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Iterated conditional expectation (ICE) g-computation is an estimation approach for addressing time-varying confounding for both longitudinal and time-to-event data. Unlike other g-computation implementations, ICE avoids the need to specify models for each time-varying covariate. For variance estimation, previous work has suggested the bootstrap. However, bootstrapping can be computationally intense. Here, we present ICE g-computation as a set of stacked estimating equations. Therefore, the variance for the ICE g-computation estimator can be consistently estimated using the empirical sandwich variance estimator. Performance of the variance estimator was evaluated empirically with a simulation study. The proposed approach is also demonstrated with an illustrative example on the effect of cigarette smoking on the prevalence of hypertension. In the simulation study, the empirical sandwich variance estimator appropriately estimated the variance. When comparing runtimes between the sandwich variance estimator and the bootstrap for the applied example, the sandwich estimator was substantially faster, even when bootstraps were run in parallel. The empirical sandwich variance estimator is a viable option for variance estimation with ICE g-computation., (© 2024 John Wiley & Sons Ltd.)

Background and Objectives: This study aimed to understand how gout is currently managed in Australian primary care and to assess the level of interest in changing the delivery of care for gout., Method: This pragmatic qualitative study was conducted among Australian general practitioners (GPs), pharmacists and adults living with gout. Semi-structured interviews were conducted and analysed using thematic analysis., Results: The key theme identified was that chronic gout has low priority compared to managing other conditions, and management is often responsive to patient action. Lack of confidence was expressed about medication regimens for multimorbidities. Regarding changing care delivery, there was widespread interest in enhancing pharmacists' role in providing medication reviews and guidance, but there were conflicting views between some pharmacists and GPs about clinical decisions and prescribing arrangements., Discussion: Interpreting findings based on Wagner's chronic care model, it is apparent that there are multiple potential opportunities to change practice that might improve gout management.

Background: Epidemic forms of hepatitis E cause high mortality among pregnant people, with case fatality risks over 30% and adverse fetal outcomes. In 2022, the first mass reactive vaccination campaign against hepatitis E was conducted in South Sudan with the HEV239 vaccine. We aimed to assess whether vaccination against hepatitis E in pregnancy increases the risk of fetal loss in a cohort of vaccinated and unvaccinated pregnant people., Methods: In this emulated target trial, an exhaustive pregnancy census was conducted in Bentiu internally displaced persons camp after the second of three vaccination rounds. Women and girls aged 14-45 years with no current jaundice or acute illness were eligible for participation. Individuals who consented were revisited 28 days after their delivery date to document the pregnancy outcome. We used an emulated target trial framework to address biases inherent in observational studies. We matched vaccinated to unvaccinated participants on age, gestational age, and vaccination propensity score and estimated cumulative incidence functions for fetal loss in vaccinated compared to unvaccinated women in a competing risks framework using the Aalen-Johansen estimator., Findings: Between May 16 and June 30, 2022, 3421 participants were enrolled and followed up for inclusion in analysis. Among 2741 women who had a pregnancy outcome after the start of the vaccination campaign, 67 (2·4%) were vaccinated before conception, 2036 (74·3%) were vaccinated during pregnancy, and 638 (23·2%) were not vaccinated. Among the 2407 women retained in the matched analyses, the cumulative risk of fetal loss among individuals vaccinated during pregnancy was 7·2% (95% CI 5·6-8·7) compared with 6·1% (3·7-9·2) among unvaccinated individuals, implying a risk ratio of 1·2 (95% CI 0·7-1·9)., Interpretation: No evidence of increased risk of fetal loss was found among individuals vaccinated during pregnancy., Funding: Médecins Sans Frontières., Competing Interests: Declaration of interests Médecins Sans Frontières provided support in the form of salaries for ASA, VKA, PGi, PN, JD, MH, PGa, NS, MA, MR, and IC and indirectly provided salary support for Epicentre employees RCN and EG. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Frailty is a dynamic syndrome characterized by reduced physiological reserve to maintain homeostasis. Prospective studies have reported frailty worsening in women with breast cancer during chemotherapy, with improvements following treatment. We evaluated whether the Faurot frailty index, a validated claims-based frailty measure, could identify changes in frailty during chemotherapy treatment and identified predictors of trajectory patterns., Methods: We included women (65+ years) with stage I-III breast cancer undergoing adjuvant chemotherapy in the SEER-Medicare database (2003-2019). We estimated the Faurot frailty index (range: 0-1; higher scores indicate greater frailty) at chemotherapy initiation, 4 months postinitiation, and 10 months postinitiation. Changes in frailty were compared to a matched noncancer comparator cohort. We identified patterns of frailty trajectories during the year following chemotherapy initiation using K-means clustering., Results: Twenty-one thousand five hundred and ninety-nine women initiated adjuvant chemotherapy. Mean claims-based frailty increased from 0.037 at initiation to 0.055 4 months postchemotherapy initiation and fell to 0.049 10 months postinitiation. Noncancer comparators experienced a small increase in claims-based frailty over time (0.055-0.062). We identified 6 trajectory patterns: a robust group (78%), 2 resilient groups (16%), and 3 nonresilient groups (6%). Black women and women with claims for home hospital beds, wheelchairs, and Parkinson's disease were more likely to experience nonresilient trajectories., Conclusions: We observed changes in a claims-based frailty index during chemotherapy that are consistent with prior studies using clinical measures of frailty and identified predictors of nonresilient frailty trajectories. Our study demonstrates the feasibility of using claims-based frailty indices to assess changes in frailty during cancer treatment., (© The Author(s) 2024. Published by Oxford University Press.)

