Marginal Cox Proportional Hazards Models Research Articles

Virologically suppressed switch to Dolutegravir/Lamivudine 2-Drug regimen versus switch to commonly prescribed 3-Drug regimens in the United States

BackgroundTwo-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States.MethodsVirologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined.ResultsA total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC (n = 1,450), BIC/FTC/TAF (n = 5,691), or a DTG-based 3DR (n = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%).ConclusionsAmong virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH.

Allopurinol, Febuxostat, and Nonuse of Xanthine Oxidoreductase Inhibitor Treatment in Patients Receiving Hemodialysis: A Longitudinal Analysis

Rationale & ObjectiveAllopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis. Study DesignRetrospective observational cohort study. Setting & ParticipantsData of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan’s Kanagawa and Tokyo metropolitan areas were collected. ExposureAllopurinol, febuxostat, and non-treatment. OutcomesAll-cause mortality, cardiovascular disease (CVD) events, heart failure (HF), acute myocardial infarction (AMI), and stroke. Analytical ApproachFor the main analyses, marginal structural Cox proportional hazards models were used to estimate hazard ratios (HRs) adjusted for time-varying confounding and selection bias due to censoring. ResultsAllopurinol and febuxostat showed significantly better survival than non-treatment for all-cause mortality (HR: 0.40, 95% confidence interval [CI]: 0.30–0.54; HR: 0.49, 95% CI: 0.38–0.63, respectively), without significant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than non-treatment, whereas febuxostat did not for CVD events (HR: 0.89, 95% CI: 0.84–0.95; HR: 1.01, 95% CI: 0.96–1.07, respectively), HF (HR: 0.71, 95% CI: 0.56–0.90; HR: 1.03, 95% CI: 0.87–1.21, respectively), and AMI (HR: 0.48, 95% CI: 0.25–0.91; HR: 0.76, 95% CI: 0.49–1.19, respectively). No comparisons showed significant results for stroke. LimitationsThe ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases. ConclusionsAllopurinol and febuxostat improved survival for all-cause mortality. Allopurinol, and not febuxostat, reduced the risk of CVD events, HF, and AMI.

Forced Expiratory Volume in 1 Second Variability Predicts Lung Transplant or Mortality in People with Cystic Fibrosis in the United States.

Rationale: Declines in percent predicted forced expiratory volume in 1 second (ppFEV1) are an important marker of clinical progression of cystic fibrosis (CF). Objectives: We examined ppFEV1 variability in relation to a combined outcome of lung transplant or death. Methods: We estimated the association between ppFEV1 variability and the combined outcome of lung transplant or death. We included children aged 8 years and older with CF and two prior years of ppFEV1 data before baseline between 2005 and 2021. We defined ppFEV1 increased variability as any relative increase or decrease of at least 10% in ppFEV1 from a 2-year averaged baseline. A marginal structural Cox proportional hazards model was used. We examined a cumulative measure of ppFEV1 variability, defined as the cumulative proportion of visits with ppFEV1 variability at each visit. Kaplan-Meier survival curves were generated on the basis of quartiles of the cumulative distribution of ppFEV1 variability. Results: We included 9,706 patients with CF in our cohort. The median age at cohort entry was 8.3 (interquartile range, 8.2-8.4) years; 50% of patients were female; 94% were White; and the median baseline ppFEV1 was 94.4 (interquartile range, 81.6-106.1). The unadjusted hazard ratio for increased ppFEV1 variability on lung transplant/mortality was 4.13 (95% confidence interval, 3.48-4.90), and the weighted hazard ratio was 1.49 (95% confidence interval, 1.19-1.86). Survival curves stratified by quartile of cumulative variability demonstrated an increased hazard of lung transplant/mortality as the proportion of cumulative ppFEV1 variability increased. Conclusions: We found a strong association between ppFEV1 variability and lung transplant or mortality in a cohort of people with CF in the United States.

Association Between Statin Use and the Incidence of Clinically Diagnosed Osteoarthritis: A Nationwide Retrospective Cohort Study in Taiwan.

