Restricted Mean Research Articles

Propensity-score matched analysis of patent foramen ovale closure in real-world study cohort with cryptogenic ischemic stroke

IntroductionPatent foramen ovale (PFO) occurs in 25% of the general population and in 40% of cryptogenic ischemic stroke patients. Recent trials support PFO closure in selected patients with cryptogenic stroke. We examined the outcomes of transcatheter PFO closure in a real-world study cohort with cryptogenic stroke. MethodsConsecutive ischemic stroke patients who were classified as cryptogenic on the TOAST aetiology and diagnosed with a PFO were included. All patients underwent either transcatheter PFO closure or medical therapy. A 2:1 propensity score matching by sex and Risk-of-Paradoxical-Embolism (RoPE) score was performed. Multivariable regression models adjusted for sex and RoPE score. ResultsOur cohort comprised 232 patients with mean age 44.3 years (SD 10.8) and median follow-up 1486.5 days. 33.2% were female. PFO closure (n=84) and medical therapy (n=148) groups were well-matched with <10% mean-difference in sex and RoPE score. Two patients in the treated group (2.4%) and seven in the control group (4.7%) had a recurrent ischemic stroke event. Multivariable Cox regression demonstrated a hazard-ratio of 0.26 (95%CI 0.03-2.13, P=0.21) for PFO closure compared to control. The incidence of atrial fibrillation (AF) detected post-PFO closure was similar between the treated and control (1.19% vs 1.35%, multivariable logistic regression odds-ratio 0.90, 95%CI 0.04-9.81, P=0.94). There were no major periprocedural complications documented. The difference in restricted mean survival-time free from stroke at two years between treated and control was 26.2 days (95%CI 5.52-46.85, P=0.013). ConclusionsIn this Asian cohort, we report a low incidence of ischemic stroke recurrence and new-onset AF in patients who underwent PFO closure. When compared to the medical therapy group, there was no significant difference in the incidence of stroke recurrence and new-onset AF. Further studies involving larger real-world cohorts are warranted to identify patients who are more likely to benefit from PFO closure.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Single high-dose radiation therapy and liquid fiducial markers can be used in dogs with incompletely resected soft tissue sarcomas.

To evaluate the outcome and effects of single high-dose radiation therapy with the aid of liquid fiducial markers in dogs following resection of soft tissue sarcomas (STSs). 36 client-owned dogs. Dogs with a histologic diagnosis of a grade II or III STS that underwent liquid fiducial guided single fraction, 20-Gy stereotactic radiation therapy following surgical excision of an STS between May 2017 and March 2019 were prospectively enrolled in this study. Data collected from the medical records included patient signalment, tumor-related information, treatment details, and outcome. Kaplan-Meier survival analysis was performed for overall survival time (OST) and disease-free interval (DFI). The median OST and DFI were not reached, so restricted mean OST and DFI were also calculated. 36 dogs were included in the study. All dogs underwent radiation therapy a mean of 36.1 days (range, 20 to 59 days) after surgery. Acute and delayed radiation toxicity effects occurred in 80.5% and 36.1% of dogs, respectively, all of which affected the skin. Tumor recurrence was noted in 24.3% of dogs with a median time to recurrence of 272 days (range, 14 to 843 days). The restricted mean OST was 1,556 days (range, 1,383 to 1,728 days) and restricted mean DFI was 1,330 days (range, 1,101 to 1,559 days). The results of this study showed that administering a single 20-Gy fraction of radiation in combination with a liquid fiducial marker to treat marginally or incompletely resected STS in the absence of gross disease resulted in similar OST and DFI compared to other previously reported radiation protocols.

