their propensity score to 961 (1%) patients receiving primary care only while 969 (100%) patients from the nurse practitioner clinic were matched to 969 (7%) patients receiving nephrologist care. After matching to patients receiving primary care alone, those receiving nurse practitioner care had greater use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (82% versus 79%; absolute differences [ADs] 3.4% [95% confidence interval, 0.0% to 6.9%]) and statins (75% versus 66%; AD 9.7% [5.8% to 13.6%]), fewer prescriptions of nonsteroidal anti-inflammatory drugs (10% versus 17%; AD -7.2% [-10.4% to -4.2%]), greater eGFR and albuminuria monitoring, and lower rates of all-cause hospitalization (34.1 versus 43.3; rate difference -9.2 [-14.7 to -3.8] per 100 person-years) and all-cause mortality (3.3 versus 6.0; rate difference -2.7 [-3.6 to -1.7] per 100 person-years). When matched to patients receiving nephrologist care, those receiving nurse practitioner care were also more likely to be prescribed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and statins, with no difference in the risks of experiencing adverse clinical outcomes., Conclusions: Nurse practitioner care for patients with CKD was associated with better guideline-concordant care than primary care alone or nephrologist care, with clinical outcomes that were better than or equivalent to primary care alone and similar to those with care by nephrologists., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;12&#95;08&#95;CJN0000000000000305.mp3., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Introduction: The prevalence of chronic kidney disease (CKD) in Australia varies substantially across reports. Using a large, nationally representative general practice data source, we determined the contemporary prevalence and staging of CKD in the Australian primary care., Methods: We performed a retrospective, community-based observational study of 2,720,529 adults with ≥1 visit to a general practice participating in the MedicineInsight program and ≥1 serum creatinine measurement (with or without a urine albumin-to-creatinine ratio [UACR] measurement) between 2011 and 2020. CKD prevalence was estimated using 3 definitions based on estimated glomerular filtration rate (eGFR) and UACR measurements with varying degrees of rigidity in terms of the number of measurements assessed to define CKD ("least", "moderate" and "most" rigid)., Results: CKD prevalence in the cohort progressively increased over the 10-year study period, irrespective of the method used to define CKD. In 2020, CKD prevalence in the cohort was 8.4%, 4.7%, and 3.1% using the least, moderate, and most rigid definition, respectively. The number of patients with UACR measurements was low such that, among those with CKD in 2020, only 3.8%, 3.2%, and 1.5%, respectively, had both eGFR and UACR measurements available in the corresponding year. Patients in whom both eGFR and UACR measurements were available mostly had moderate or high risk of CKD progression (83.6%, 80.6%, and 76.2%, respectively)., Conclusion: In this large, nationally representative study, we observed an increasing trend in CKD prevalence in primary care settings in Australia. Most patients with CKD were at moderate to high risk of CKD progression. These findings highlight the need for early detection and effective management to slow progression of CKD., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: During the Coronavirus disease (COVID-19) pandemic, countries implemented border control and quarantine measures to reduce transmission. The Alberta Border Testing Pilot Program (ABTPP) allowed international travellers entering Alberta to reduce their quarantine period following two negative COVID-19 tests. We evaluated participant experiences with the ABTPP and implementation., Method: We used a parallel convergent mixed-methods design to explore participant experiences through electronic web-based questionnaires ( n  = 21,089; n  = 13,839) and semi-structured telephone interviews ( n  = 30). We evaluated implementation through three staff focus groups ( n  = 11). We analysed questionnaires using descriptive statistics and analysed interviews using inductive and deductive thematic analysis. We deductively coded focus group data using the 2009 Consolidated Framework for Implementation Research (CFIR)., Results: Questionnaires indicated minimal issues with registration forms (91.7%), symptom reports (95.5%), and COVID-19 testing (95.7%). Most respondents (95.1%) expressed willingness to participate in the ABTPP again. Interviews revealed three themes related to participant experience: program efficiency, clarity of information, and requisite effort. Focus groups identified key implementation facilitators including the single health information system, strong stakeholder partnerships, and good communication across partnerships. Barriers included program complexity, implementation timeline, and evolving external context., Discussion: Participants reported high satisfaction with the ABTPP. Border testing programs should have high efficiency, require low effort, and use messaging that is clear and consistent. The effective implementation of border testing programs may be facilitated by strong leadership, adaptability, automated components, good communication, and simple technology. Learnings from participants and staff may help improve the implementation of border control programs for future pandemics or other emergencies., Conclusions: The ABTTP was a novel border control measure during the COVID-19 pandemic. Our evaluation of both participant and staff experiences demonstrated high levels of traveller satisfaction and identified areas for improvement that can inform the development of future border control measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Kersen, Scory, Akeju, Weaver, Barnieh, Ronksley, Leal, Blue, O'Neill, Campbell, Tonelli and Lunney.)

Background: Ranitidine was the most prescribed histamine-2 receptor antagonist (H 2 RA) in Canada when recalled in 2019 because of potential carcinogenicity. We sought to compare geographic and temporal patterns in use of prescription ranitidine and 3 other HRAs and estimated population exposure to ranitidine in 6 provinces between 1996 and 2019., Methods: This population-based serial cross-sectional study used prescription claims for H 2 RAs dispensed from community pharmacies in Nova Scotia, Ontario, Manitoba, Saskatchewan, Alberta and British Columbia. We estimated the period prevalence of ranitidine use per 100 population by province, age category and sex. We estimated exposure to ranitidine between 2015 and 2019 using defined daily doses (DDDs)., Results: Overall, 2.4 million ranitidine prescriptions were dispensed to patients aged 65 years and older, and 1.7 million were dispensed to younger adults. Among older adults, the median period prevalence of ranitidine use among females was 16% (interquartile range [IQR] 13%-27%) higher than among males. Among younger adults, the median prevalence was 50% (IQR 37%-70%) higher among females. Among older adults, between 1996 and 1999, use was highest in Nova Scotia (33%) and Ontario (30%), lower in the prairies (Manitoba [18%], Saskatchewan [26%], Alberta [17%]) and lowest in BC (11%). By 2015-2019, use of ranitidine among older adults dropped by at least 50% in all provinces except BC. We estimate that at least 142 million DDDs of prescribed ranitidine were consumed annually in 6 provinces (2015-2019)., Interpretation: Over the 24-year period in 6 provinces, patients aged 65 years and older were dispensed 2.4 million prescriptions of ranitidine and younger adults were dispensed 1.7 million prescriptions of ranitidine. These estimates of ranitidine exposure can be used for planning studies of cancer risk and identifying target populations for cancer surveillance., Competing Interests: Competing interests: Laura Targownik has served on advisory boards or created educational materials for Janssen AbbVie Canada, Takeda Canada, Merck Canada, Pfizer Canada, Janssen Canada, Roche Canada, Sandoz Canada, JAMP Pharmaceuticals and Celltrion Pharmaceuticals. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Objective: To estimate the rates of diabetes complications and revascularization procedures among people with diabetes who have experienced homelessness compared with a matched cohort of nonhomeless control subjects., Research Design and Methods: A propensity-matched cohort study was conducted using administrative health data from Ontario, Canada. Inclusion criteria included a diagnosis of diabetes and at least one hospital encounter between April 2006 and March 2019. Homeless status was identified using a validated administrative data algorithm. Eligible people with a history of homelessness were matched to nonhomeless control subjects with similar sociodemographic and clinical characteristics. Rate ratios (RRs) for macrovascular complications, revascularization procedures, acute glycemic emergencies, skin/soft tissue infections, and amputation were calculated using generalized linear models with negative binomial distribution and robust SEs., Results: Of 1,076,437 people who were eligible for inclusion in the study, 6,944 were identified as homeless. A suitable nonhomeless match was found for 5,219 individuals. The rate of macrovascular complications was higher for people with a history of homelessness compared with nonhomeless control subjects (RR 1.85, 95% CI 1.64-2.07), as were rates of hospitalization for glycemia (RR 5.64, 95% CI 4.07-7.81) and skin/soft tissue infections (RR 3.78, 95% CI 3.31-4.32). By contrast, the rates of coronary revascularization procedures were lower for people with a history of homelessness (RR 0.76, 95% CI 0.62-0.94)., Conclusions: These findings contribute to our understanding of the impact of homelessness on long-term diabetes outcomes. The higher rates of complications among people with a history of homelessness present an opportunity for tailored interventions to mitigate these disparities., (© 2023 by the American Diabetes Association.)

Background: The challenges presented by multimorbidity continue to rise in the United States. Little is known about how the relative contribution of individual chronic conditions to multimorbidity has changed over time, and how this varies by race/ethnicity. The objective of this study was to describe trends in multimorbidity by race/ethnicity, as well as to determine the differential contribution of individual chronic conditions to multimorbidity in hospitalized populations over a 20-year period within the United States., Methods: This is a serial cross-sectional study using the Nationwide Inpatient Sample (NIS) from 1993 to 2012. We identified all hospitalized patients aged ≥ 18 years old with available data on race/ethnicity. Multimorbidity was defined as the presence of 3 or more conditions based on the Elixhauser comorbidity index. The relative change in the proportion of hospitalized patients with multimorbidity, overall and by race/ethnicity (Black, White, Hispanic, Asian/Pacific Islander, Native American) were tabulated and presented graphically. Population attributable fractions were estimated from modified Poisson regression models adjusted for sex, age, and insurance type. These fractions were used to describe the relative contribution of individual chronic conditions to multimorbidity over time and across racial/ethnic groups., Results: There were 123,613,970 hospitalizations captured within the NIS between 1993 and 2012. The prevalence of multimorbidity increased in all race/ethnic groups over the 20-year period, most notably among White, Black, and Native American populations (+ 29.4%, + 29.7%, and + 32.0%, respectively). In both 1993 and 2012, Black hospitalized patients had a higher prevalence of multimorbidity (25.1% and 54.8%, respectively) compared to all other race/ethnic groups. Native American populations exhibited the largest overall increase in multimorbidity (+ 32.0%). Furthermore, the contribution of metabolic diseases to multimorbidity increased, particularly among Hispanic patients who had the highest population attributable fraction values for diabetes without complications (15.0%), diabetes with complications (5.1%), and obesity (5.8%)., Conclusions: From 1993 to 2012, the secular increases in the prevalence of multimorbidity as well as changes in the differential contribution of individual chronic conditions has varied substantially by race/ethnicity. These findings further elucidate the racial/ethnic gaps prevalent in multimorbidity within the United States., Prior Presentations: Preliminary finding of this study were presented at the Society of General Internal Medicine (SGIM) Annual Conference, Washington, DC, April 21, 2017., (© 2023. The Author(s).)

