Social determinants of access to timely elective surgery in Ontario, Canada: a cross-sectional population level study.

BACKGROUND: Equitable access to surgical care has clinical and policy implications. We assess the association between social disadvantage and wait times for elective surgical procedures in Ontario. METHODS: We conducted a cross-sectional analysis using administrative data sets of adults receiving nonurgent inguinal hernia repair, cholecystectomy, hip arthroplasty, knee arthroplasty, arthroscopy, benign uterine surgery and cataract surgery from April 2013 to December 2019. We assessed the relation between exceeding target wait times and the highest versus lowest quintile of marginalization dimensions by use of generalized estimating equations logistic regression. RESULTS: Of the 1 385 673 procedures included, 174 633 (12.6%) exceeded the target wait time. Adjusted analysis for cataract surgery found significantly increased odds of exceeding wait times for residential instability (adjusted odd ratio [OR] 1.16, 95% confidence interval [CI] 1.11-1.21) and recent immigration (adjusted OR 1.12, 95% CI 1.07-1.18). The highest deprivation quintile was associated with 18% (adjusted OR 1.18, 95% CI 1.12-1.24) and 20% (adjusted OR 1.20, 95% CI 1.12-1.28) increased odds of exceeding wait times for knee and hip arthroplasty, respectively. Residence in areas where higher proportions of residents self-identify as being part of a visible minority group was independently associated with reduced odds of exceeding target wait times for hip arthroplasty (adjusted OR 0.82, 95% CI 0.75-0.91), cholecystectomy (adjusted OR 0.68, 95% CI 0.59-0.79) and hernia repair (adjusted OR 0.65, 95% CI 0.56-0.77) with an opposite effect in benign uterine surgery (adjusted OR 1.28, 95% CI 1.17-1.40). INTERPRETATION: Social disadvantage had a small and inconsistent impact on receiving care within wait time targets. Future research should consider these differences as they relate to resource distribution and the organization of clinical service delivery.

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).

Identification of people with low prevalence diseases in administrative healthcare records: A case study of HIV in British Columbia, Canada.

INTRODUCTION: Case-finding algorithms can be applied to administrative healthcare records to identify people with diseases, including people with HIV (PWH). When supplementing an existing registry of a low prevalence disease, near-perfect specificity helps minimize impacts of adding in algorithm-identified false positive cases. We evaluated the performance of algorithms applied to healthcare records to supplement an HIV registry in British Columbia (BC), Canada. METHODS: We applied algorithms based on HIV-related diagnostic codes to healthcare practitioner and hospitalization records. We evaluated 28 algorithms in a validation sub-sample of 7,124 persons with positive HIV tests (2,817 with a prior negative test) from the STOP HIV/AIDS data linkage-a linkage of healthcare, clinical, and HIV test records for PWH in BC, resembling a disease registry (1996-2020). Algorithms were primarily assessed based on their specificity-derived from this validation sub-sample-and their impact on the estimate of the total number of PWH in BC as of 2020. RESULTS: In the validation sub-sample, median age at positive HIV test was 37 years (Q1: 30, Q3: 46), 80.1% were men, and 48.9% resided in the Vancouver Coastal Health Authority. For all algorithms, specificity exceeded 97% and sensitivity ranged from 81% to 95%. To supplement the HIV registry, we selected an algorithm with 99.89% (95% CI: 99.76% - 100.00%) specificity and 82.21% (95% CI: 81.26% - 83.16%) sensitivity, requiring five HIV-related healthcare practitioner encounters or two HIV-related hospitalizations within a 12-month window, or one hospitalization with HIV as the most responsible diagnosis. Upon adding PWH identified by this highly-specific algorithm to the registry, 8,774 PWH were present in BC as of March 2020, of whom 333 (3.8%) were algorithm-identified. DISCUSSION: In the context of an existing low prevalence disease registry, the results of our validation study demonstrate the value of highly-specific case-finding algorithms applied to administrative healthcare records to enhance our ability to estimate the number of PWH living in BC.

Population-Based Repeated Cross-Sectional Study of Hospitalizations for Comorbid Physical and Psychiatric Disorders in Young Adults in Ontario, Canada.