COMMON ARTICLE 1 OF THE GENEVA CONVENTIONS AND THE METHOD OF TREATY INTERPRETATION

AbstractIn its updated Commentaries on the 1949 Geneva Conventions, the International Committee of the Red Cross (ICRC) embraces the ‘external’ interpretation of Article 1 common to the four Geneva Conventions, according to which States have certain negative (complicity-type) and positive (prevention/response) obligations to ‘ensure respect’ for the Conventions by other actors. This interpretation has been gaining support since the 1960s, though the ICRC's new Commentaries have served as a catalyst for some States recently to express contrary views. This article focuses on two major methodological shortcomings in the existing literature, offering a much firmer foundation for the external obligation under common Article 1. First, it demonstrates the overwhelming support in subsequent practice for external obligations. Previous studies have failed to explain the method by which this practice is taken into account, given the existence of some inconsistent practice. This article addresses this general question of treaty interpretation, critiquing the approach of the International Law Commission that relegates majority practice to supplementary means of interpretation and proposing instead a principled approach that better fits and justifies the judicial practice here. Secondly, the article challenges two common assumptions about the travaux: first, that an original, restrictive meaning was intended, and secondly that the travaux of Additional Protocol I offer no support for external obligations. Given the ubiquity of military assistance and partnering, these findings have far-reaching consequences for the liability of States.

Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer: a narrative review.

The application of immunotherapy in cancers, including liver cancer, has been increasing. However, non-proportional hazard (NPH) is often observed in cancer immunotherapy trials. In presence of violation of proportional hazard (PH) assumption, restricted mean survival time (RMST) ratio was proposed as an alternative to hazard ratio (HR) for evaluating the treatment effects of such trials. To shorten the total study duration, an intermediate endpoint with shorter follow-up such as progressionfree survival (PFS) is used as the primary endpoint. Our aim is to evaluate the applicability of RMST ratio in addition to the HR in assessing the level of PFS serving as a surrogacy of overall survival (OS). Phase II or phase III hepatocellular carcinoma (HCC) immunotherapy studies that were published between January 2013 and August 2022 were identified via the search in PubMed. Weighted leastsquare regression (WLSR) was applied to analyze the trial level data with the sample size of study being set as the weight. The evaluation was conducted twice with RMST ratio and HR being applied in respective evaluation to examine the level of PFS as a surrogacy for OS. Based on the results of eight included trials, the R-square values of WLSR with either HR or RMST ratio being applied were 0.31 and 0.16 separately, indicating a moderate and low correlation between PFS and OS respectively. In this study, our results demonstrated the potential of RMST ratio in addition to HR for evaluating the level of surrogacy in immunotherapy trials. Furthermore, including more large scale and homogeneous studies into the research may help better understand the level of surrogacy in liver cancer.

Prognostic value of comorbidities in older patients with cancer: the ELCAPA cohort study

In older patients, comorbidities competed with cancer for mortality risk. We assessed the prognostic value of comorbidities in older patients with cancer. We analysed all patients >70 years of age with colorectal, breast, prostate, or lung cancer included in the prospective ELCAPA cohort. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) score was used to assess comorbidities. The primary endpoint was overall survival (OS) at 3, 12, and 36 months. The adjusted difference in the restricted mean survival time (RMST) was used to assess the strength of the relationship between comorbidities and survival. Of the 1551 patients included (median age 82 years; interquartile range 78-86 years), 502 (32%), 575 (38%), 283 (18%), and 191 (12%) had colorectal, breast, prostate, and lung cancer, respectively, and 50% had metastatic disease. Hypertension, kidney failure, and cognitive impairment were the most common comorbidities (67%, 38%, and 29% of the patients, respectively). A CIRS-G score >17, two or more severe comorbidities, more than seven comorbidities, heart failure, and cognitive impairment were independently associated with shorter OS. The greatest effect size was observed for CIRS-G >17 (versus CIRS-G <11): at 36 months, the adjusted differences in the RMST (95% confidence interval) were-6.0 months (-9.3 to-2.6 months) for colorectal cancer,-9.1 months (-13.2 to-4.9 months) for breast cancer,-8.3 months (-12.8 to-3.9 months) for prostate cancer, and-5.5 months (-9.9 to-1.1 months) for lung cancer (P < 0.05 for all). Comorbidities' type, number, and severity were independently associated with shorter OS. A 17-point cut-off over 56 for the total CIRS-G score could be considered in clinical practice.