Schizophrenia does not present uniformly among patients and as a result this patient population is characterized by a diversity in the type and amount of healthcare supports needed for daily functioning. Despite this, little work has been completed to understand the heterogeneity that exists among these patients. In this work we used a data-driven approach to identify subgroups of high-cost patients with schizophrenia to identify potentially actionable interventions for the improvement of outcomes and to inform conversations on how to most efficiently allocate resources in an already strained system. Administrative health data was used to conduct a retrospective analysis of "high-cost" adult patients with schizophrenia residing in Alberta, Canada in 2017. Costs were derived from inpatient encounters, outpatient primary care and specialist encounters, emergency department encounters, and drug costs. Latent class analysis was used to group patients based on their unique clinical profiles. Latent class analysis of 1659 patients revealed the following patient groups: (1) young, high-needs males early in their disease course; (2) actively managed middle-aged patients; (3) elderly patients with multiple chronic conditions and polypharmacy; (4) unstably housed males with low treatment rates; (5) unstably housed females with high acute care use and low treatment rates. This taxonomy may be used to inform policy, including the identification of interventions most likely to improve care and reduce health spending for each subgroup., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Objective: To define the time frames, measures used and modifying factors influencing recovery, return to school/learn (RTL) and return to sport (RTS) after sport-related concussion (SRC)., Design: Systematic review and meta-analysis., Data Sources: 8 databases searched through 22 March 2022., Eligibility Criteria: Studies with diagnosed/suspected SRC and interventions facilitating RTL/RTS or investigating the time and modifying factors for clinical recovery. Outcomes included days until symptom free, days until RTL and days until RTS. We documented study design, population, methodology and results. Risk of bias was evaluated using a modified Scottish Intercollegiate Guidelines Network tool., Results: 278 studies were included (80.6% cohort studies and 92.8% from North America). 7.9% were considered high-quality studies, while 23.0% were considered high risk of bias and inadmissible. The mean days until symptom free was 14.0 days (95% CI: 12.7, 15.4; I 2 =98.0%). The mean days until RTL was 8.3 (95% CI: 5.6, 11.1; I 2 =99.3%), with 93% of athletes having a full RTL by 10 days without new academic support. The mean days until RTS was 19.8 days (95% CI: 18.8, 20.7; I 2 =99.3%), with high heterogeneity between studies. Several measures define and track recovery, with initial symptom burden remaining the strongest predictor of longer days until RTS. Continuing to play and delayed access to healthcare providers were associated with longer recovery. Premorbid and postmorbid factors (eg, depression/anxiety, migraine history) may modify recovery time frames. Though point estimates suggest that female sex or younger age cohorts take longer to recover, the heterogeneity of study designs, outcomes and overlap in CIs with male sex or older age cohorts suggests that all have similar recovery patterns., Conclusion: Most athletes have full RTL by 10 days but take twice as long for an RTS., Prospero Registration Number: CRD42020159928., Competing Interests: Competing interests: MP is a consultant and Chief Medical Officer for Major League Soccer. She serves as a senior advisor to the NFL’s Head, Neck & Spine Committee, is a member of the FA Research Task Force, the NOCSAE Scientific Advisory Committee and a member of the Concussion in Sport Expert Panel. She also serves on the IOC Mental Health Working Group, the USOPC Mental Health Advisory Committee, the US Soccer Medical Advisory Committee, and has received grant funding from the National Collegiate Athletic Association-Department of Defense CARE 2.0 project. LP is a CASEM board member and the president elect in 2022–2023. She has received research funding from National Institutes of Health. She has received travel expenses and honoraria for conference presentations. KJS has current or past grant funding from the Canadian Institutes of Health Research, NFL Scientific Advisory Board, IOC Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary with funds paid to her institution and not to her personally. She is an associate editor of BJSM (unpaid) and has received travel and accommodation support for meetings where she has presented. She is coordinating the writing of the systematic reviews that will inform the Sixth International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews. She is a member of the AFL Concussion Scientific Committee (unpaid position) and Brain Canada (unpaid positions). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass-roots to professional. AMB has received peer-reviewed research funding from the Social Sciences and Humanities Research Council. She is also a Sport Information Resource Center board member and Canadian Athletic Therapists Association committee member. She received an honorarium for the administrative aspects of the concussion consensus reviews. AC is the director of the National Collegiate Athletic Association Injury Surveillance Program at the Datalys Center for Sports Injury Research and Prevention. He discloses funding from the National Collegiate Athletic Association as director of the National Collegiate Athletic Association Injury Surveillance Program. He also discloses funding from the North Carolina Translational and Clinical Sciences Institute, the Atlantic Coast Conference Center for Research in Intercollegiate Athletics, as well as the Canadian Institutes of Health Research-Human Development, Child and Youth Health Institute, on separate, unrelated projects. AC has also previously received honoraria for speaking engagements with the Sports Neuropsychology Society and the American Medical Society for Sports Medicine, as well as travel support from the American Medical Society for Sports Medicine. He also serves on the editorial/education team of the Football Medicine and Performance Association publication and on the editorial board of the Journal of Sport Rehabilitation. CLM has current or past research grant funding from National Institutes of Health, Department of Defense, Centers for Disease Control and Prevention, National Collegiate Athletic Association, Pennsylvania Department of Health, AMSSM and Children’s Hospital of Philadelphia. She serves (uncompensated) on the editorial boards of the Journal of Adolescent Health, and as an associate editor of the journals Exercise, Sport, and Movement, and Frontiers in Neuroergonomics. She serves (uncompensated) on the medical advisory boards for concussion patient advocacy organisations for Untold Foundation, Pink Concussions and Headway Foundation. JKR-M has received current or past research funding from the Centers for Disease Control and Prevention; Department of Defense-USA Medical Research Acquisition Activity; National Collegiate Athletic Association-Department of Defense Mind Matters Challenge; National Athletic Trainers’ Association Foundation; NFL; and National Operating Committee on Standards for Athletic Equipment. She has consulted for Allied Health Education (paid) and received speaker honorarium and travel reimbursements for talks given. She is on the editorial boards (all unpaid) for Journal of Athletic Training, Journal of Sport Rehabilitation, and Frontiers in Sports and Active Living. Previously, she served on the editorial board for the International Journal of Athletic Training and Therapy (paid). She served previously (unpaid) on USA Football’s Football Development Council and is currently on USA Football’s Girls Football Council. VA receives funding from the Australian National Health and Medical Research Council and the Medical Research Future Fund, and Royalties from Pearson Publishing for the Test of Everyday Attention for Children. She also receives an honorarium for her role as associate editor for the American Psychological Society journal, Neuropsychology. She has a formal partnership with the Australian Football League with any associated funds going to her employer, the Murdoch Children’s Research Institute. GAD is a member of the Scientific Committee of the Sixth International Consensus Conference on Concussion in Sport; an honorary member of the AFL Concussion Scientific Committee; section editor, Sport and Rehabilitation, Neurosurgery; and has attended meetings organised by sporting organisations including the NFL, NRL, IOC, IIHF and FIFA, however has not received any payment, research funding or other monies from these groups other than for travel costs. PF received grant funding from the NFL’s 'Play Smart. Play Safe.' Initiative and is an executive committee member of the Canadian Concussion Network (financed by the Canadian Institute of Health Research). JJL receives grant/research support from National Institutes of Health, Department of Defense and the AMSSM. He is a member of the scientific advisory board for Neuronasal, Highmark Innovations and Quadrant Biosciences. He holds minority stock options in Highmark Innovations and in 360 Concussion Care. He is an expert consultant to the National Collegiate Athletic Association. He consults with NFL and NHL teams on athlete care but does not receive any compensation from these organisations. He is a member (unpaid) of the editorial board of the Journal of Head Trauma Rehabilitation. SH is a co-founder and senior advisor, The Sports Institute at UW Medicine, member of the Centers for Disease Control and Prevention and National Center for Injury Prevention and Control Board Pediatric Mild Traumatic Brain Injury Guideline Workgroup, member of the National Collegiate Athletic Association Concussion Safety Advisory Group, member of the Concussion in Sport Expert Panel, a team physician for the Seattle Mariners and a former team physician, Seattle Seahawks. SB has current or past research funding from the National Institutes of Health; Centers for Disease Control and Prevention; Department of Defense-USA Medical Research Acquisition Activity; National Collegiate Athletic Association; National Athletic Trainers’ Association Foundation; National Football League/Under Armour/GE; Simbex and ElmindA. He has consulted for US Soccer (paid), US Cycling (unpaid), University of Calgary SHRed Concussions external advisory board (unpaid), medicolegal litigation, and received speaker honorarium and travel reimbursements (including CISG) for talks given. He is coauthor of 'Biomechanics of Injury (third edition)' and has a patent pending on 'Brain Metabolism Monitoring Through CCO Measurements Using All-Fiber-Integrated Super-Continuum Source' (US application no. 17/164,490). He is on the and is/was on the editorial boards (all unpaid) for Journal of Athletic Training (2015–present), Concussion (2014–present), Athletic Training & Sports Health Care (2008 to present) and British Journal of Sports Medicine (2008–2019)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To synthesise the evidence regarding the risks and benefits of physical activity (PA), prescribed aerobic exercise treatment, rest, cognitive activity and sleep during the first 14 days after sport-related concussion (SRC)., Design: Meta-analysis was performed for PA/prescribed exercise interventions and a narrative synthesis for rest, cognitive activity and sleep. Risk of bias (ROB) was determined using the Scottish Intercollegiate Guidelines Network and quality assessed using Grading of Recommendations, Assessment, Development and Evaluations., Data Sources: MEDLINE, Embase, APA PsycInfo, Cochrane Central Register of Controlled Trials, CINAHL Plus and SPORTDiscus. Searches were conducted in October 2019 and updated in March 2022., Eligibility Criteria: Original research articles with sport-related mechanism of injury in >50% of study sample and that evaluated how PA, prescribed exercise, rest, cognitive activity and/or sleep impact recovery following SRC. Reviews, conference proceedings, commentaries, editorials, case series, animal studies and articles published before 1 January 2001 were excluded., Results: 46 studies were included and 34 had acceptable/low ROB. Prescribed exercise was assessed in 21 studies, PA in 15 studies (6 PA/exercise studies also assessed cognitive activity), 2 assessed cognitive activity only and 9 assessed sleep. In a meta-analysis of seven studies, PA and prescribed exercise improved recovery by a mean of -4.64 days (95% CI -6.69, -2.59). After SRC, early return to light PA (initial 2 days), prescribed aerobic exercise treatment (days 2-14) and reduced screen use (initial 2 days) safely facilitate recovery. Early prescribed aerobic exercise also reduces delayed recovery, and sleep disturbance is associated with slower recovery., Conclusion: Early PA, prescribed aerobic exercise and reduced screen time are beneficial following SRC. Strict physical rest until symptom resolution is not effective, and sleep disturbance impairs recovery after SRC., Prospero Registration Number: CRD42020158928., Competing Interests: Competing interests: JJL receives grant/research support from NIH, DoD and AMSSM. He is a member of the Scientific Advisory Boards for Neuronasal, Highmark Innovations and Quadrant Biosciences; has minority stock options in Highmark Innovations and 360 Concussion Care; is an expert consultant to NCAA; consults with NFL and NHL teams on athlete care but does not receive any compensation from these organisations. GAD is an honorary member of the AFL Concussion Scientific Committee and has attended meetings organised by sporting organisations including the NFL, NRL, IIHF and FIFA; however, he has not received any payment, research funding or other monies from these groups other than for travel costs. BW receives grant/research support from NIH, DoD and AMSSM. NDS receives clinical consulting fees from the National Hockey League and Major League Soccer. BGK receives grant support from NIH. IG receives funding from Fonds de la recherche du Québec–Santé; Canadian Institutes of Health Research; Research Institute of the McGill University Health Center; School of Physical and Occupational Therapy, McGill University. CCG receives grant/research support from Hit-IQ (2022–2023); NIH NINDS (R01 NS110757 2019–2024); NINDS (U54 NS121688 2021–2026); UCLA Brain Injury Research Center, UCLA Steve Tisch BrainSPORT Program, Easton Clinic for Brain Health; a clinical consultant (provides clinical care to athletes) for NBA, NFL-Neurological Care Program, NHL/NHLPA, Los Angeles Lakers; a member of the Advisory Boards (non-compensated) for Major League Soccer, National Basketball Association and US Soccer Federation, as well as Advisory Boards (stock shareholder) for Highmark Interactive; other financial or material support: book royalties—Blackwell/Wiley Publishing: prioritised neurological differential diagnosis. KJS is a lead and coinvestigator on grants related to concussion and traumatic brain injury funded by several governments or other organisations (including but not limited to the Canadian Institutes of Health Research, Canadian Academy of Sport and Exercise Medicine, National Football League Scientific Advisory Board, Public Health Agency of Canada/Parachute Canada, Hotchkiss Brain Institute, Wellcome Trust, International Olympic Committee, Highmark Innovations, Mitacs Accelerate, University of Calgary), with funds paid to her institution and not to her personally. She is an associate professor and clinician scientist at the University of Calgary in the Sport Injury Prevention Research Centre and is a physiotherapy consultant, primarily working with patients with concussion and traumatic brain injuries. She is an associate editor of BJSM (unpaid) and has received travel and accommodation support for meetings where she has presented. She is coordinating the writing of the systematic reviews that will inform the 6th International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews. She is a member of the Scientific Advisory Board for Eye Guide (share options), and member of the AFL Concussion Scientific Committee (unpaid position) and Brain Canada (unpaid position)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We evaluated interventions to facilitate recovery in children, adolescents and adults with a sport-related concussion (SRC)., Design: Systematic review including risk of bias (modified Scottish Intercollegiate Guidelines Network tool)., Data Sources: MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, APA PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL Plus with Full Text, SPORTDiscus and Scopus searched until March 2022., Study Eligibility Criteria: (1) Original research including randomised controlled trials (RCTs), quasi-experimental designs, cohort, comparative effectiveness studies; (2) focus on SRC; (3) English; (4) peer-reviewed and (5) evaluated treatment., Results: 6533 studies were screened, 154 full texts reviewed and 13 met inclusion (10 RCTs, 1 quasi-experimental and 2 cohort studies; 1 high-quality study, 7 acceptable and 5 at high risk of bias). Interventions, comparisons, timing and outcomes varied, precluding meta-analysis. For adolescents and adults with dizziness, neck pain and/or headaches >10 days following concussion, individualised cervicovestibular rehabilitation may decrease time to return to sport compared with rest followed by gradual exertion (HR 3.91 (95% CI 1.34 to 11.34)) and when compared with a subtherapeutic intervention (HR 2.91 (95% CI 1.01 to 8.43)). For adolescents with vestibular symptoms/impairments, vestibular rehabilitation may decrease time to medical clearance (vestibular rehab group 50.2 days (95% CI 39.9 to 60.4) compared with control 58.4 (95% CI 41.7 to 75.3) days). For adolescents with persisting symptoms >30 days, active rehabilitation and collaborative care may decrease symptoms., Conclusions: Cervicovestibular rehabilitation is recommended for adolescents and adults with dizziness, neck pain and/or headaches for >10 days. Vestibular rehabilitation (for adolescents with dizziness/vestibular impairments >5 days) and active rehabilitation and/or collaborative care (for adolescents with persisting symptoms >30 days) may be of benefit., Competing Interests: Competing interests: VA Financial: Australian National Health and Medical Research Council and Medical Research Future fund: research grants. Royalties: Pearson Publishing (Test of Everyday Attention) Collaboration: Australian Football League (Partnership agreement to fund research—funds go to my institute) Boards: Editorship: Journal of Neuropsychology, Neuropsychology, Journal of Clinical & Experimental Neuropsychology. GAD is a member of the Scientific Committee of the 6th International Consensus Conference on Concussion in Sport; an honorary member of the AFL Concussion Scientific Committee; Section Editor, Sport and Rehabilitation, NEUROSURGERY; and has attended meetings organised by sporting organisations including the NFL, NRL, IIHF, IOC and FIFA; however, has not received any payment, research funding or other monies from these groups other than for travel costs. CTD Pharmaceutical:-2021 pharmaceutical funded invited expert panelist (Teva) for CGRP monoclonal antibody treatment in chronic migraine-2022 pharmaceutical funded grant for growth hormone deficiency following concussion Grants/Research Support: Canadian Department of National Defense, HBI, CIHR, Tri-council funding New Frontiers, Alberta Provincial government, Foundations for PMR Patents: urine metabolites diagnosis of concussion. NF International independent FIFA Concussion Advisory Group GOTS Concussion Committee Innovation and Technology Panel, UK Department for Digital, Culture, Media and SportInternational Consensus Group on Concussion in Sports (CISG), NINDSCDE Sports Concussion CDE Subacute Subgroup (National Institute of Health) IFAB Concussion Expert Group Member: Swiss Neurology Society, Swiss Society for Clinical Neurophysiology, European Neuro-Ophthalmology Society, Concussion in Sport Group (CISG) Editorial Board Member: Journal of Concussion, Journal of Science and Medicine in Football. IG has paid employment relationships with McGill University and the McGill University Health CenterI have received grants in the last 3 years from: Canadian Institutes of Health Research, Fonds de recherche du Québec—Santé, Research Institute of the McGill University Health Center, McGill University, Institut National du Sport du QuébecI have no conflicts of interest with regards to the material being presented or discussed at the conference. KMG has received grant funding from NFL for the NFL LONG study. He also serves on the NCAA Scientific Advisory Board in an unpaid capacity. KAH has nothing to disclose. SAH is co-founder and senior advisor, The Sports Institute at UW Medicine (unpaid), Centers for Disease Control and Prevention and National Center for Injury Prevention and Control Board Pediatric Mild Traumatic Brain Injury Guideline Workgroup (unpaid), Concussion in Sport Group (Travel support), NCAA Concussion Safety Advisory Group (unpaid), Team Physician, Seattle Mariners; Former Team Physician, Seattle Seahawks; occasional payment for expert travel testimony, support for professional meetings. Mr CJ has nothing to declare. MM is a sport and exercise medicine physician working in private consulting practice and is the Chief Medical Officer at the Australian Football League. Shareholder of Olympic Park Sports Medicine Centre in Melbourne. Ex-senior physician at the Hawthorn Football Club (AFL) Ex-Chief Executive Officer of the AFL Doctors Association. Research grants received from the Australian Football League, outside the submitted work.Travel support received from the Australian Football League, FIFA and the International Olympic Committee to attend and present at international conferences. Member of the Scientific Committee for the 6th International Consensus Conference on Concussion in Sport. Honorary member of the International Concussion in Sport Group. Honorary member of the Australian Rugby Union Concussion Advisory Group.Independent Concussion Consultant for World Rugby. CLM reports no financial COI Volunteer positions: Concussion team physician, Shipley School Board of Trustees, American College of Sports Medicine Board of Directors, American Medical Society for Sports Medicine Board of Directors, Pediatric Research in Sports Medicine Executive Committee, Council on Sports Medicine and Fitness, American Academy of Pediatrics Advisory Board, Untold Foundation, Pink Concussions, Headway Foundation Editorial Board, Journal of Adolescent Health, Frontiers in Neuroergonomics, Exercise, Sport and Movement. JP is Editor BJSM (honorarium), Member of World Rugby Concussion Advisory Group (unpaid), Independent Concussion Consultant for World Rugby (fee per consultation), Medical consultant to South African Rugby (unpaid), Co-chair of the Scientific Committee, 6th International Conference on Concussion in Sport (unpaid), Board member of the Concussion in Sport Group (unpaid), Scientific Board member, EyeGuideTM (unpaid). JKR-M has current or past research funding from the Centers for Disease Control and Prevention; Department of Defense—USA Medical Research Acquisition Activity, National Collegiate Athletic Association-Department of Defense Mind Matters Challenge; National Athletic Trainers’ Association Foundation; National Football League; and National Operating Committee on Standards for Athletic Equipment. She has consulted for Allied Health Education (paid) and received speaker honorarium and travel reimbursements for talks given. She is on the editorial boards (all unpaid) for Journal of Athletic Training, Journal of Sport Rehabilitation and Frontiers in Sports and Active Living. Previously she served on the editorial board for the International Journal of Athletic Training and Therapy (paid). She served previously (unpaid) on USA Football’s Football Development Council and is currently on USA Football’s Girls Football Council. She is also a member of several committees or the National Athletic Trainers’ Association and the North Carolina High School Athletic Association’s Sports Medicine Advisory Committee. PER has nothing to declare. KJS has received grant funding from the Canadian Institutes of Health Research, National Football League Scientific Advisory Board, International Olympic Committee Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary) with funds paid to her institution and not to her personally. She is an Associate Editor of BJSM (unpaid) and has received travel and accommodation support for meetings where she has presented. She is coordinating the writing of the systematic reviews that will inform the 6th International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews. She is a member of the AFL Concussion Scientific Committee (unpaid position) and Brain Canada (unpaid positions). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass roots to professional. NDS: Employee salary from the University of British Columbia, Research grants from the Canadian Institutes of Health Research, Canada Foundation for Innovation, WorkSafeBC and the US Department of Defense (no salary contributions), Research salary support from the Michael Smith Foundation for Health Research, Editorial board member for Neuropsychology and the Journal of Head Trauma Rehabilitation (unpaid), Chair of the American Congress of Rehabilitation Medicine Mild TBI Task Force (unpaid), Member of the Scientific Advisory Committee, Brain Injury Canada (unpaid), Clinical neuropsychological consulting fees from the National Hockey League, Major League Soccer, and NDS Inc (<10% of total income). KOY: is editor-in-chief of the journal Neuropsychology and receives an editorial stipend from the American Psychological Association. He is an unpaid consulting editor for the journals Archives of Clinical Neuropsychology and Journal of Head Trauma Rehabilitation. He is an unpaid member of the Scientific Advisory Committee for Brain Injury Canada. He is the chair of the Canadian Concussion Network, which is funded by a grant from Canadian Institutes of Health Research (CIHR) to his institution; He is the principal applicant on the grant but receives no income from it. He is a principal investigator on another grant from CIHR from which he derives no income. He is a coinvestigator on research grants from CIHR, the US National Institutes of Health (NIH), Brain Canada Foundation and National Football League Scientific Advisory Board; He derives income only from the grant from NIH. He serves as a member of a CIHR grant review panel for which he receive a small honorarium. He receives book royalties from Guilford Press and Cambridge University Press. He has received travel support and honorarium for presentations to multiple organisations. He has served or serves on the following committees/boards for which I receives honorarium: 1. Independent Data Monitoring Committee (IDMC), Care for Post-Concussive Symptoms Effectiveness (CARE4PCS-2) Trial, National Institute for Child Health and Human Development 2. Observational Study Monitoring Board (OSMB), Approaches and Decisions in Acute Pediatric TBI (ADAPT) Trial, National Institute of Neurological Disorders and Stroke National Research Advisory Council, National Pediatric Rehabilitation Resource Center, Center for Pediatric Rehabilitation: Growing Research, Education, and Sharing Science (C-PROGRESS), Virginia Tech University., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this paper is to summarise the consensus methodology that was used to inform the International Consensus Statement on Concussion in Sport (Amsterdam 2022). Building on a Delphi process to inform the questions and outcomes from the 5th International Conference on Concussion in Sport, the Scientific Committee identified key questions, the answers to which would help encapsulate the current science in sport-related concussion and help guide clinical practice. Over 3½ years, delayed by 2 years due to the pandemic, author groups conducted systematic reviews on each selected topic. The 6th International Conference on Concussion in Sport was held in Amsterdam (27-30 October 2022) and consisted of 2 days of systematic review presentations, panel discussions, question and answer engagement with the 600 attendees, and abstract presentations. This was followed by a closed third day of consensus deliberations by an expert panel of 29 with observers in attendance. The fourth day, also closed, was dedicated to a workshop to discuss and refine the sports concussion tools (Concussion Recognition Tool 6 (CRT6), Sport Concussion Assessment Tool 6 (SCAT6), Child SCAT6, Sport Concussion Office Assessment Tool 6 (SCOAT6) and Child SCOAT6). We include a summary of recommendations for methodological improvements for future research that grew out of the systematic reviews., Competing Interests: a Competing interests: OHA is a Senior Physiotherapist at University Hospitals Dorset NHS Foundation Trust (England) and is Para Football Physiotherapy Lead/Para Football Classification Lead at the Football Association (England). He also works on a consultancy basis with the Football Association as the squad physiotherapist to the England Cerebral Palsy Football squad, and teaches on the Football Association’s Advanced Trauma and Medical Management in Football course on a consultancy basis. He has a Visiting Senior Lecturer position at the University of Portsmouth, England (unpaid). He sits on several disability sport committees including Para Football Foundation as Medical Unit Co-Lead (unpaid), the International Federation of Cerebral Palsy Football as Medical and Sports Science Director (unpaid), and the International Blind Sports Association as Medical Committee member (unpaid). He has Associate Editor positions at the British Journal of Sports Medicine (unpaid) and British Medical Journal (BMJ) Open Sports & Exercise Medicine (unpaid). He is also an Institutional Ethics Committee external member for World Rugby (unpaid), and co-chair of the Concussion in Para Sport Group (unpaid). AB has received peer-reviewed research funding from the Social Sciences and Humanities Research Council. She is also a Sport Information Resource Centre board member and Canadian Athletic Therapists Association committee member. She has received an honorarium for the administrative aspects of the reviews. CB is an Associate Professor of Physical Medicine & Rehabilitation (PM&R) at Spaulding Rehabilitation Hospital/Harvard Medical School and Chief Medical Officer at Spaulding Rehabilitation Hospital. She receives grant funding from the United States (US) Center for Disease Control (CDC) and Prevention and the U.S. National Institute on Disability, Independent Living, and Rehabilitation Research. She serves on the Board of Directors of the United States Olympic & Paralympic Committee (unpaid) as well as the International Paralympic Committee Medical Committee (unpaid) and the International Olympic Committee Medical & Scientific Commission (unpaid). She serves as an Associate Editor of the British Journal of Sports Medicine (unpaid) as well as the PM&R Journal (unpaid). SB current or past research funding from the National Institutes of Health; Centers for Disease Control and Prevention (CDC); Department of Defense - USA Medical Research Acquisition Activity, National Collegiate Athletic Association (NCAA); National Athletic Trainers’ Association Foundation; National Football League (NFL)/Under Armour/General Electric (GE); Simbex; and ElmindA. He has consulted for US Soccer (paid), US Cycling (unpaid), University of Calgary SHRed Concussions external advisory board (unpaid), medicolegal litigation, and received speaker honorarium and travel reimbursements (including Concussion in Sport Group -CISG) for talks given. He is coauthor of “Biomechanics of Injury (3rd edition)” and has a patent pending on “Brain Metabolism Monitoring Through CCO Measurements Using All-Fiber-Integrated Super-Continuum Source” (US Application No. 17/164,490). He is/was on the editorial boards (all unpaid) for Journal of Athletic Training (2015 to present), Concussion (2014 to present), Athletic Training & Sports Health Care (2008 to present), British Journal of Sport Medicine (2008 to 2019). JSB is supported by the University of Calgary, the Natural Sciences and Engineering Research Council [CGSD3-559333- 2021], and an honorarium for the methods author work associated with Reviews two and four. RCC is a Senior Advisor NFL Head Neck & Spine Committee VP NOCSAE and Chair Scientific Advisory CommitteeCo-Founder Medical Director Concussion Legacy FoundationRoyalties Houghton Mifflin Harcourt Legal Expert Opinion. JDC National Collegiate Athletic Association payments for expert testimony. National Hockey League (NHL) payments for expert testimony. GAD is a member of the Scientific Committee of the 6th International Conference on Concussion in Sport; anhonorary member of the Australian Football League (AFL) Concussion Scientific Committee; Section Editor, Sport and Rehabilitation, NEUROSURGERY; and has attended meetings organised by sporting organisations including the NFL, National Rugby League (NRL), International Ice Hockey Federation (IIHF), International Olympic Committee (IOC) and Federation International de Football Association (FIFA); however, has not received any payment, research funding or other monies from these groups other than for travel costs. JD has nothing to disclose. RJE is a paid consultant for the NHL and co-chair of the NHL/NHL Players Association (NHLPA) Concussion Subcommittee. He is also a paid consultant and chair of the Major League Soccer concussion committee, and a consultant to the US Soccer Federation. He previously served as a neuropsychology consultant to Princeton University Athletic Medicine and EyeGuide. He is currently a co-Primary Investigator (PI) for a grant funded by the NFL (NFL-Long) through Boston Children’s Hospital. He occasionally provides expert testimony in matters related to mTBI and sports concussion, and occasionally receives honoraria and travel support/reimbursement for professional meetings. PE is a data consultant to the National Hockey League; received an honorarium for the administrative aspects of the reviews. CAE has received external peer-reviewed research funding from Canadian Institutes of Health Research (CIHR), Canada Foundation for Innovation, International Olympic Committee Medical and Scientific Committee, NFL Play Smart Play Safe Program, and World Rugby. She is an Associate Editor of British Journal of Sport Medicine (BJSM) (unpaid) and has received travel and accommodation support for meetings where she has presented. She is an external advisory board member (unpaid) for HitIQ. KAH has nothing to disclose. GI, PhD serves as a scientific advisor for NanoDX®, Sway Operations, LLC, and Highmark, Inc. He has a clinical and consulting practice in forensic neuropsychology, including expert testimony, involving individuals who have sustained mTBIs (including former athletes). He has received research funding from several test publishing companies, including ImPACT Applications, Inc., CNS Vital Signs, and Psychological Assessment Resources (PAR, Inc.). He has received research funding as a principal investigator from the NFL, and subcontract grant funding as a collaborator from the Harvard Integrated Program to Protect and Improve the Health of NFL Players Association Members. He has received research funding from the Wounded Warrior Project™. He acknowledges unrestricted philanthropic support from ImPACT Applications, Inc., the Mooney-Reed Charitable Foundation, Boston Bolts, the National Rugby League, and the Schoen Adams Research Institute at Spaulding Rehabilitation. JJL receives grant/research support from National Institutes of Health (NIH), Department of Defence (DoD) and American Medical Society for Sports Medicine (AMSSM); is a member of the Scientific Advisory Board for Neuronasal, Highmark Innovations, and Quadrant Biosciences; minority stock options in Highmark Innovations and 360 Concussion Care; expert consultant to NCAA. Consults with NFL and NHL teams on athlete care but does not receive any compensation from these organisations; Editorial Board of Journal of Head Trauma Rehabilitation. MM is sport and exercise medicine physician working in private consulting practice. He is the Chief Medical Officer for the Australian Football League (AFL) and an independent consultant to World Rugby. He is a Shareholder of Olympic Park Sports Medicine Centre in Melbourne. He has previously held positions as the senior physician at the Hawthorn Hawks Football Club (AFL) and Chief Executive Officer of the AFL Doctors Association. He has received research grants from the Australian Football League, outside the submitted work. He has received travel support received from the Australian Football League, FIFA and the International Olympic Committee to attend and present at international conferences. Member of the Scientific Committee for the 6th International Conference on Concussion in Sport. Honorary member of the International CISG and an honorary member of the Australian Rugby Union Concussion Advisory Group. MMcC reports research grants from the US NIH, US Department of Defense, US CDC, US Department of Veterans Affairs, Abbott Laboratories, NFL, and NCAA, and consultancy with the Green Bay Packers and Neurotrauma Sciences, Inc. MMcN 1. Chair, Ethics Expert Group, World Antidoping Agency (WADA) (2021–23) (paid) 2. Member, International Boxing Association, Ethics and Integrity Committee, (2021–22; resigned Oct 2022) (paid) 3. Chair, Therapeutic Use Exemption Fairness Committee (2020–) (paid) 4. Member, Steering Group, Sex Segregation in Sport, International Association of Athletics Federations (IAAF)/World Athletics, (2019–20) (unpaid) 5. Member, International Ice Hockey Federation, Ethics and Integrity Committee (2019–21) (paid) 6. Member, International Olympic Committee Consensus Statement Expert Group on Injuries in Children and Adolescents (2017) (unpaid) 7. Member, Ethics Expert Group, WADA (2016–21) (unpaid) 8. Member, International Olympic Committee Consensus Statement Expert Group on Pain Management (2016)) (unpaid). WM is employed as the Chief Medical Officer of the National Hockey League. JP: Editor BJSM (honorarium); Member of World Rugby Concussion Advisory Group (unpaid); Independent Concussion Consultant for World Rugby (fee per consultation); Medical consultant to South African Rugby (unpaid); Co-chair of the Scientific Committee, 6th International Conference on Concussion in Sport (unpaid); Board member of the CISG (unpaid); Scientific Board member, EyeGuideTM (unpaid). ZP has no conflicts of interests to declare. MP declares the following: Consultant, Chief Medical Officer (CMO), Major League Soccer; Senior Advisor, NFL Head, Neck NCAA-CARE-DoD 2.0, ended 2020; Have received honoraria and reimbursement for travel for speaking and conferences attended; Have written chapters for UpToDate, and received royalties for the Netter’s Sports Medicine textbook; Have provided work as an expert for cases involving concussion, team physician and other sports medicine topics. AMR: Stipend for the clerical and administrative aspects of the systematic review. Tonal Strength Institute: Research grant (not specifically related to the present work). Alberta Bone and Joint Strategic Clinical Network: Research grant (not specifically related to the present work). PER has no conflicts of interest to declare. GMS is an owner of a multidisciplinary practice (managing patients with MSK pain disorders). He is a board member of Hockey Calgary (Calgary, AB, Canada) and Chair of the Alberta Association of Physiotherapy. He received funding for the administrative aspects of the writing of two of the systematic reviews that informed the consensus process. KJS has received grant funding from the CIHR, NFL Scientific Advisory Board, International Olympic Committee Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary, with funds paid to her institution and not to her personally. She is an Associate Editor of BJSM (unpaid), Independent consultant to World Rugby and has received travel and accommodation support for meetings where she has presented. She coordinated the writing of the systematic reviews that informed Amsterdam International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews (with funds paid to her institution). She is a member of the AFL Concussion Scientific Committee (unpaid position), Brain Canada (unpaid positions) and Board member of the Concussion in Sport Group (CISG)(unpaid). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass roots to professional. JT: Doctoral funding through the CIHR; Jason also received an honorarium for the administrative parts of the review. KOY holds the Ronald and Irene Ward Chair in Pediatric Brain Injury funded by the Alberta Children’s Hospital Foundation. He is a principal investigator on grants from the CIHR, and co-investigator on research grants from CIHR, Brain Canada Foundation, Social Science and Humanities Research Council (Canada), and NFL Scientific Advisory Board. He is the Editor of Neuropsychology, for which he receives an editorial stipend from the American Psychological Association. He chairs the Canadian Concussion Network, which is funded by CIHR. He is a member of the Scientific Advisory Committee for Brain Injury Canada and the National Research Advisory Council for the National Pediatric Rehabilitation Resource Center., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: People with kidney failure often require surgery and experience worse postoperative outcomes compared to the general population, but existing risk prediction tools have excluded those with kidney failure during development or exhibit poor performance. Our objective was to derive, internally validate, and estimate the clinical utility of risk prediction models for people with kidney failure undergoing non-cardiac surgery., Design, Setting, Participants, and Measures: This study involved derivation and internal validation of prognostic risk prediction models using a retrospective, population-based cohort. We identified adults from Alberta, Canada with pre-existing kidney failure (estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73m 2 or receipt of maintenance dialysis) undergoing non-cardiac surgery between 2005-2019. Three nested prognostic risk prediction models were assembled using clinical and logistical rationale. Model 1 included age, sex, dialysis modality, surgery type and setting. Model 2 added comorbidities, and Model 3 added preoperative hemoglobin and albumin. Death or major cardiac events (acute myocardial infarction or nonfatal ventricular arrhythmia) within 30 days after surgery were modelled using logistic regression models., Results: The development cohort included 38,541 surgeries, with 1,204 outcomes (after 3.1% of surgeries); 61% were performed in males, the median age was 64 years (interquartile range [IQR]: 53, 73), and 61% were receiving hemodialysis at the time of surgery. All three internally validated models performed well, with c-statistics ranging from 0.783 (95% Confidence Interval [CI]: 0.770, 0.797) for Model 1 to 0.818 (95%CI: 0.803, 0.826) for Model 3. Calibration slopes and intercepts were excellent for all models, though Models 2 and 3 demonstrated improvement in net reclassification. Decision curve analysis estimated that use of any model to guide perioperative interventions such as cardiac monitoring would result in potential net benefit over default strategies., Conclusions: We developed and internally validated three novel models to predict major clinical events for people with kidney failure having surgery. Models including comorbidities and laboratory variables showed improved accuracy of risk stratification and provided the greatest potential net benefit for guiding perioperative decisions. Once externally validated, these models may inform perioperative shared decision making and risk-guided strategies for this population., (© 2023. The Author(s).)