To investigate the effect of higher cumulative defined daily dose per year (cDDD/y) compared with lower cDDD/y of statin use in the incidence of any joint osteoarthritis (OA). In this population-based retrospective cohort study, patients who were aged ≥40 years were newly initiated on statin therapy between 2002 and 2011, and had a statin prescription for ≥90 days in the first year of treatment were identified from the 2000 Longitudinal Generation Tracking Database. All patients were separated into groups with higher cDDD/y (>120 cDDD/y) and lower cDDD/y (≤120 cDDD/y; as an active comparator) values. Propensity score matching was performed to balance potential confounders. All recruited patients were followed up for 8 years. Marginal Cox proportional hazard models were used to estimate time-to-event outcomes of OA. Compared with lower cDDD/y use, higher cDDD/y use did not reduce the risk of any joint OA (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.14). Dose-related analysis did not reveal any dose-dependent association. A series of sensitivity analyses showed similar results. Joint-specific analyses revealed that statin did not reduce the incidence of knee, hand, hip, and weight-bearing (knee or hip) OA. Higher cDDD/y statin use did not reduce the risk of OA in this Taiwanese nationwide cohort study. The complexity of OA pathogenesis might contribute to the ineffectiveness of statin. Repurposing statin with its anti-inflammation properties might be ineffective for OA development, and balancing the catabolism and anabolism of cartilage might be a major strategy for OA prevention.

Ambulatory Risk Stratification for Worsening Heart Failure in Patients with Reduced and Preserved Ejection Fraction Using Diagnostic Parameters Available in Implantable Cardiac Monitors.

Ambulatory risk stratification for worsening heart failure (HF) using diagnostics measured by insertable cardiac monitors (ICM) may depend on the left ventricular ejection fraction (LVEF). We evaluated risk stratification performance in patients with reduced versus preserved LVEF. ICM patients with a history of HF events (HFEs) were included from the Optum® de-identified Electronic Health Record dataset merged with ICM device-collected data during 2007-2021. ICM measures nighttime heart rate (NHR), heart rate variability (HRV), atrial fibrillation (AF) burden, rate during AF, and activity duration (ACT) daily. Each diagnostic was categorized into high, medium, or low risk using previously defined features. HFEs were HF-related inpatient, observation unit, or emergency department stays with IV diuresis administration. Patients were divided into two cohorts: LVEF ≤ 40% and LVEF > 40%. A marginal Cox proportional hazards model compared HFEs for different risk groups. A total of 1020 ICM patients with 18,383 follow-up months and 301 months with HFEs (1.6%) were included. Monthly evaluations with a high risk were 2.3, 4.2, 5.0, and 4.5 times (p < 0.001 for all) more likely to have HFEs in the next 30 days compared to those with a low risk for AF, ACT, NHR, and HRV, respectively. HFE rates were higher for patients with LVEF > 40% compared to LVEF ≤ 40% (2.0% vs. 1.3%), and the relative risk between high-risk and low-risk for each diagnostic parameter was higher for patients with LVEF ≤ 40%. Diagnostics measured by ICM identified patients at risk for impending HFEs. Patients with preserved LVEF showed a higher absolute risk, and the relative risk between risk groups was higher in patients with reduced LVEF.

Influence of implant length and diameter on implant failure: A retrospective study