직장어린이집 교실에서 일어나는 위험한 놀이에 관한 유아반 교사의 경험 연구

Objectives This study aimed to understand the experiences of early childhood teachers about risk play in the classroom, and in particular, paid attention to the complex effects of the physical and social characteristics of the workplace child care center.&#x0D; Methods The investigator selected six early childhood teachers that were concerned about risky play in the classroom at workplace child care centers. They were interviewed with visual methodology in 24 sessions about 22 weeks, analyzed through four stages: transcription, abbreviation by subject, semantic categorization, semantic conceptualization.&#x0D; Results First, teachers used the predicted degree of injury, the possibility of learning, the existence of prior consultation, existence of rules as criteria for acceptability, and divided the experience into risk-taking challenging play and risky behavior. Based on this, risk-taking challenging play is to use risky materials attributes or utilization of materials in this way, but challenging the limitations of the body or environment was considered risky behavior. Second, teachers expressed difficulties due to fear for injuries and external negative perception, violation of classroom management rules. They had experiences uncertainty where physical safety is not guaranteed, deviating from the purpose of education, freewheelingness against the static order, collisionality against manners for others. Third, despite, the teachers were having new moves such as encouraging challenges to risky play, change the meaning of infants' free bodies in the classroom, think about conflicts and boundaries in space, and cooperate with parents and faculty. In addition, Teachers demanded manpower, communicate and understand about risks and safety, time to think about classrooms and risky play, opportunities to share cases and educate.&#x0D; Conclusions Teachers had a movement to understand child-risk-space as an integral element, away from rigid boundaries inside and outside the classroom and the restrictive meaning of risk and education. Therefore, it suggests educational subjects become collaborators of risky play and create a self-sustaining meaning.

Combined Computed Tomography Angiography-Computed Tomography Perfusion in the Identification and Prognostic Assessment of Myocardial Bridging from the CORE320 Study: 5-Year Follow-Up

Our objective is to use computed tomography angiography (CTA) and computed tomography perfusion (CTP) to identify the ischemic significance of myocardial bridging (MB). We also seek to determine the long-term prognostication of MB in the presence or absence of obstructive coronary artery disease (CAD). The CORE320, a prospective, multicenter study including 381 patients with known or suspected CAD clinically referred for invasive coronary angiography who underwent combined (CTA-CTP) and single-photon emission computed tomography before conventional coronary angiography. The incidence of MB was identified in 135 patients (35.4%) with 93.9% identified in the left anterior descending artery. MB were divided as partially encased versus fully encased. There was no difference in ischemia identified between partially encased MB and fully encased MB (37 [40%] vs 25 [35%], p=0.54]. Ischemia was identified at similar rates in partially versus fully encased MB by single-photon emission computed tomography at (8 [9%] vs 8 [11%], p=0.57] and CTP (34 [37%] vs 21 [30%], p=0.33]. There was no difference in the primary outcome of 5-year outcome of combined incidence of myocardial infarction or death. The restricted mean survival time in patients with CTA with <50% stenosis with or without a MB was 4.906 years (95% confidence interval 4.759 to 5.000) and 4.891 years (95% confidence interval 4.718 to 5.000), respectively (p=0.824). Cardiac computed tomography perfusion imaging can assess both anatomic and functional significance of myocardial bridging with diagnostic accuracy similar to current standard imaging. Furthermore, 5-year cardiovascular events were not different with the presence of MB in both obstructive and non-obstructive CAD.

Semiparametric estimation of restricted mean survival time as a function of restriction time.