Rationale: Obstructive sleep apnea (OSA) is a common treatable condition with important health and societal consequences. Objectives: We aimed to assess the annual incidence and prevalence of clinically recognized and geographic clustering of OSA in Alberta, Canada, using administrative health data case definitions. Methods: We used two administrative health databases in Alberta to identify ICD-9 and ICD-10 (International Classification of Diseases, Ninth and 10th Revisions, respectively) diagnostic codes for adults and children at least 2 years old diagnosed with OSA between 2003 and 2020. We defined OSA using an algorithm developed and validated in Alberta: at least three claims or one hospitalization within 2 years. We mapped residential postal codes to 70 subregional health authorities (SRHAs). Crude, age group- and sex-specific incidence and prevalence, and age group- and sex-standardized rates were calculated for Alberta and SRHAs. Spatial scan statistics identified clusters of SRHAs in which OSA cases were higher (hot spots) or lower (cold spots) than expected. Results: Between 2003 and 2020, OSA prevalence increased from 0.14% to 4.59%. The annual incidence of OSA increased after 2013. Incidence and prevalence were higher in older adults and children aged 2-11 years compared with 12-17 years. Cluster analysis revealed regional variation in OSA incidence and prevalence over time with no consistent pattern except for cold spots in one large metropolitan center (Calgary). Conclusions: From 2003 to 2020, the incidence and prevalence of clinically recognized OSA increased but varied by geography. Administrative health data can be used to guide interventions aimed at improving health service delivery and the quality of OSA care.