PURPOSE: To measure trends in the rates and costs of hospitalizations over a 15-year period among young adults with physical and/or psychiatric disorders. METHODS: This population-based, repeated cross-sectional study identified all 18- to 26- year-olds hospitalized in Ontario, Canada from April 1, 2003 and March 31, 2018 (fiscal years 2003-2017). Using discharge diagnoses, we assigned hospitalizations to one of four categories: 1) psychiatric disorder only; 2) primary psychiatric disorder with comorbid physical illness; 3) primary physical with comorbid psychiatric disorder; and 4) physical illness only. We compared health service utilization and changes in rates of hospitalizations over time using restricted cubic spline regression. Secondary outcome measures included change in hospital costs for each hospitalization category over the study period. RESULTS: Of 1,076,951 hospitalizations in young adults (73.7% female), 195,726 (18.2%) had a psychiatric disorder (either primary or comorbid). There were 129,676 hospitalizations (12.0%) with psychiatric disorders only, 36,287 (3.4%) with primary psychiatric and comorbid physical disorders, 29,763 (2.8%) with primary physical and comorbid psychiatric disorders, and 881,225 (81.8%) with physical disorders only. Rates of hospitalization for psychiatric disorders only increased 81% from 4.32 to 7.84/1,000 population, and those with physical health disorders with comorbid psychiatric disorders increased 172% from 0.47 to 1.28/1,000 population. Substance-related disorders were the most common comorbid psychiatric disorders among youth hospitalized for physical illness and increased 260% from 0.9 to 3.3/1,000 population. DISCUSSION: Hospitalizations among young adults with primary and comorbid psychiatric disorders have increased significantly over the past 15 years. Health system resources should be adequately directed to meet the shifting and complex needs of hospitalized young adults.

Characterizing opioid agonist therapy uptake and factors associated with treatment retention among people with HIV in British Columbia, Canada.

Accidental overdoses are now the leading cause of death among people with HIV (PWH) in British Columbia (BC). We examined the utilization and retention of opioid agonist therapy (OAT). Adult PWH (≥19 years) with ≥ 1 OAT dispensation in BC between 2008 and 2020 were included (n = 1,515). OAT treatment episodes were formed based on specific criteria for slow-release oral morphine (SROM), methadone, injectable OAT (iOAT), and buprenorphine/naloxone. Retention in treatment was defined as any episode lasting ≥ 12 months. Logistic regression with generalized estimating equations modeled retention-associated factors. There was a 56.6% decline in OAT retention over time. Buprenorphine treatment exhibited significantly lower odds of retention (OR: 0.58; 95% CI: 0.36-0.92) compared to methadone. Conversely, no significant change in retention odds was observed for SROM (0.72; 0.33-1.54) and iOAT (0.81; 0.31-2.12). Factors associated with increased odds of retention included a 10-year increase in age (1.69; 1.46-1.95), previous retention history (1.96; 1.40-2.73), achieving OAT therapeutic dose (8.22; 6.67-10.14), and suppressed HIV viral load (1.35; 1.10-1.67). Individuals with a lifetime HCV diagnosis receiving iOAT were more likely to retain (3.61; 1.20-10.83). Each additional year on OAT during the study period was associated with a 4% increase in the odds of retention. A significant proportion of PWH had a history of OAT prescribing but experienced low retention rates. Retention outcomes were more positive for SROM and iOAT. The association between OAT medication type and retention odds may be particularly influenced by HCV diagnosis. Optimal management of opioid use disorder among PWH, with an emphasis on attaining the therapeutic dose is crucial.

Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics.

OBJECTIVE: This paper describes the baseline characteristics of the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) study, one of the largest cardiovascular (CV) outcome studies in the field of obesity, which evaluates the effect of semaglutide versus placebo on major CV events. METHODS: SELECT enrolled individuals with overweight or obesity without diabetes, with prior myocardial infarction, stroke, and/or peripheral artery disease. This study reports participants' baseline characteristics in the full study population and subgroups defined by baseline glycated hemoglobin (HbA1c ; <5.7%, ≥5.7 to <6.0%, ≥6.0 to <6.5%), baseline waist to height ratio tertile, and qualifying prior CV event or condition. RESULTS: The study enrolled 17,605 participants (72.5% male) with an average (SD) age of 61.6 (8.9) years and BMI of 33.34 (5.04) kg/m2 . The most common prior CV event was myocardial infarction (76.3% of participants), followed by stroke (23.3%) and peripheral artery disease (8.6%). Furthermore, 24.3% had a heart failure diagnosis. Two-thirds of participants (66%) had HbA1c in the prediabetes range (5.7%-6.4%). Across groups of increasing HbA1c , prevalence of all CV risk factors increased. CONCLUSIONS: The enrolled population in SELECT includes participants across a broad range of relevant risk categories. This will allow the study to garner information about the CV benefits of semaglutide across these relevant clinical subgroups.