The restricted mean survival time (RMST) is an appealing measurement in clinical or epidemiological studies with censored survival outcome and receives a lot of attention in the past decades. It provides a useful alternative to the Cox model for evaluating the covariate effect on survival time. The covariate effect on RMST usually varies with the restriction time. However, existing methods cannot address this problem properly. In this article, we propose a semiparametric framework that directly models RMST as a function of the restriction time. Our proposed model adopts a widely-used proportional form, enabling the estimation of RMST predictions across an interval using a unified model. Furthermore, the covariate effect for multiple restriction time points can be derived simultaneously. We develop estimators based on estimating equations theories and establish the asymptotic properties of the proposed estimators. The finite sample properties of the estimators are evaluated through extensive simulation studies. We further illustrate the application of our proposed method through the analysis of two real data examples. Supplementary Material are available online.

CausalCmprsk: An R package for nonparametric and Cox-based estimation of average treatment effects in competing risks data

Background and ObjectiveCompeting risks data arise in both observational and experimental clinical studies with time-to-event outcomes, when each patient might follow one of the multiple mutually exclusive competing paths. Ignoring competing risks in the analysis can result in biased conclusions. In addition, possible confounding bias of the treatment-outcome relationship has to be addressed, when estimating treatment effects from observational data. In order to provide tools for estimation of average treatment effects on time-to-event outcomes in the presence of competing risks, we developed the R package causalCmprsk. We illustrate the package functionality in the estimation of effects of a right heart catheterization procedure on discharge and in-hospital death from observational data. MethodsThe causalCmprsk package implements an inverse probability weighting estimation approach, aiming to emulate baseline randomization and alleviate possible treatment selection bias. The package allows for different types of weights, representing different target populations. causalCmprsk builds on existing methods from survival analysis and adapts them to the causal analysis in non-parametric and semi-parametric frameworks. ResultsThe causalCmprsk package has two main functions: fit.cox assumes a semiparametric structural Cox proportional hazards model for the counterfactual cause-specific hazards, while fit.nonpar does not impose any structural assumptions. In both frameworks, causalCmprsk implements estimators of (i) absolute risks for each treatment arm, e.g., cumulative hazards or cumulative incidence functions, and (ii) relative treatment effects, e.g., hazard ratios, or restricted mean time differences. The latter treatment effect measure translates the treatment effect from probability into more intuitive time domain and allows the user to quantify, for example, by how many days or months the treatment accelerates the recovery or postpones illness or death. ConclusionsThe causalCmprsk package provides a convenient and useful tool for causal analysis of competing risks data. It allows the user to distinguish between different causes of the end of follow-up and provides several time-varying measures of treatment effects. The package is accompanied by a vignette that contains more details, examples and code, making the package accessible even for non-expert users.

Is surgical treatment of hepatocellular carcinoma at high-volume centers worth the additional cost?

BackgroundCase volume has been associated with improved outcomes for patients undergoing treatment for hepatocellular carcinoma, often with higher hospital expenditures. We sought to define the cost-effectiveness of hepatocellular carcinoma treatment at high-volume centers. MethodsPatients diagnosed with hepatocellular carcinoma from 2013 to 2017 were identified from Medicare Standard Analytic Files. High-volume centers were defined as the top decile of facilities performing hepatectomies in a year. A multivariable generalized linear model with gamma distribution and a restricted mean survival time model were used to estimate costs and survival differences relative to high-volume center status. The incremental cost-effectiveness ratio was used to define the additional cost incurred for a 1-year incremental gain in survival. ResultsAmong 13,666 patients, 8,467 (62.0%) were treated at high-volume centers. Median expenditure was higher ($19,148, interquartile range $15,280–$29,128) among patients treated at high-volume centers versus low-volume centers ($18,209, interquartile range $14,959–$29,752). Despite similar median length-of-stay (6 days, interquartile range 4–9), a slightly higher proportion of patients were discharged to home from high-volume centers (n = 4,903, 57.9%) versus low-volume centers (n = 2,868, 55.2%) (P = .002). A 0.14-year (95% confidence interval 0.06–0.22) (1 month and 3 weeks) survival benefit was associated with an incremental cost of $1,070 (95% confidence interval $749–$1,392) among patients undergoing surgery at high-volume centers. The incremental cost-effectiveness ratio for treatment at a high-volume center was $7,951 (95% confidence interval $4,236–$21,217) for an additional year of survival, which was below the cost-effective threshold of $21,217. ConclusionSurgical care at high-volume centers offers the potential to deliver cancer care in a more cost-effective and value-based manner.