ObjectiveDental implants are widely accepted in the dental community. Although several studies have reported high dental implant survival rates, complications can still occur. Implant failure is associated with different risk factors, including implant length and diameter. However, no clear consensus has yet been reached. This study aimed to evaluate the influence of different risk factors associated with implant failure. MethodsThis study included patients who received dental implants at Kyoto University Hospital. The inclusion criteria were dental implants placed between January 1, 2005 and December 31, 2022. Data on patient- and implant-related variables were collected. We used a marginal Cox proportional hazards models to investigate the association between the potential factors and implant failure. ResultsThis study included 147 patients who received 479 dental implants. Eleven of the 147 patients experienced implant failure, whereas 17 of the 479 implants failed. The cumulative survival rate of dental implants at the final time point was 95.3%. Multivariable marginal Cox analysis showed suggestive evidence that implant length (<10 mm) greatly increased the risk of implant failure compared with implant length (≥10 mm) (reference: <10 mm, hazard ratio, 0.07; 95% confidence interval, 0.01–0.34; p = 0.001). ConclusionsA cumulative survival rate comparable to that reported in other studies was achieved over prolonged periods of time. Although implant failure is multifactorial and implant length is only one of many factors contributing to implant loss, clinicians must be aware of the potential influence of implant length and make treatment decisions.

Air pollution and serious bleeding events in high-risk older adults

ImportanceDespite biological plausibility, very few epidemiologic studies have investigated the risks of clinically significant bleeding events due to particulate air pollution. ObjectiveTo measure the independent and synergistic effects of PM2.5 exposure and anticoagulant use on serious bleeding events. DesignRetrospective cohort study (2008–2016). SettingNationwide Medicare population. ParticipantsA 50% random sample of Medicare Part D-eligible Fee-for-Service beneficiaries at high risk for cardiovascular and thromboembolic events. ExposuresFine particulate matter (PM2.5) and anticoagulant drugs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin). Main outcomes and measuresThe outcomes were acute hospitalizations for gastrointestinal bleeding, intracranial bleeding, or epistaxis. Hazard ratios and 95% CIs for PM2.5 exposure were estimated by fitting inverse probability weighted marginal structural Cox proportional hazards models. The relative excess risk due to interaction was used to assess additive-scale interaction between PM2.5 exposure and anticoagulant use. ResultsThe study cohort included 1.86 million high-risk older adults (mean age 77, 60% male, 87% White, 8% Black, 30% anticoagulant users, mean PM2.5 exposure 8.81 μg/m3). A 10 μg/m3 increase in PM2.5 was associated with a 48% (95% CI: 45%–52%), 58% (95% CI: 49%–68%) and 55% (95% CI: 37%–76%) increased risk of gastrointestinal bleeding, intracranial bleeding, and epistaxis, respectively. Significant additive interaction between PM2.5 exposure and anticoagulant use was observed for gastrointestinal and intracranial bleeding. ConclusionsAmong older adults at high risk for cardiovascular and thromboembolic events, increasing PM2.5 exposure was significantly associated with increased risk of gastrointestinal bleeding, intracranial bleeding, and epistaxis. In addition, PM2.5 exposure and anticoagulant use may act together to increase risks of severe gastrointestinal and intracranial bleeding. Thus, clinicians may recommend that high-risk individuals limit their outdoor air pollution exposure during periods of increased PM2.5 concentrations. Our findings may inform environmental policies to protect the health of vulnerable populations.

Differences in risk stratification for worsening heart failure in patient with reduced versus preserved ejection fraction using diagnostic parameters available in implantable cardiac monitors