Neighbourhood context and diagnosed mental health conditions among immigrant and non-immigrant youth: a population-based cohort study in British Columbia, Canada.

PURPOSE: Evidence from systematic reviews suggests that adult immigrants living in areas of higher immigrant density (areas with a higher proportion of foreign-born residents) tend to experience fewer mental health problems-likely through less discrimination, greater access to culturally/linguistically appropriate services, and greater social support. Less is known about how such contexts are associated with mental health during childhood-a key period in the onset and development of many mental health challenges. This study examined associations between neighbourhood immigrant density and youth mental health conditions in British Columbia (BC; Canada). METHODS: Census-derived neighbourhood characteristics were linked to medical records for youth present in ten of BC's largest school districts from age 5 through 19 over the study period (1995-2016; n = 138,090). Occurrence of physician assessed diagnoses of mood and/or anxiety disorders, attention deficit hyperactivity disorder (ADHD), and conduct disorder was inferred through International Classification of Diseases (ICD) diagnostic codes in universal public health insurance records. Multi-level logistic regression was used to model associations between neighbourhood characteristics and odds of diagnoses for each condition; models were stratified by generation status (first-generation: foreign-born; second-generation: Canadian-born to a foreign-born parent; non-immigrant). RESULTS: Higher neighbourhood immigrant density was associated with lower odds of disorders among first-generation immigrant youth (e.g., adjusted odds of mood-anxiety disorders for those in neighbourhoods with the highest immigrant density were 0.67 times lower (95% CI: 0.49, 0.92) than those in neighbourhoods with the lowest immigrant density). Such protective associations generally extended to second-generation and non-immigrant youth, but were-for some disorders-stronger for first-generation than second-generation or non-immigrant youth. CONCLUSIONS: Findings suggest there may be protective mechanisms associated with higher neighbourhood immigrant density for mental health conditions in immigrant and non-immigrant youth. It is important that future work examines potential pathways by which contextual factors impact immigrant and non-immigrant youth mental health.

Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.

BACKGROUND/AIMS: The HIV Prevention Trials Network 083 trial was a group-sequential non-inferiority trial designed to compare HIV incidence under a novel experimental regimen for HIV prevention, long-acting injectable cabotegravir, with an active-control regimen of daily oral tenofovir disoproxil fumarate/emtricitabine (brand name Truvada). In March of 2020, just as the trial had completed enrollment, the COVID-19 pandemic threatened to prevent trial participants from attending study visits and obtaining study medication, motivating the study team to update the interim monitoring plan. The Data and Safety Monitoring Board subsequently stopped the trial at the first interim review due to strong early evidence of efficacy. METHODS: Here we describe some unique aspects of the trial's design, monitoring, analysis, and interpretation. We illustrate the importance of computing point estimates, confidence intervals, and p values based on the sampling distribution induced by sequential monitoring. RESULTS: Accurate analysis, decision-making and interpretation of trial results rely on pre-specification of a stopping boundary, including the scale on which the stopping rule will be implemented, the specific test statistics to be calculated, and how the boundary will be adjusted if the available information fraction at interim review is different from planned. After appropriate adjustment for the sampling distribution and overrun, the HIV Prevention Trials Network 083 trial provided strong evidence that the experimental regimen was superior to the active control. CONCLUSIONS: For the HIV Prevention Trials Network 083 trial, the difference between corrected inferential statistics and naive results was quite small-as will often be the case-nevertheless, it is appropriate to report and publish the most accurate and unbiased statistical results.

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial.