Communicating and understanding statistical measures when quantifying the between-group difference in competing risks.

Competing risks issues are common in clinical trials and epidemiological studies for patients in follow-up who may experience a variety of possible outcomes. Under such competing risks, two hazard-based statistical methods, cause-specific hazard (CSH) and subdistribution hazard (SDH), are frequently used to assess treatment effects among groups. However, the outcomes of the CSH-based and SDH-based methods have a close connection with the proportional hazards (CSH or SDH) assumption and may have an non-intuitive interpretation. Recently, restricted mean time lost (RMTL) has been used as an alternative summary measure for analysing competing risks, due to its clinical interpretability and robustness to the proportional hazards assumption. Considering the above approaches, we summarize the differences between hazard-based and RMTL-based methods from the aspects of practical interpretation, proportional hazards model assumption and the selection of restricted time points, and propose corresponding suggestions for the analysis of between-group differences under competing risks. Moreover, an R package 'cRMTL' and corresponding step-by-step guidance are available to help users for applying these approaches.

Induction immunochemotherapy followed by radiotherapy for patients with unresectable locally advanced or metastatic esophageal cancer: A propensity score-matched analysis

BackgroundThe study aimed to investigate the efficacy of induction immunochemotherapy before radiotherapy (RT) for patients with locally advanced or metastatic esophageal cancer. MethodsPatients with unresectable locally advanced or metastatic esophageal cancer who received induction immunochemotherapy followed by RT (ICIs + RT group) and RT alone (RT group) were retrospectively identified in two cancer centers, respectively. Propensity score matching (PSM) was used to balance the potential confounders between the two groups. Overall survival (OS), progression-free survival (PFS), and recurrence patterns were evaluated. ResultsA total of 467 patients were reviewed, and 66 were matched in each group. After PSM, the 1- and 2-year OS rates were 84.6% and 57.9% in ICIs + RT group, and 71.1% and 43.0% in RT group (HR 0.60, 95% CI 0.36–1.00, p = 0.050). The absolute increase of restricted mean survival time (RMST) for OS in ICIs + RT group compared with RT group were 0.89 years (p = 0.023) at one year and 2.59 years at two years (p = 0.030). The median PFS time, 1- and 2-year PFS rates were 20.3 months, 69.3%, and 45.7% in ICIs + RT group, and 12.2 months, 51.4%, and 35.8% in RT group (HR 0.64, 95% CI 0.41–0.99, p = 0.045). The cumulative locoregional recurrence (LRR) rate was significantly lower in ICIs + RT group (1-year rate, 17.4% vs. 38.8%, p = 0.011), and distant metastasis (DM) rates were comparable (p = 0.755). Consolidation ICIs was associated with a trend of improved 1-year OS and PFS. ConclusionInduction immunochemotherapy followed by RT might improve locoregional control and survival outcomes for patients with unresectable locally advanced or metastatic esophageal cancer.

Using Restricted Mean Survival Time to Improve Interpretability of Time-to-Event Data Analysis.

Using Restricted Mean Survival Time to Improve Interpretability of Time-to-Event Data Analysis.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial

Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n=38) or control (n=46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p=0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p=0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p=0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p=0.02). There were no safety concerns. BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Variable selection using inverse probability of censoring weighting.

In this article, we propose two variable selection methods for adjusting the censoring information for survival times, such as the restricted mean survival time. To adjust for the influence of censoring, we consider an inverse probability of censoring weighted for subjects with events. We derive a least absolute shrinkage and selection operator (lasso)-type variable selection method, which considers an inverse weighting for of the squared losses, and an information criterion-type variable selection method, which applies an inverse weighting of the survival probability to the power of each density function in the likelihood function. We prove the consistency of the inverse probability of censoring weighted lasso estimator and the maximum inverse probability of censoring weighted likelihood estimator. The performance of the inverse probability of censoring weighted lasso and inverse probability of censoring weighted information criterion are evaluated via a simulation study with six scenarios, and then their variable selection ability is demonstrated using data from two clinical studies. The results confirm that inverse probability of censoring weighted lasso and the inverse probability of censoring weighted likelihood function produce good estimation accuracy and consistent variable selection. We conclude that our two proposed methods are useful variable selection tools for adjusting the censoring information for survival time analyses.