Abstract Background Ambulatory management of heart failure (HF) patients require the ability to identify when patients are at highest risk of impending HF events (HFE). The risk stratification ability based on diagnostic parameters measured by implantable cardiac monitors may differ depending on the left ventricular ejection fraction (LVEF) of HF patients. Objective The purpose of this study was to evaluate the difference in risk stratification performance of individual diagnostic parameters currently available in ICMs in identifying patients at increasing risk of HFE in patients with reduced versus preserved LVEF. Methods Patients with history of HFE who were implanted with an ICM was identified from the aggregated and de-identified electronic health record (EHR) database during 2007-2021. The device collected data were merged with the EHR data to create a de-identified database of real-world patients. Currently approved ICMs measure nighttime heart rate (NHR), heart rate variability (HRV), atrial fibrillation (AF) burden, ventricular rate during AF, and activity duration (ACT) daily and stores and transmits this information for the lifetime of the device. Each diagnostic parameter was categorized into high, medium, or low risk using a combination of features predefined in earlier studies. HFEs were defined as inpatient stay with a primary diagnosis of HF or HF related observation unit or emergency visit with IV diuresis administration. Patients were divided into two cohorts of patients with (1) median LVEF ≤ 40% (HFrEF), and (2) median LVEF &amp;gt; 40% (HFpEF). Performance evaluation was performed by simulating monthly follow-ups which consisted of looking at the individual parameter risk states in the last 30 days and evaluating the occurrence of HF events in the following 30 days. A marginal Cox proportional hazards model was used to compare HF events for different risk groups (high, medium, and low) for each individual diagnostic parameter. Results There was a total of 267 patients with median LVEF ≤ 40% (64±13 years old, 67% male) and 622 patients with LVEF&amp;gt;40% (69 ±12 years old, 47% male). For the reduced LVEF cohort, there was a total of 4,867 follow-up months with 65 monthly evaluations (1.3%) had an HF event in the next 30 days. For the preserved LVEF cohort, there was a total of 11,057 follow-up months with 224 monthly evaluations (2.0%) had an HF event in the next 30 days. The event rate comparisons between the risk groups for each individual diagnostic parameter are shown in Figure. As compared to ICM patients with HFrEF, ICM patients with HFpEF had higher absolute event rate across all risk groups, thus lowering the relative risk stratification between risk groups. Conclusion ICM patients with HFpEF showed a higher event rate and hence a higher absolute risk for each risk group, however relative risk between risk groups and hence the risk stratification performance for identifying risk for worsening HF was better in patients with HFrEF.

Differences in Stroke Recurrence Risk Between Atrial Fibrillation Detected on ECG and 14-Day Cardiac Monitoring.

Ischemic stroke and transient ischemic attack (TIA) standard-of-care etiological investigations include an ECG and prolonged cardiac monitoring (PCM). Atrial fibrillation (AF) detected after stroke has been generally considered a single entity, regardless of how it is diagnosed. We hypothesized that ECG-detected AF is associated with a higher risk of stroke recurrence than AF detected on 14-day Holter (PCM-detected AF). We conducted a retrospective, registry-based, cohort study of consecutive patients with ischemic stroke and TIA included in the London Ontario Stroke Registry between 2018 and 2020, with ECG-detected and PCM-detected AF lasting ≥30 seconds. We quantified PCM-detected AF burden. The primary outcome was recurrent ischemic stroke, ascertained by systematically reviewing all medical records until November 2022. We applied marginal cause-specific Cox proportional hazards models adjusted for qualifying event type (ischemic stroke versus TIA), CHA₂DS₂-VASc score, anticoagulation, left ventricular ejection fraction, left atrial size, and high-sensitivity troponin T to estimate adjusted hazard ratios for recurrent ischemic stroke. We included 366 patients with ischemic stroke and TIA with AF, 218 ECG-detected, and 148 PCM-detected. Median PCM duration was 12 (interquartile range, 8.8-14.0) days. Median PCM-detected AF duration was 5.2 (interquartile range, 0.3-33.0) hours, with a burden (total AF duration/total net monitoring duration) of 2.23% (interquartile range, 0.13%-12.25%). Anticoagulation rate at the end of follow-up or at the first event was 83.1%. After a median follow-up of 17 (interquartile range, 5-34) months, recurrent ischemic strokes occurred in 16 patients with ECG-detected AF (13 on anticoagulants) and 2 with PCM-detected AF (both on anticoagulants). Recurrent ischemic stroke rates for ECG-detected and PCM-detected AF groups were 4.05 and 0.72 per 100 patient-years (adjusted hazard ratio, 5.06 [95% CI, 1.13-22.7]; P=0.034). ECG-detected AF was associated with 5-fold higher adjusted recurrent ischemic stroke risk than PCM-detected AF in a cohort of ischemic stroke and TIA with >80% anticoagulation rate.

Comparison of Different Modeling Approaches for Prescription Opioid Use and Its Association With Adverse Events.