Background: Aortic valve stenosis is a progressive disorder with variable progression rates. The factors affecting aortic stenosis (AS) progression remain largely unknown., Objectives: This systematic review and meta-analysis sought to determine AS progression rates and to assess the impact of baseline AS severity and sex on disease progression., Methods: The authors searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 1, 2020, for prospective studies evaluating the progression of AS with the use of echocardiography (mean gradient [MG], peak velocity [PV], peak gradient [PG], or aortic valve area [AVA]) or computed tomography (calcium score [AVC]). Random-effects meta-analysis was performed to evaluate the rate of AS progression for each parameter stratified by baseline severity, and meta-regression was performed to determine the impact of baseline severity and of sex on AS progression rate., Results: A total of 24 studies including 5,450 patients (40% female) met inclusion criteria. The pooled annualized progression of MG was +4.10 mm Hg (95% CI: 2.80-5.41 mm Hg), AVA -0.08 cm 2 (95% CI: 0.06-0.10 cm 2 ), PV +0.19 m/s (95% CI: 0.13-0.24 m/s), PG +7.86 mm Hg (95% CI: 4.98-10.75 mm Hg), and AVC +158.5 AU (95% CI: 55.0-261.9 AU). Increasing baseline severity of AS was predictive of higher rates of progression for MG (P < 0.001), PV (P = 0.001), and AVC (P < 0.001), but not AVA (P = 0.34) or PG (P = 0.21). Only 4 studies reported AS progression stratified by sex, with only PV and AVC having 3 studies to perform a meta-analysis. No difference between sex was observed for PV (P = 0.397) or AVC (P = 0.572), but the level of confidence was low., Conclusions: This study provides progression rates for both hemodynamic and anatomic parameters of AS and shows that increasing hemodynamic and anatomic baseline severity is associated with faster AS progression. More studies are needed to determine if sex differences affect AS progression. (Aortic Valve Stenosis Progression Rate: A Systematic Review and Meta-Analysis; CRD42021207726)., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Chest pain is a common cause for emergency department (ED) presentations. After myocardial infarction (MI) has been ruled out by means of electrocardiography and troponin testing, decisions around anatomic or functional testing may be informed by clinical risk scores. We conducted a systematic review to synthesize evidence of the prognostic performance of chest pain risk scores among ED patients who have had MI ruled out by means of a high-sensitivity troponin assay., Methods: We queried multiple databases from inception to May 17, 2022. We included studies that quantified risk of 30-day major adverse cardiac events (MACE), at different cutoffs of clinical risk scores, among adult patients who had MI ruled out by means of a high-sensitivity troponin assay. Prognostic performance of each score was synthesized and described, but meta-analysis was not possible., Results: Six studies met inclusion criteria. Short-term MACE risk among patients who had MI ruled out by means of high-sensitivity cardiac troponin assays was very low. The HEART score, with a cutoff of 3 or less, predicted a very low risk of MACE among the greatest proportion of patients. Other scores had lower sensitivity or classified fewer patients as low risk., Conclusions: The HEART score with a cutoff value of 3 or less accurately identified the greatest number of patients at low risk of 30-day MACE. However, MACE risk among patients who have MI ruled out by means of high-sensitivity troponin testing is sufficiently low that clinical risk stratification or noninvasive testing may be of little additional value in identifying patients with coronary disease., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to estimate the association between estimated glomerular filtration rate (eGFR) and acute myocardial infarction (AMI) or death after ambulatory noncardiac surgery., Summary Background Data: People with chronic kidney disease (CKD) commonly undergo surgical procedures. Although most are performed in an ambulatory setting, the risk of major perioperative outcomes after ambulatory surgery for people with CKD is unknown., Methods: In this retrospective population-based cohort study using administrative health data from Alberta, Canada, we included adults with measured preoperative kidney function undergoing ambulatory noncardiac surgery between April 1, 2005 and February 28, 2017. Participants were categorized into 6 eGFR categories (in mL/min/1.73m 2 )of ≥60 (G1-2), 45 to 59 (G3a), 30 to 44 (G3b), 15 to 29 (G4), <15 not receiving dialysis (G5ND), and those receiving chronic dialysis (G5D). The odds of AMI or death within 30 days of surgery were estimated using multivariable generalized estimating equation models., Results: We identified 543,160 procedures in 323,521 people with a median age of 66 years (IQR 56-76); 52% were female. Overall, 2338 people (0.7%) died or had an AMI within 30 days of surgery. Compared with the G1-2 category, the adjusted odds ratio of death or AMI increased from 1.1 (95% confidence interval: 1.0-1.3) for G3a to 3.1 (2.6-3.6) for G5D. Emergency Department and Urgent Care Center visits within 30 days were frequent (17%), though similar across eGFR categories., Conclusions: Ambulatory surgery was associated with a low risk of major postoperative events. This risk was higher for people with CKD, which may inform their perioperative shared decision-making and management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Our aim in this study was to describe patterns and patient-level factors associated with use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) among adults with diabetes being treated in Alberta, Canada., Methods: Using linked administrative data sets from 2014 to 2019, we defined a retrospective cohort of adults with prevalent or incident type 2 diabetes with indications for SGLT2i use and who did not have advanced kidney disease (glomerular filtration rate <30 mL/min per 1.73 m 2 ) or previous amputation. We describe medication dispensation patterns of SGLT2is over time in the overall cohort and among the subgroup with cardiovascular disease (CVD). Multivariable logistic regression was used to determine patients' characteristics associated with SGLT2i use., Results: Of the 341,827 patients with diabetes (mean age, 60.7 years; 45.6% female), 107,244 (31.3%) had CVD. The proportion of patients with an SGLT2i prescription increased in a linear fashion to a maximum of 10.8% (95% confidence interval [CI], 10.7% to 10.9%) of the eligible cohort by the end of the observation period (March 2019). The proportion of filled prescriptions was similar for patients with CVD (10.4%; 95% CI, 10.1% to 10.6%) and for those without CVD (10.9%; 95% CI, 10.8% to 11.0%). Patients' characteristics associated with lower odds of filling an SGLT2i prescription included female sex, older age and lower income., Conclusions: The use of SGLT2is is increasing among patients with diabetes but remains low even in those with CVD. Policy and practice changes to increase prescribing, especially in older adults, may help to reduce morbidity and mortality related to cardiovascular and renal complications., (Copyright © 2022 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: People with kidney failure receiving dialysis (CKD-G5D) are more likely to undergo surgery and experience poorer postoperative outcomes than those without kidney failure. In this scoping review, we aimed to systematically identify and summarize perioperative strategies, protocols, pathways, and interventions that have been studied or implemented for people with CKD-G5D., Methods: We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane Database of Systematic Reviews, and Cochrane Controlled Trials registry (inception to February 2020), in addition to an extensive grey literature search, for sources that reported on a perioperative strategy to guide management for people with CKD-G5D. We summarized the overall study characteristics and perioperative management strategies and identified evidence gaps based on surgery type and perioperative domain. Publication trends over time were assessed, stratified by surgery type and study design., Results: We included 183 studies; the most common study design was a randomized controlled trial (27%), with 67% of publications focused on either kidney transplantation or dialysis vascular access. Transplant-related studies often focused on fluid and volume management strategies and risk stratification, whereas dialysis vascular access studies focused most often on imaging. The number of publications increased over time, across all surgery types, though driven by non-randomized study designs., Conclusions: Despite many current gaps in perioperative research for patients with CKD-G5D, evidence generation supporting perioperative management is increasing, with recent growth driven primarily by non-randomized studies. Our review may inform organization of evidence-based strategies into perioperative care pathways where evidence is available while also highlighting gaps that future perioperative research can address., (© 2022 Wiley Periodicals LLC.)