Comparison of survival analysis approaches to modelling age at first sex among youth in Kisesa Tanzania.

Many studies analyze sexual and reproductive event data using descriptive life tables. Survival analysis has better power to estimate factors associated with age at first sex (AFS), but proportional hazards models may not be right model to use. This study used accelerated failure time (AFT) models, restricted Mean Survival time model (RMST) models, with semi and non-parametric methods to assess age at first sex (AFS), factors associated with AFS, and verify underlying assumptions for each analysis. Self-reported sexual debut data was used from respondents 15-24 years in eight cross-sectional surveys between 1994-2016, and from adolescents' survey in an observational community study (2019-2020) in northwest Tanzania. Median AFS was estimated in each survey using non-parametric and parametric models. Cox regression, AFT parametric models (exponential, gamma, generalized gamma, Gompertz, Weibull, log-normal and log-logistic), and RMST were used to estimate and identify factors associated with AFS. The models were compared using Akaike information criterion (AIC) and Bayesian information criterion (BIC), where lower values represent a better model fit. The results showed that in every survey, the Cox regression model had higher AIC and BIC compared to the other models. Overall, AFT had the best fit in every survey round. The estimated median AFS using the parametric and non-parametric methods were close. In the adolescent survey, log-logistic AFT showed that females and those attending secondary and higher education level had a longer time to first sex (Time ratio (TR) = 1.03; 95% CI: 1.01-1.06, TR = 1.05; 95% CI: 1.02-1.08, respectively) compared to males and those who reported not being in school. Cell phone ownership (TR = 0.94, 95% CI: 0.91-0.96), alcohol consumption (TR = 0.88; 95% CI: 0.84-0.93), and employed adolescents (TR = 0.95, 95% CI: 0.92-0.98) shortened time to first sex. The AFT model is better than Cox PH model in estimating AFS among the young population.

Understanding the effects of universal test and treat on longitudinal HIV care outcomes among South African youth: a retrospective cohort study

IntroductionLittle is known about the effects of universal test and treat (UTT) policies on HIV care outcomes among youth living with HIV (YLHIV). Moreover, there is a paucity of information regarding when YLHIV are most susceptible to disengagement from care under the newest treatment guidelines. The longitudinal HIV care continuum is an underutilized tool that can provide a holistic understanding of population-level HIV care trajectories and be used to compare treatment outcomes across groups. We aimed to explore effects of the UTT policy on longitudinal outcomes among South African YLHIV and identify temporally precise opportunities for re-engaging this priority population in the UTT era.MethodsUsing medical record data, we conducted a retrospective cohort study among youth aged 18–24 diagnosed with HIV from August 2015-December 2018 in nine health care facilities in South Africa. We used Fine and Gray sub-distribution proportional hazards models to characterize longitudinal care continuum outcomes in the population overall and stratified by treatment era of diagnosis. We estimated the proportion of individuals in each stage of the continuum over time and the restricted mean time spent in each stage in the first year following diagnosis. Sub-group estimates were compared using differences.ResultsA total of 420 YLHIV were included. By day 365 following diagnosis, just 23% of individuals had no 90-or-more-day lapse in care and were virally suppressed. Those diagnosed in the UTT era spent less time as ART-naïve (mean difference=-19.3 days; 95% CI: -27.7, -10.9) and more time virally suppressed (mean difference = 17.7; 95% CI: 1.0, 34.4) compared to those diagnosed pre-UTT. Most individuals who were diagnosed in the UTT era and experienced a 90-or-more-day lapse in care disengaged between diagnosis and linkage to care or ART initiation and viral suppression.ConclusionsImplementation of UTT yielded modest improvements in time spent on ART and virally suppressed among South African YLHIV— however, meeting UNAIDS’ 95-95-95 targets remains a challenge. Retention in care and re-engagement interventions that can be implemented between diagnosis and linkage to care and between ART initiation and viral suppression (e.g., longitudinal counseling) may be particularly important to improving care outcomes among South African YLHIV in the UTT era.