Previous research linking opioid prescribing to adverse drug events has failed to properly account for the time-varying nature of opioid exposure. This study aimed to explore how the risk of opioid-related emergency department visits, readmissions, or deaths (composite outcome) varies with opioid dose and duration, comparing different novel modeling techniques. A prospective cohort of 1,511 hospitalized patients discharged from 2 McGill-affiliated hospitals in Montreal, 2014-2016, was followed from the first postdischarge opioid dispensation until 1 year after discharge. Marginal structural Cox proportional hazards models and their flexible extensions were used to explore the association between time-varying opioid use and the composite outcome. Weighted cumulative exposure models assessed cumulative effects of past use and explored how its impact depends on the recency of exposure. The patient mean age was 69.6 (standard deviation= 14.9) years; 57.7% were male. In marginal structural model analyses, current opioid use was associated with a 71% increase in the hazard of opioid-related adverse events (adjusted hazard ratio = 1.71, 95% confidence interval: 1.21, 2.43). The weighted cumulative exposure results suggested that the risk cumulates over the previous 50 days of opioid consumption. Flexible modeling techniques helped assess how the risk of opioid-related adverse events may be associated with time-varying opioid exposures while accounting for nonlinear relationships and the recency of past use.

Improving marginal hazard ratio estimation using quadratic inference functions.

Clustered and multivariate failure time data are commonly encountered in biomedical studies and a marginal regression approach is often employed to identify the potential risk factors of a failure. We consider a semiparametric marginal Cox proportional hazards model for right-censored survival data with potential correlation. We propose to use a quadratic inference function method based on the generalized method of moments to obtain the optimal hazard ratio estimators. The inverse of the working correlation matrix is represented by the linear combination of basis matrices in the context of the estimating equation. We investigate the asymptotic properties of the regression estimators from the proposed method. The optimality of the hazard ratio estimators is discussed. Our simulation study shows that the estimator from the quadratic inference approach is more efficient than those from existing estimating equation methods whether the working correlation structure is correctly specified or not. Finally, we apply the model and the proposed estimation method to analyze a study of tooth loss and have uncovered new insights that were previously inaccessible using existing methods.

Estimation and testing for clustered interval-censored bivariate survival data with application using the semi-parametric version of the Clayton-Oakes model.

The Kaplan-Meier estimator is ubiquitously used to estimate survival probabilities for time-to-event data. It is nonparametric, and thus does not require specification of a survival distribution, but it does assume that the risk set at any time t consists of independent observations. This assumption does not hold for data from paired organ systems such as occur in ophthalmology (eyes) or otolaryngology (ears), or for other types of clustered data. In this article, we estimate marginal survival probabilities in the setting of clustered data, and provide confidence limits for these estimates with intra-cluster correlation accounted for by an interval-censored version of the Clayton-Oakes model. We develop a goodness-of-fit test for general bivariate interval-censored data and apply it to the proposed interval-censored version of the Clayton-Oakes model. We also propose a likelihood ratio test for the comparison of survival distributions between two groups in the setting of clustered data under the assumption of a constant between-group hazard ratio. This methodology can be used both for balanced and unbalanced cluster sizes, and also when the cluster size is informative. We compare our test to the ordinary log rank test and the Lin-Wei (LW) test based on the marginal Cox proportional Hazards model with robust standard errors obtained from the sandwich estimator. Simulation results indicate that the ordinary log rank test over-inflates type I error, while the proposed unconditional likelihood ratio test has appropriate type I error and higher power than the LW test. The method is demonstrated in real examples from the Sorbinil Retinopathy Trial, and the Age-Related Macular Degeneration Study. Raw data from these two trials are provided.

Improving sandwich variance estimation for marginal Cox analysis of cluster randomized trials.