Mastitis, the most frequent disease in dairy cattle. Resistance to mastitis is a complex, polygenic trait controlled by several genes, each with small effects. Genome-wide association studies have been widely used to identify genomic variants associated with complex traits, including resistance to mastitis, to elucidate the underlying genetic architecture of the trait. However, no systematic review and gene prioritization analysis have been conducted to date on GWAS results for resistance to mastitis in dairy cattle. Hence, the objective was to perform a systematic review and gene prioritization analysis of GWAS studies to identify potential functional candidate genes associated with resistance to mastitis-related traits in dairy cattle. Four electronic databases were searched from inception to December 2020, supplemented with multiple sources of gray literature, to identify eligible articles. Annotation for genes and quantitative trait loci (QTL), and QTL enrichment analysis were conducted using GALLO. Gene prioritization analysis was performed by a guilty-by-association approach using GUILDify and ToppGene. From 52 articles included within this systematic review, 30 articles were used for further functional analyses. Gene and QTL annotation resulted in 9,125 and 43,646 unique genes and QTL, respectively, from 39 studies. In general, overlapping of genes across studies was very low (mean ± SD = 0.02% ± 0.07%). Most annotated genes were associated with somatic cell count-related traits and the Holstein breed. Within all annotated genes, 74 genes were shared among Holstein, Jersey, and Ayrshire breeds. Approximately 7.5% of annotated QTL were related to QTL class "health." Within the health QTL class, 2.6 and 2.2% of QTL were associated with clinical mastitis and somatic cell count-related traits. Enrichment analysis of QTL demonstrated that many enriched QTL were associated with somatic cell score located in Bos taurus autosomes 5, 6, 16, and 20. The prioritization analysis resulted in 427 significant genes after multiple test correction (false discovery rate of 5%) from 26 studies. Most prioritized genes were located in Bos taurus autosomes 19 and 7, and most top-ranked genes were from the cytokine superfamily (e.g., chemokines, interleukins, transforming growth factors, and tumor necrosis factor genes). Although most prioritized genes (397) were associated with somatic cell count-related traits, only 54 genes were associated with clinical mastitis-related traits. Twenty-four genes (ABCC9, ACHE, ADCYAP1, ARC, BCL2L1, CDKN1A, EPO, GABBR2, GDNF, GNRHR, IKBKE, JAG1, KCNJ8, KCNQ1, LIFR, MC3R, MYOZ3, NFKB1, OSMR, PPP3CA, PRLR, SHARPIN, SLC1A3, and TNFRSF25) were reported for both somatic cell count and clinical mastitis-related traits. Prioritized genes were mainly associated with immune response, regulation of secretion, locomotion, cell proliferation, and development. In conclusion, this study provided a fine-mapping of previously identified genomic regions associated with resistance to mastitis and identified key functional candidate genes for resistance to mastitis, which can be used to develop enhanced genomic strategies to combat mastitis by increasing mastitis resistance through genetic selection., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Importance: Though it is presumed that children and adolescents with migraine are at risk of internalizing symptoms and disorders, high-level summative evidence to support this clinical belief is lacking., Objective: To determine if there is an association between internalizing symptoms and disorders and migraine in children and adolescents., Data Sources: A librarian-led, peer-reviewed search was performed using MEDLINE, Embase, PsycINFO, and CINAHL databases (inception to March 28, 2022)., Study Selection: Case-control, cohort, and cross-sectional studies on the association between internalizing symptoms and disorders and migraine in children and adolescents 18 years or younger were eligible., Data Extraction and Synthesis: Two investigators independently completed abstract and full-text screening, data extraction, and quality appraisal using the Newcastle-Ottawa scales. Studies were pooled with random-effects meta-analyses using standardized mean differences (SMD) or odds ratios (OR) with 95% CIs. Where sufficient data for pooling were unavailable, studies were described qualitatively., Main Outcomes and Measures: The primary outcome was migraine diagnosis; additional outcomes included migraine outcomes and incidence. Associations between these outcomes and internalizing symptoms and disorders were evaluated., Results: The study team screened 4946 studies and included 80 studies in the systematic review. Seventy-four studies reported on the association between internalizing symptoms and disorders and migraine, and 51 studies were amenable to pooling. Meta-analyses comparing children and adolescents with migraine with healthy controls showed: (1) an association between migraine and anxiety symptoms (SMD, 1.13; 95% CI, 0.64-1.63); (2) an association between migraine and depressive symptoms (SMD, 0.67; 95% CI, 0.46-0.87); and (3) significantly higher odds of anxiety disorders (OR, 1.93, 95% CI, 1.49-2.50) and depressive disorders (OR, 2.01, 95% CI, 1.46-2.78) in those with, vs without, migraine. Stratification of results did not reveal differences between clinical vs community/population-based samples and there was no evidence of publication bias. Twenty studies assessing the association between internalizing symptoms or disorders and migraine outcomes (n = 18) or incident migraine (n = 2) were summarized descriptively given significant heterogeneity, with minimal conclusions drawn., Conclusions and Relevance: In this study, children and adolescents with migraine were at higher risk of anxiety and depression symptoms and disorders compared with healthy controls. It may be beneficial to routinely screen children and adolescents with migraine for anxiety and depression in clinical practice. It is unclear whether having anxiety and depressive symptoms or disorders has an affect on migraine outcomes or incidence.