Long-term outcomes of mitral valve replacement in dialysis patients: evidence from a nationwide database.

To compare the late outcomes between mechanical and bioprostheses after isolated mitral valve replacement (MVR) in dialysis-dependent patients. A nationwide propensity-matched retrospective cohort study was conducted involving dialysis patients who underwent primary mitral replacement between 2001 and 2018. Ten-year postoperative outcomes were compared between mitral bioprosthesis and mechanical prosthesis using the Cox proportional hazard model and restricted mean survival time (RMST). The all-cause mortality was 20.8 and 13.0 events per 100 person-years, with a 10-year RMST of 7.40 and 7.31 years for bioprosthesis and mechanical prosthesis, respectively. Major bleeding was the most common adverse event for both bioprosthesis and mechanical prosthesis, with an incidence rate of 19.5 and 19.1 events per 100 person-years, respectively. The incidence of valve reoperation was higher among those who received bioprosthesis (0.55 events per 100 person-years). After 1:1 matching, the all-cause mortality was 15.45 and 14.54 events per 100 person-years for bioprosthesis and mechanical prosthesis, respectively. The RMST at 10 years was comparable between the two groups after matching (5.10 years for bioprosthesis vs. 4.59 years for mechanical prosthesis), with an RMST difference of -0.03. Further, no difference was observed in the incidence of major adverse valve-related events between bioprosthesis and mechanical valves. However, bioprosthesis was associated with a higher incidence of mitral valve reoperation among all major adverse events (RMST difference -0.24 years, 95% CI -0.48 to -0.01, P =0.047). This study found no association between valve selection and long-term survival outcomes in dialysis patients after MVR. However, bioprosthetic valves may be associated with a slightly higher incidence of reoperation, while other valve-related adverse events, including major bleeding and stroke, were comparable between the two types of prostheses.

Measuring time in buprenorphine treatment stages among people with HIV and opioid use disorder by retention definition and its association with cocaine and hazardous alcohol use

BackgroundWe use a novel, longitudinal approach to describe average time spent in opioid use disorder (OUD) cascade of care stages for people with HIV (PWH) and with OUD, incorporating four definitions of treatment retention. Using this approach, we describe the impact of cocaine or hazardous alcohol use on time spent retained on buprenorphine.MethodsWe followed PWH with OUD enrolled in the Johns Hopkins HIV Clinical Cohort from their first buprenorphine treatment episode between 2013 and 2020. We estimated 4-year restricted mean time spent on buprenorphine below buprenorphine retention threshold, on buprenorphine above retention threshold, off buprenorphine and in HIV care, loss to follow-up, and death. Retention definitions were based on retention threshold (180 vs 90 days) and allowable treatment gap (7 vs 30 days). Differences in 2-year restricted mean time spent retained on buprenorphine were estimated for patients with and without cocaine or hazardous alcohol use.ResultsThe study sample (N = 179) was 63% male, 82% non-Hispanic Black, and mean age was 53 (SD 8) years. Patients spent on average 13.9 months (95% CI 11.4, 16.4) on buprenorphine over 4 years. There were differences in time spent retained on buprenorphine based on the retention definition, ranging from 6.5 months (95% CI 4.6, 8.5) to 9.6 months (95% CI 7.4, 11.8). Patients with cocaine use spent fewer months retained on buprenorphine. There were no differences for patients with hazardous alcohol use.ConclusionsPWH with OUD spend relatively little time receiving buprenorphine in their HIV primary care clinic. Concurrent cocaine use at buprenorphine initiation negatively impact time on buprenorphine.