Cluster randomized trials (CRTs) frequently recruit a small number of clusters, therefore necessitating the application of small-sample corrections for valid inference. A recent systematic review indicated that CRTs reporting right-censored, time-to-event outcomes are not uncommon and that the marginal Cox proportional hazards model is one of the common approaches used for primary analysis. While small-sample corrections have been studied under marginal models with continuous, binary, and count outcomes, no prior research has been devoted to the development and evaluation of bias-corrected sandwich variance estimators when clustered time-to-event outcomes are analyzed by the marginal Cox model. To improve current practice, we propose nine bias-corrected sandwich variance estimators for the analysis of CRTs using the marginal Cox model and report on a simulation study to evaluate their small-sample properties. Our results indicate that the optimal choice of bias-corrected sandwich variance estimator for CRTs with survival outcomes can depend on the variability of cluster sizes and can also slightly differ whether it is evaluated according to relative bias or type I error rate. Finally, we illustrate the new variance estimators in a real-world CRT where the conclusion about intervention effectiveness differs depending on the use of small-sample bias corrections. The proposed sandwich variance estimators are implemented in an R package CoxBcv.

Racial disparities in overall survival after the introduction of cyclin-dependent kinase 4/6 inhibitors for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have improved HR + /HER2- metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends stratified by race in patients with HR + /HER2- MBC after the approval of CDK4/6i, as part of the standard of care, in 2015. We performed a population-based study using the SEER database. Patients with HR + /HER2- MBC were divided into two time-based cohorts: 1) pre-CDK4/6i era (diagnosed in 2011-2013) and 2) post-CDK4/6i era (diagnosed in 2015-2017). We used propensity score matching and identified 2,684 patients in each cohort that matched in several characteristics. Kaplan-Meier methods were used to estimate 2-year OS. Association between cohort and OS was evaluated using marginal Cox proportional hazards models with robust sandwich variance estimator. We conducted competing risk analysis to estimate the risk of breast cancer death in both cohorts. The 2-year OS rate was 65% for the post-CDK4/6i era and 62% for the pre-CDK4/6i era (stratified log-rank p = 0.025). The 2-year OS for non-Hispanic White (NHW) patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p = 0.033). However, OS did not improve for non-Hispanic Black (NHB) (54% vs. 54%, p = 0.876) or Hispanic (67% vs. 65%, p = 0.617) groups. The risk of breast cancer death decreased in the post-CDK4/6i era as compared to the pre-CDK4/6i era (2-year risk of breast cancer death: 33% vs. 30%, p = 0.015); however, this effect was observed only in NHW (sHR 0.84, p = 0.005) women, but not in NHB (sHR 0.94, p = 0.630) or Hispanic (sHR 0.91, p = 0.550) women. Our study confirms that outcomes for HR + /HER2- MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without significant improvement in OS in NHB or Hispanics.

Effect of Human Immunodeficiency Virus Infection on Human Papillomavirus Clearance Among Women in Senegal, West Africa.

Persistent infection with high-risk human papillomavirus (HPV) is associated with development of invasive cervical cancer. Longitudinal data was collected from 174 Senegalese women. We employed marginal Cox proportional hazards models to examine the effect of human immunodeficiency virus (HIV) status (HIV positive vs HIV negative) and HIV type (HIV-1 vs HIV-2 vs dual HIV-1/HIV-2) on clearance of type-specific HPV infection. Analyses were stratified by incident versus prevalent HPV infection. Incident HPV infections in HIV-positive women were less likely to clear than those in HIV-negative women (adjusted hazard ratio [HR] = 0.60; 95% confidence interval [CI], .38-.94). Among HIV-positive women, HIV-2-infected women and HIV-1/2 dually infected women were more likely to clear HPV incident infections than HIV-1-infected women (HR = 1.66; 95% CI, .95-2.92 and HR = 2.17; 95% CI, 1.12-4.22, respectively). Incident HPV infections in HIV-positive women with CD4 cell count ≤500 cells/μL were less likely to clear than those in HIV-positive women with CD4 cell count >500 cells/μL (HR = 0.65; 95% CI, .42-1.01). No significant associations were observed for prevalent HPV infections. HIV infection reduced the likelihood of clearance of incident HPV infection. Furthermore, among HIV-positive women, low CD4 cell count and dual HIV infection were each associated with reduced likelihood of clearance.