Evidence of the effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized, double-blind clinical trial was conducted from June 2016 through June 2020. Of 3120 screened adults, 356 patients were eligible and enrolled, and 337 patients (mean age, 53.9; 141 [41.8%] women), randomized to 1300 mg TXA orally or 1000 mg TXA through IV (n = 168) vs placebo (n = 169) thrice daily for maximum 30 days. Three hundred thirty patients were activated when their platelet counts fell below 30 000 per µL; 279 (83%) had complete outcome ascertainment. World Health Organization (WHO) grade ≥2 bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, with an adjusted odds ratio of 0.83 (95% confidence interval [CI], 0.50-1.34; P = .44). There was no statistically significant difference in the mean number of platelet transfusions (mean difference, 0.1; 95% CI, -1.9 to 2.0), mean days alive without grade ≥2 bleeding (mean difference, 0.8; 95% CI, -0.4 to 2.0), thrombotic events (6/163 [3.7%] TXA, 9/163 [5.5%] placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea (116/164 [70.7%] TXA and 114/163 [69.9%] placebo); febrile neutropenia (111/164 [67.7%] TXA, 105/163 [64.4%] placebo); fatigue (106/164 [64.6%] TXA, 109/163 [66.9%] placebo); and nausea (104/164 [63.4%] TXA, 97/163 [59.5%] placebo). Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with TXA compared with placebo did not significantly reduce the risk of WHO grade ≥2 bleeding.

Social context factors and refugee children's emotional health.

BACKGROUND: Refugee children face numerous challenges associated with pre-migration trauma and post-migration adaptation. Much research pertaining to refugee children's well-being focuses on psychiatric symptoms. Relatively few studies have examined how social context factors-such as perceptions of peer belonging, and support from adults at home and at school-contribute to the emotional health of refugee children. Informed by social-ecological theories emphasizing dynamic interactions between the contexts in which children develop, we examined associations between social context factors and emotional health in refugee children. METHODS: Data were drawn from a population-based data linkage in British Columbia, Canada. The analytic sample included 682 grade 4 students (Mage 9.2 years; 46.3% female) with a refugee background who responded to the Middle Years Development Instrument (MDI) during the 2010/2011-2016/2017 school years. The MDI is a self-report survey of children's social and emotional competencies and social context factors completed at school. Regression analyses were used to examine associations of social context factors (school climate, supportive adults at school and at home, and peer belonging) with indicators of emotional health (life satisfaction, self-concept, optimism, and sadness). Refugee generation status (first/second) was considered through stratification and testing of interactions with social context factors. RESULTS: Perceived supportive school climate, support from adults in school and at home, and peer belonging were each independently associated with better emotional health. Results were similar for first- and second-generation children. CONCLUSION: Taken together, results suggest a unique role of the school context to refugee children's emotional health. School-based programming that promotes positive school climate can be considered as an important approach to support newcomer refugee children and their families.

A Novel Catheterization Laboratory Radiation Shielding System: Results of Pre-Clinical Testing.

BACKGROUND: This pre-clinical study evaluated the efficacy of a novel shielding system to reduce scatter radiation in the cardiac catheterization laboratory. METHODS: Using a scatter radiation phantom in a standard cardiac catheterization laboratory, a radiation physicist recorded radiation measurements at 20 reference points on the operator side of the table. Measurements were made with fluoroscopy and cine with the C-arm in the posterior-anterior (PA) and 40 degrees left anterior oblique (LAO) orientations. Scatter radiation doses were compared with and without use of the shielding system. RESULTS: Use of the shielding system was associated with >94.2% reduction in scatter radiation across all reference points in the PA and LAO projections with fluoroscopy and cine. With the shielding system, dose reductions at the location of the primary operator ranged from 97.8% to 99.8%. At locations of maximum scatter radiation, use of the shielding system resulted in dose reductions ranging from 97.8% to 99.8% with fluoroscopy and from 97.9% to 99.8% with cine. CONCLUSIONS: In this pre-clinical study, a novel radiation shielding system was observed to dramatically reduce scatter radiation doses. Based on these results, clinical testing is warranted to determine whether the shielding system will enable operators and staff to perform interventional procedures with less radiation exposure that may obviate the need to wear standard lead apparel. INDEXING WORDS: Radiation safety; occupational health; occupational hazard.

Quantifying pulmonary perfusion from noncontrast computed tomography.