Background and Objectives: Menstrual abnormalities and shortened reproductive lifespan are associated with shorter life expectancy and higher cardiovascular and osteoporosis risk in the general population, although the magnitude of these reproductive factor irregularities in females with CKD is unclear. This systematic review and meta-analysis aimed to summarize the current knowledge regarding menstrual abnormalities and reproductive lifespan among females with CKD., Design, Setting, Participants, & Measurements: A comprehensive bibliographic search (MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature [CINAHL]) was completed from database inception to February 2022 to identify all original articles reporting on females of reproductive age with nondialysis-dependent/nonkidney transplant CKD, dialysis-dependent CKD, or kidney transplantation and menstruation patterns, age of menarche, and/or menopause. Data extraction and study quality assessment were completed in duplicate. Random effects meta-analyses were used to derive pooled proportions estimates., Results: Forty-six studies were identified, and 35 were meta-analyzed, stratified by KRT modality and reported outcome. Menstrual abnormalities were present in 19%-47% of patients on hemodialysis and 75% of patients on peritoneal dialysis. Kidney transplantation was associated with a 7%-30% decrease in menstrual abnormalities. Reproductive lifespan was 32 years (95% confidence interval, 30 to 34 years). Although significant heterogeneity was present, study quality ranged from fair to good, and no evidence of publication bias was noted., Conclusions: Menstrual abnormalities and shorter reproductive lifespan are common in females with CKD, although kidney transplantation may improve menstrual health., (Copyright © 2022 by the American Society of Nephrology.)