Epilepsy Risk Following Bariatric Surgery for Weight Loss.

A previous study reported finding that epilepsy risk is elevated after bariatric surgery for weight loss; however, this association has not been adequately explored. Our objectives were to (1) estimate the risk of epilepsy after bariatric surgery for weight loss relative to a nonsurgical cohort of patients with an obesity diagnosis and (2) identify epilepsy risk factors among bariatric surgery recipients. We conducted a population-based retrospective cohort study using linked health administrative databases in Ontario, Canada. Participants were accrued between July 1, 2010, and December 31, 2016, and followed until December 31, 2019. All Ontario residents aged 18 years and older who had bariatric surgery during the accrual period were eligible for inclusion in our exposed cohort. Patients hospitalized with a diagnosis of obesity and who did not have bariatric surgery during the accrual period were eligible for inclusion in our unexposed cohort. We excluded patients with a history of seizures, epilepsy, various seizure or epilepsy risk factors, psychiatric disorders, or drug or alcohol abuse/dependence. In our primary analysis, we used inverse probability of treatment weighting to control for confounding. A marginal Cox proportional hazards model was then used to estimate the risk of epilepsy associated with bariatric surgery. A Cox model was also used to identify epilepsy risk factors among exposed participants. The final sample included 16,958 exposed participants and 622,514 unexposed participants. After inverse probability of treatment weighting, the estimated rates of epilepsy were 50.1 and 34.1 per 100,000 person-years among those who did and did not have bariatric surgery, respectively. The hazard ratio for developing epilepsy after bariatric surgery was 1.45 (95% CI = 1.35, 1.56). Among participants who received bariatric surgery, stroke during follow-up increased epilepsy risk (HR = 14.03, 95% CI = 4.26, 46.25). In this study, we found that patients with a history of bariatric surgery were at increased risk of developing epilepsy. These findings suggest that epilepsy is a long-term risk associated with bariatric surgery for weight loss.

Association between contact with mental health and substance use services and reincarceration after release from prison.

ObjectivePeople released from prison who experience mental health and substance use problems are at high risk of reincarceration. This study aimed to examine the association between contact with mental health and substance use treatment services, and reincarceration, among adults released from prison.MethodsPre-release survey data from 1,115 adults released from prisons in Queensland, Australia were linked with administrative health and correctional records covering a median of 787 days post-release. We constructed marginal structural Cox proportional hazards models, adjusting for pre-release variables and time-varying indicators of emergent mental health and substance use problems, to examine the association between contact with mental health and substance use treatment services, and reincarceration.ResultsThe adjusted hazard ratio (AHR) for reincarceration associated with mental health service contact was 1.76 (95%CI 1.23,2.51). Among those not on parole following release, the AHR for reincarceration associated with substance use treatment service contact was 3.16 (95%CI 2.09,4.77); we found no evidence for an association among those who were released on parole (AHR = 1.07; 95%CI 0.80,1.43).ConclusionsAlthough we cannot eliminate the possibility of residual confounding, our findings suggest that infrequent or unsustained contact with community-based mental health and substance use treatment services is not protective against reincarceration, and may even be iatrogenic. Increased investment in high-quality and timely behavioural health services for people released from prison may simultaneously improve health outcomes, and reduce reincarceration.

The association of long-acting insulin analogue use versus neutral protamine Hagedorn insulin use and the risk of major adverse cardiovascular events among individuals with type 2 diabetes: A population-based cohort study.