PURPOSE: Computed tomography (CT)-derived ventilation methods compute respiratory induced volume changes as a surrogate for pulmonary ventilation. Currently, there are no known methods to derive perfusion information from noncontrast CT. We introduce a novel CT-Perfusion (CT-P) method for computing the magnitude mass changes apparent on dynamic noncontrast CT as a surrogate for pulmonary perfusion. METHODS: CT-Perfusion is based on a mass conservation model which describes the unknown mass change as a linear combination of spatially corresponding inhale and exhale HU estimated voxel densities. CT-P requires a deformable image registration (DIR) between the inhale/exhale lung CT pair, a preprocessing lung volume segmentation, and an estimate for the Jacobian of the DIR transformation. Given this information, the CT-P image, which provides the magnitude mass change for each voxel within the lung volume, is formulated as the solution to a constrained linear least squares problem defined by a series of subregional mean magnitude mass change measurements. Similar to previous robust CT-ventilation methods, the amount of uncertainty in a subregional sample mean measurement is related to measurement resolution and can be characterized with respect to a tolerance parameter τ . Spatial Spearman correlation between single photon emission CT perfusion (SPECT-P) and the proposed CT-P method was assessed in two patient cohorts via a parameter sweep of τ . The first cohort was comprised of 15 patients diagnosed with pulmonary embolism (PE) who had SPECT-P and 4DCT imaging acquired within 24 h of PE diagnosis. The second cohort was comprised of 15 nonsmall cell lung cancer patients who had SPECT-P and 4DCT images acquired prior to radiotherapy. For each test case, CT-P images were computed for 30 different uncertainty parameter values, uniformly sampled from the range [0.01, 0.125], and the Spearman correlation between the SPECT-P and the resulting CT-P images were computed. RESULTS: The median correlations between CT-P and SPECT-P taken over all 30 test cases ranged between 0.49 and 0.57 across the parameter sweep. For the optimal tolerance τ = 0.0385, the CT-P and SPECT-P correlations across all 30 test cases ranged between 0.02 and 0.82. A one-sample sign test was applied separately to the PE and lung cancer cohorts. A low Spearmen correlation of 15% was set as the null median value and two-sided alternative was tested. The PE patients showed a median correlation of 0.57 (IQR = 0.305). One-sample sign test was statistically significant with 96.5 % confidence interval: 0.20-0.63, P < 0.00001. Lung cancer patients had a median correlation of 0.57(IQR = 0.230). Again, a one-sample sign test for median was statistically significant with 96.5 percent confidence interval: 0.45-0.71, P < 0.00001. CONCLUSION: CT-Perfusion is the first mechanistic model designed to quantify magnitude blood mass changes on noncontrast dynamic CT as a surrogate for pulmonary perfusion. While the reported correlations with SPECT-P are promising, further investigation is required to determine the optimal CT acquisition protocol and numerical method implementation for CT-P imaging.

Validating International Classification of Disease 10th Revision algorithms for identifying influenza and respiratory syncytial virus hospitalizations.

OBJECTIVE: Routinely collected health administrative data can be used to efficiently assess disease burden in large populations, but it is important to evaluate the validity of these data. The objective of this study was to develop and validate International Classification of Disease 10th revision (ICD -10) algorithms that identify laboratory-confirmed influenza or laboratory-confirmed respiratory syncytial virus (RSV) hospitalizations using population-based health administrative data from Ontario, Canada. STUDY DESIGN AND SETTING: Influenza and RSV laboratory data from the 2014-15, 2015-16, 2016-17 and 2017-18 respiratory virus seasons were obtained from the Ontario Laboratories Information System (OLIS) and were linked to hospital discharge abstract data to generate influenza and RSV reference cohorts. These reference cohorts were used to assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ICD-10 algorithms. To minimize misclassification in future studies, we prioritized specificity and PPV in selecting top-performing algorithms. RESULTS: 83,638 and 61,117 hospitalized patients were included in the influenza and RSV reference cohorts, respectively. The best influenza algorithm had a sensitivity of 73% (95% CI 72% to 74%), specificity of 99% (95% CI 99% to 99%), PPV of 94% (95% CI 94% to 95%), and NPV of 94% (95% CI 94% to 95%). The best RSV algorithm had a sensitivity of 69% (95% CI 68% to 70%), specificity of 99% (95% CI 99% to 99%), PPV of 91% (95% CI 90% to 91%) and NPV of 97% (95% CI 97% to 97%). CONCLUSION: We identified two highly specific algorithms that best ascertain patients hospitalized with influenza or RSV. These algorithms may be applied to hospitalized patients if data on laboratory tests are not available, and will thereby improve the power of future epidemiologic studies of influenza, RSV, and potentially other severe acute respiratory infections.

Approval policies for modifications to machine learning-based software as a medical device: A study of bio-creep.