Introduction: The use of gender-affirming oestrogen therapy (GAOT) is an integral part of the gender-affirming transition process for transgender women (assigned male at birth who identify as women) and gender-diverse individuals. However, its use may present significant cardiovascular implications, which may be influenced by systemic oestradiol levels. Therefore, we aim to establish the association between serum oestradiol levels and incidence of adverse cardiovascular events in individuals using GAOT., Methods and Analysis: We will conduct a systematic review addressing the association between serum oestradiol levels and risk of adverse cardiovascular events in individuals using GAOT. Our primary outcome is the incidence of adverse cardiovascular events, our secondary outcome is the incidence of cardiovascular-related mortality and our tertiary outcome is cardiovascular-related risk factors. Electronic databases (Cochrane Central Register of Controlled Trials, Embase, MEDLINE and Web of Science) will be searched from inception until September 2022. Two investigators will independently complete screening to determine appropriateness of inclusion. Extracted data will include information on serum sex hormone levels (oestradiol and testosterone), participants, GAOT (route of administration, formulations, dosages and duration of exposure), incidence of cardiovascular outcomes, study quality and risk of bias. Inter-reviewer reliability will be calculated at both phases. Data will be presented both descriptively and meta-analysed using a random effects model, if appropriate. Heterogeneity will be explored and meta-regressed if noted., Ethics and Dissemination: Ethics approval is not needed. We will disseminate findings through international conferences, distributions to transgender and gender-diverse support organisations, decision-makers and key stakeholders. The final systematic review will be published in a peer-reviewed journal., Trial Registration Number: CRD42021247717., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: In 2019, two Canadian provinces became the first jurisdictions in North America to pass deemed consent legislation to increase deceased organ donation and transplantation rates. We sought to explore the perspectives of the deemed consent legislation for organ donation in Canada from the viewpoint of individuals commenting on press articles., Design, Setting, Participants, & Measurements: In this qualitative descriptive study, we extracted public comments regarding deemed consent from online articles published by four major Canadian news outlets between January 2019 and July 2020. A total of 4357 comments were extracted from 35 eligible news articles. Comments were independently analyzed by two research team members using a conventional content analysis approach., Results: Commenters' perceptions of the deemed consent legislation for organ donation in Canada predominantly fit within three organizational groups: perceived positive implications of the bills, perceived negative implications of the bills, and key considerations. Three themes emerged within each group that summarized perspectives of the proposed legislation. Themes regarding the perceived positive implications of the bills included majority rules, societal effect, and prioritizing donation. Themes regarding the perceived negative implications of the bills were a right to choose, the potential for abuse and errors, and a possible slippery slope. Improving government transparency and communication, clarifying questions and addressing concerns, and providing evidence for the bills were identified as key considerations., Conclusions: If deemed consent legislation is meant to increase organ donation and transplantation, addressing public concerns will be important to ensure successful implementation., (Copyright © 2022 by the American Society of Nephrology.)

In this study on medication adherence among newly diagnosed patients with uncomplicated, incident hypertension, we conducted a retrospective cohort study using available administrative and laboratory data from April 1, 2012 to March 31, 2017 in Alberta, Canada to understand the extent to which baseline laboratory assessment and/or subsequent follow-up was associated with persistence with antihypertensive therapy. We determined the frequency of baseline and follow-up testing and compared the rates of medication persistence by patient-, neighbourhood-, and treatment-related factors. Of 103 232 patients with newly diagnosed, uncomplicated hypertension who filled their first prescription within our study timeframe, 52.5% were non-persistent within 6 months. Persistent patients were more often female and residing in neighbourhoods with higher social status (with exception to rurality). Aside from older age, the strongest predictor of persistence was performance of laboratory testing related to hypertension with an apparent effect in which higher levels of medication persistence were seen with more frequent laboratory testing. We concluded that medication persistence was far from optimal, dropping off considerably after 6 months for more than half of patients. Medication persistence is a substantial barrier to realizing the full societal benefits of antihypertensive treatment. Ongoing follow up with patients, including laboratory testing, may be a critical component of better long term treatment persistence., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Introduction: Understanding the reasons for the wide variation in health care spending among patients with schizophrenia may benefit the development of interventions aimed at improving patient outcomes and health care spending efficiency. The aim of our study was to determine factors associated with high health care spending in the patient population., Methods: A serial cross-sectional study used the administrative health records of residents of Alberta, Canada between 1 January 2008 and 31 December 2017 and provincial costing methodologies to calculate total health care spending and sector-specific costs. Factors that modified the odds of being a high cost (i.e. 95th percentile or higher) patient with schizophrenia were estimated using generalized estimating equations., Results: This study captured 242 818 person-years of observations among 38 177 unique patients with schizophrenia. Increased odds of being a high-cost patient were associated with younger age (18-29 years), male sex, unstable housing status and requiring care from multiple medical specialties. The strongest estimated associations between high cost status and comorbidity were for metastatic cancer (OR = 2.26) and cirrhosis (OR = 2.07). In contrast, polypharmacy was associated with a decreased odds of being high cost compared with untreated patients., Conclusion: Factors associated with being a high-cost patient are the result of complex interactions between individual, structural and treatment-related factors. Efforts to improve patient outcomes and address rising health care costs must consider the value of allocating resources towards early detection and support of patients with schizophrenia along with the prevention/management of comorbidity., Competing Interests: None.