To compare the risk of cardiovascular outcomes associated with long-acting insulin analogues versus neutral protamine Hagedorn (NPH) insulin among patients with type 2 diabetes. We conducted a population-based retrospective cohort study using the UK Clinical Practice Research Datalink Aurum, linked with hospitalization and vital statistics data. Patients with type 2 diabetes who initiated basal insulin treatment between 2002 and 2018 were included in the study. Exposure was defined as current use of long-acting insulin analogues or NPH insulin, defined using a time-varying approach. The primary outcome was major adverse cardiovascular events (MACE; a composite endpoint of myocardial infarction, ischaemic stroke and cardiovascular death). We used a marginal structural Cox proportional hazards model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for MACE with current use of long-acting insulin analogues versus NPH insulin, and in secondary analyses, by long-acting insulin molecule. Our cohort included 57 334 patients. A total of 3494 MACE occurred over a mean follow-up of 1.6 years (incidence rate 37.4, 95% CI 36.2 to 38.7 per 1000 person-years). Long-acting insulin analogues were associated with a decreased risk of MACE compared to NPH insulin (HR 0.89, 95% CI 0.83 to 0.96). Current use of long-acting insulin analogues is associated with a modestly reduced risk of MACE compared to current use of NPH insulin among patients with type 2 diabetes. This study could have important implications for drug plan managers and guideline-writing committees for recommendations of insulin treatment for type 2 diabetes.

Risk of Recurrent Acute Arterial Events Associated With Thiopurines and Anti-Tumor Necrosis Factor in Inflammatory Bowel Diseases

Patients with inflammatory bowel disease (IBD) are at increased risk of acute arterial events. Treatment with anti-tumor necrosis factor (anti-TNF) agents has been associated with a protective effect against the first occurrence of acute arterial events, but the impact of treatment with anti-TNF in patients with a previous history of acute arterial events remains unclear. We assessed the effect of anti-TNF and thiopurines on the risk of recurrent acute arterial events in patients with IBD in a nationwide cohort. Based on the French nationwide health insurance database, patients with IBD and a previous history of an acute arterial event were followed up from January 1, 2009, until December 31, 2018. The risk of acute arterial event recurrence associated with anti-TNF and thiopurine exposure was assessed using marginal structural Cox proportional hazard models adjusted for baseline and time-varying covariates. A total of 27,185 patients were included. During 121,822 person-years (median follow-up period, 4.0 y), 6865 recurrent acute arterial events occurred (incidence rate per 1000 person-years, 56.4; 95% CI, 55.0-57.7). Exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events compared with the absence of exposure to either treatment (hazard ratio, 0.75; 95% CI, 0.63-0.90 and hazard ratio, 0.76; 95% CI, 0.66-0.88, respectively). In a nationwide cohort study of patients with IBD and a previous history of an acute arterial event, exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events.

Impact of thiopurines and tumour necrosis factor antagonists on primary sclerosing cholangitis outcomes in patients with inflammatory bowel disease.

Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are at risk of biliary tract cancer and liver damage (possibly leading to liver transplantation), and are often treated for IBD with thiopurines and/or tumour necrosis factor antagonists (anti-TNF) on a long-term basis. To assess the risk of biliary tract cancer and liver transplantation in patients exposed to thiopurines and/or anti TNF agents in a French nationwide cohort. We performed a population-based study of patients aged 18 years or older with PSC and IBD in the French national health insurance database. Patients were followed from 1 January 2009 to 31 December 2018. The risks of biliary tract cancer and liver transplantation associated with thiopurines and anti-TNF exposure were assessed with marginal structural Cox proportional hazard models, adjusting for baseline demographics and comorbidities, and time-varying medications and PSC activity. Among the 1929 patients with PSC and IBD included, 37 biliary tract cancers and 83 liver transplantations occurred. Compared with patients not exposed to thiopurines or anti-TNF agents, patients exposed to thiopurines (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.39-2.82) or anti-TNF agents (HR, 0.59; 95% CI, 0.13-2.80) had no excess risk of biliary tract cancer. Similarly, patients exposed to thiopurines (HR, 0.67; 95% CI, 0.30-1.48) or anti-TNF agents (HR, 0.68; CI, 0.22-2.09) had no excess risk of liver transplantation. Patients with PSC and IBD who are exposed to thiopurines or anti-TNF agents are not at excess risk of biliary tract cancer or liver transplantation.