Successful deployment of machine learning algorithms in healthcare requires careful assessments of their performance and safety. To date, the FDA approves locked algorithms prior to marketing and requires future updates to undergo separate premarket reviews. However, this negates a key feature of machine learning-the ability to learn from a growing dataset and improve over time. This paper frames the design of an approval policy, which we refer to as an automatic algorithmic change protocol (aACP), as an online hypothesis testing problem. As this process has obvious analogy with noninferiority testing of new drugs, we investigate how repeated testing and adoption of modifications might lead to gradual deterioration in prediction accuracy, also known as "biocreep" in the drug development literature. We consider simple policies that one might consider but do not necessarily offer any error-rate guarantees, as well as policies that do provide error-rate control. For the latter, we define two online error-rates appropriate for this context: bad approval count (BAC) and bad approval and benchmark ratios (BABR). We control these rates in the simple setting of a constant population and data source using policies aACP-BAC and aACP-BABR, which combine alpha-investing, group-sequential, and gate-keeping methods. In simulation studies, bio-creep regularly occurred when using policies with no error-rate guarantees, whereas aACP-BAC and aACP-BABR controlled the rate of bio-creep without substantially impacting our ability to approve beneficial modifications.

Rejoinder to Discussions on "Approval policies for modifications to machine learning-based software as a medical device: A study of bio-creep".

We thank the discussants for sharing their unique perspectives on the problem of designing automatic algorithm change protocols (aACPs) for machine learning-based software as a medical device. Both Pennello et al. and Rose highlighted a number of challenges that arise in real-world settings, and we whole-heartedly agree that substantial extensions of our work are needed to understand if and how aACPs can be safely deployed in practice. Our work demonstrated that aACPs that appear to be harmless may allow for biocreep, even when the data distribution is assumed to be representative and stationary over time. While we investigated two solutions that protect against this specific issue, many more statistical and practical challenges remain and we look forward to future research on this topic.

Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.

The Association of Residential Instability and Hospitalizations among Homeless and Vulnerably Housed Individuals: Results from a Prospective Cohort Study.

The present study examined the association of residential instability with hospitalizations among homeless and vulnerably housed individuals over a 4-year time period. Survey data were linked to administrative records on hospitalizations. Specifically, we used data from the Health and Housing in Transition study, a prospective cohort study that tracked the health and housing status of homeless and vulnerably housed individuals in Canada. Responses from Vancouver-based participants (n = 378) from baseline and 3 follow-ups were linked to their administrative health records on hospitalizations (Discharge Abstract Database - Hospital Separation Files; 2008-2012). A generalized estimating equations model was used to examine associations between the number of residential moves and any hospitalizations during each year (none versus ≥ 1 hospitalizations). Analyses included demographic and health variables. Survey data were collected via structured interviews. Hospitalizations were derived from provincial administrative health records. A higher number of residential moves were associated with hospitalization over the study period (adjusted odds ratio: 1.14; 95% confidence interval: 1.01, 1.28). Transgender, female gender, perceived social support, better self-reported mental health, and having ≥ 3 chronic health conditions also predicted having been hospitalized over the study period, whereas high school/higher education was negatively associated with hospitalizations. Our results indicate that residential instability is associated with increased risk of hospitalization, illustrating the importance of addressing housing as a social determinant of health.

Associations of Birth Factors and Socio-Economic Status with Indicators of Early Emotional Development and Mental Health in Childhood: A Population-Based Linkage Study.

Using a linked population-based database established on healthcare, socio-economic, and survey datasets in British Columbia, Canada, we examined how biological, socio-demographic, and socio-economic status (SES) factors at birth related to children's emotional development and mental health. One analysis examined teacher-rated anxiety, hyperactivity, and aggression for kindergarten children (Mage = 5.7; n = 134,094). Another analysis examined administrative healthcare records comprising of physician-assigned diagnostic codes for mental health conditions (conduct disorder, attention deficit hyperactivity disorder, anxiety disorder and depression) from ages 5 through 15 (n = 89,404). Various factors at birth, including gestational age, birthweight, and maternal demographics, were related to emotional development and mental health in childhood. Across outcomes, low SES indicated detrimental associations with various aspects of children's emotional development and mental health (e.g., adjusted odds of mental health conditions were 25-39% higher for children of low income families versus others). Findings reinforce evidence that poverty (reduction) is a primary public health issue.