Background: Characteristics of patients using newer 2 nd and 3 rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018., Methods: We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018., Results: Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%)., Conclusion: Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2 nd or 3 rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA., (© 2022. The Author(s).)

Background: There is increasing evidence demonstrating the importance of the neighbourhood built environment in supporting physical activity. Physical activity provides numerous health benefits including improvements in health-related fitness (i.e., muscular, cardiorespiratory, motor, and morphological fitness). Emerging evidence also suggests that the neighbourhood built environment is associated with health-related fitness. Our aim was to summarize evidence on the associations between the neighbourhood built environment and components of health-related fitness in adults., Methods: We undertook a systematic review following PRISMA guidelines. Our data sources included electronic searches in MEDLINE, Embase, CINAHL, Web of Science, SPORTDiscus, Environment Complete, ProQuest Dissertations and Theses, and Transport Research International Documentation from inception to March 2021. Our eligibility criteria consisted of observational and experimental studies estimating associations between the neighbourhood built environment and health-related fitness among healthy adults (age ≥ 18 years). Eligible studies included objective or self-reported measures of the neighbourhood built environment and included either objective or self-reported measures of health-related fitness. Data extraction included study design, sample characteristics, measured neighbourhood built environment characteristics, and measured components of health-related fitness. We used individual Joanna Briggs Institute study checklists based on identified study designs. Our primary outcome measure was components of health-related fitness (muscular; cardiorespiratory; motor, and morphological fitness)., Results: Twenty-seven studies (sample sizes = 28 to 419,562; 2002 to 2020) met the eligibility criteria. Neighbourhood destinations were the most consistent built environment correlate across all components of health-related fitness. The greatest number of significant associations was found between the neighbourhood built environment and morphological fitness while the lowest number of associations was found for motor fitness. The neighbourhood built environment was consistently associated with health-related fitness in studies that adjusted for physical activity., Conclusion: The neighbourhood built environment is associated with health-related fitness in adults and these associations may be independent of physical activity. Longitudinal studies that adjust for physical activity (including resistance training) and sedentary behaviour, and residential self-selection are needed to obtain rigorous causal evidence for the link between the neighbourhood built environment and health-related fitness., Trial Registration: Protocol registration: PROSPERO number CRD42020179807., (© 2022. The Author(s).)

Objectives: Schizophrenia is characterized by high levels of disability often resulting in increased healthcare utilization and spending. With expanding healthcare costs across all healthcare sectors, there is a need to understand how healthcare spending has changed over time. We conducted a population-based study using administrative health data from Alberta, Canada, to describe changes in medical complexity and direct healthcare spending among patients with schizophrenia over a 10-year period., Methods: A serial cross-sectional study from January 1, 2008, to December 31, 2017, was conducted to determine changes in demographic characteristics, medical complexity, and costs among all adults (18 years or older) with schizophrenia. Total healthcare spending and sector-specific costs attributable to hospitalizations, emergency department visits, practitioner billings, and prescriptions were calculated and compared over time., Results: Over the 10-year period the contact prevalence of patients with schizophrenia increased from 0.6% ( n   =  16,183) to 1.0% ( n   =  33,176) within the province. There was a marked change in medical complexity with the number of patients living with 3 or more comorbidities increasing from 33.0% to 47.3%. Direct annual healthcare costs increased 2-fold from 321 to 639 million CAD (493 million USD) with a 7-fold increase in medication expenditures over the 10-year time frame. As of 2017, spending on pharmaceutical treatment surpassed hospitalizations as the leading spending category in this population., Conclusions: Healthcare spending among patients with schizophrenia continues to increase and may be partially attributable to growing rates of multimorbidity within this population. Although promising second-generation antipsychotic medications have entered the market, this has resulted in considerable changes in the distribution of healthcare spending over time. These findings will inform policy discussions around resource allocation and efforts to curb health spending while also improving care for patients with schizophrenia.

Introduction: Information on early, guideline discordant referrals in nephrology is limited. Our objective was to investigate trends in referral patterns to nephrology for patients with chronic kidney disease (CKD)., Methods: Retrospective cohort study of adults with ≥1 visits to a nephrologist from primary care with ≥1 serum creatinine and/or urine protein measurement <180 days before index nephrology visit, from 2006 and 2019 in Alberta, Canada. Guideline discordant referrals were those that did not meet ≥1 of: Estimated glomerular filtration rate (eGFR) ˂ 30 mL/min/1.73m2, persistent albuminuria (ACR ≥ 300 mg/g, PCR ≥ 500 mg/g, or Udip ≥ 2+), or progressive and persistent decline in eGFR until index nephrology visit (≥ 5 mL/min/1.73m2)., Results: Of 69,372 patients with CKD, 28,518 (41%) were referred in a guideline concordant manner. The overall rate of first outpatient visits to nephrology increased from 2006 to 2019, although guideline discordant referrals showed a greater increase (trend 21.9 per million population/year, 95% confidence interval 4.3, 39.4) versus guideline concordant referrals (trend 12.4 per million population/year, 95% confidence interval 5.7, 19.0). The guideline concordant cohort were more likely to be on renin-angiotensin system blockers or beta blockers (hazard ratio 1.14, 95% confidence interval 1.12, 1.16), and had a higher risk of CKD progression (hazard ratio 1.09, 95% confidence interval 1.06, 1.13), kidney failure (hazard ratio 7.65, 95% confidence interval 6.83, 8.56), cardiovascular event (hazard ratio 1.40, 95% confidence interval 1.35,1.45) and mortality (hazard ratio 1.58, 95% confidence interval 1.52, 1.63)., Conclusions: A significant proportion nephrology referrals from primary care were not consistent with current guideline-recommended criteria for referral. Further work is needed to identify quality improvement initiatives aimed at enhancing referral patterns of patients with CKD., Competing Interests: The authors have declared that no competing interests exist.

Background: Confirmatory tests are recommended for diagnosing primary aldosteronism, but the supporting evidence is unclear., Methods: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials. Studies evaluating any guideline-recommended confirmatory test (ie, saline infusion test, salt loading test, fludrocortisone suppression test, and captopril challenge test), compared with a reference standard were included. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess the risk of bias. Meta-analyses were conducted using hierarchical summary receiver operating characteristic models., Results: Fifty-five studies were included, comprising 26 studies (3654 participants) for the recumbent saline infusion test, 4 studies (633 participants) for the seated saline infusion test, 2 studies (99 participants) for the salt loading test, 7 studies (386 participants) for the fludrocortisone suppression test, and 25 studies (2585 participants) for the captopril challenge test. Risk of bias was high, affecting more than half of studies, and across all domains. Studies with case-control sampling overestimated accuracy by 7-fold (relative diagnostic odds ratio, 7.26 [95% CI, 2.46-21.43]) and partial verification or use of inconsistent reference standards overestimated accuracy by 5-fold (5.12 [95% CI, 1.48-17.77]). There were large variations in how confirmatory tests were conducted, interpreted, and verified. Under most scenarios, confirmatory testing resulted in an excess of missed cases. The certainty of evidence underlying each test (Grading of Recommendations, Assessment, Development, and Evaluations) was very low., Conclusions: Recommendations for confirmatory testing in patients with abnormal screening tests and high probability features of primary aldosteronism are based on very low-quality evidence and their routine use should be reconsidered.

Background: People with kidney failure have high risk of postoperative morbidity and mortality. Although the revised cardiac risk index (RCRI) is used to estimate the risk of major postoperative events, it has not been validated in this population. We aimed to externally validate the RCRI and determine whether updating the model improved predictions for people with kidney failure., Methods: We derived a retrospective, population-based cohort of adults with kidney failure (maintenance dialysis or sustained estimated glomerular filtration rate < 15 mL/min per 1.73 m 2 ) who had surgery in Alberta, Canada between 2005 and 2019. We categorized participants based on RCRI variables and assigned risk estimates of death or major cardiac events, and then estimated predictive performance. We re-estimated the coefficients for each RCRI variable and internally validated the updated model. Net benefit was estimated with decision curve analysis., Results: After 38,541 surgeries, 1204 events (3.1%) occurred. The estimated C-statistic for the original RCRI was 0.64 (95% confidence interval: 0.62, 0.65). Examination of calibration revealed significant risk overestimation. In the re-estimated RCRI model, discrimination was marginally different (C-statistic 0.67 [95% confidence interval: 0.66, 0.69]), though calibration was improved. No net benefit was observed when the data were examined with decision curve analysis, whereas the original RCRI was associated with harm., Conclusions: The RCRI performed poorly in a Canadian kidney failure cohort and significantly overestimated risk, suggesting that RCRI use in similar kidney failure populations should be limited. A re-estimated kidney failure-specific RCRI may be promising but needs external validation. Novel perioperative models for this population are urgently needed., (© 2022 The Authors.)