The WHO recommends hepatitis B birth-dose vaccination (HepB-BD), but it is not routinely given in most sub-Saharan African countries. We aimed to assess the immunogenicity of HepB-BD in addition to the existing hepatitis B vaccine (HepB3) schedule in Kinshasa, Democratic Republic of Congo among HBV-unexposed and HBV-exposed infants. Using an open-label, randomised, controlled design, HBV-unexposed infants were randomised (1:1) to receive the standard HepB3 vaccine series (group U3), or to receive HepB-BD in addition to HepB3 (group U4). A supplemental cohort of HBV-exposed infants (group E4) received HepB-BD and HepB3. We compared the proportion of infants with protective antibodies against HBV (HBV surface antibody ≥ 10 mIU/mL) between groups U3 and U4 and groups U4 and E4 at 12 months of age. Between August 20 and October 9, 2019, we enrolled 281 mother/infant dyads; 88 (31.3%) returned at 12 months. Most infants had protective antibodies against HBV at 12 months: 92.9% (75.7%-98.2%) in group U3, 85.7% (67.5%-94.5%) in group U4 and 96.9% (95% CI: 81.2%-99.6%) in group E4. Trends held in estimates adjusted for loss-to-follow-up (LTFU) and baseline imbalance across groups. In this first randomised trial assessing the addition of HepB-BD to the hepatitis B vaccine schedule in SSA, we found that HBV-unexposed infants who received the 3-dose and 4-dose vaccine series had similar immunogenicity against HBV at 12 months. A high proportion of infants, and notably HBV-exposed infants, had protective antibodies. Though extrapolation of findings may be limited by LTFU, this study adds real-world evidence regarding HepB-BD implementation in sub-Saharan Africa. Trial Registration: ClinicalTrials.gov identifier: NCT03897946., (© 2024 John Wiley & Sons Ltd.)

One obstacle to adopting instrumental variable (IV) methods in pharmacoepidemiology is their reliance on strong, unverifiable assumptions. We can falsify IV assumptions by leveraging the causal structure, which can strengthen or refute their plausibility and increase the validity of effect estimates. We illustrate a systematic approach to evaluate calendar time IV assumptions in estimating the known effect of thiazolidinediones on hospitalized heart failure. Using cohort entry time before and after 09/2010, when the U.S. Food and Drug Administration issued a safety communication as a proposed IV, we estimated IV and propensity score-weighted 2-year risk differences (RDs) using Medicare data (2008-2014). We (i) performed inequality tests, (ii) identified the negative control IV/outcome using causal assumptions, (iii) estimated RDs after narrowing the calendar time range and excluding patients likely associated with unmeasured confounding, (iv) derived bounds for RDs, and (v) estimated the proportion of compliers and their characteristics. The findings revealed that IV assumptions were violated and RDs were extreme, but the assumptions became more plausible upon narrowing the calendar time range and restricting the cohort by excluding prevalent heart failure (the strongest measured predictor of outcome). Systematically evaluating IV assumptions could help detect bias in IV estimators and increase their validity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Although the limitations of hazard ratios (HRs) for quantifying treatment effects in right-censored data have been widely discussed, HRs are still preferentially reported over other, more interpretable effect measures. This may stem from the fact that there are few applied examples that directly contrast the HR and its interpretation with alternative effect measures., Methods: We analyzed data from two randomized clinical trials comparing panitumumab plus standard-of-care chemotherapy (SOCC) with SOCC alone as first- and second-line treatment for metastatic colorectal cancer. We report the effect of treatment with panitumumab on progression-free survival (PFS) using a Cox proportional hazards model to estimate the HR and the Kaplan-Meier estimator of cumulative incidence (risk). Further analyses included examining the cumulative incidence curves; kernel-smoothed, non-parametric hazards curves; fitting the Cox model with a continuous time variable; and estimating restricted mean survival as well as median survival., Results: The HR was 0.82 (95% confidence interval [CI]: 0.71, 0.93), while the risk ratio (or relative risk [i.e., ratio of the cumulative incidence among the treated versus comparator]) was 0.99 (95% CI: 0.96, 1.02). These two measures suggest apparently different conclusions: either a treatment benefit or no effect. Through subsequent analyses, we demonstrated that, while the cumulative incidence of the outcome was similar by the end of follow-up regardless of treatment, the panitumumab treated group experienced longer PFS than those randomized to SOCC. Substantial nonproportional hazards were evident with panitumumab treatment reducing the hazard of progression/mortality during the first ~1.75 years but associated with an increased hazard of progress/mortality thereafter., Discussion: This example underscores the difficulties in interpreting HRs, particularly in the setting of qualitative violations of proportional hazards, and the value of quantifying treatment effects via multiple effect measures., (© 2024 John Wiley & Sons Ltd.)

Background: Frailty is a dynamic aging-related syndrome, but measuring frailty transitions is challenging. The Faurot frailty index is a validated Medicare claims-based frailty proxy based on demographic and billing information. We evaluated whether 3-year changes in the Faurot frailty index were consistent with concurrent changes in the frailty phenotype in a cohort of older adults., Methods: We used longitudinal data from the National Health and Aging Trends Study (NHATS) with Medicare claims linkage (2010-2018). We identified older adults (66+ years) in the 2011 and 2015 NHATS cohorts with at least 1 year of Medicare fee-for-service continuous enrollment (N = 6 951). We described annual changes in mean claims-based frailty for up to 3 years, based on concurrent transitions in the frailty phenotype., Results: At baseline, 32% were robust, 48% prefrail, and 19% frail based on the frailty phenotype. Mean claims-based frailty for older adults who were robust at baseline and worsened to frail increased over 3 years (0.09-0.25). Similarly, those who worsened from prefrail to frail experienced an increase in mean claims-based frailty (0.14-0.26). Improvements in the frailty phenotype did not correspond to decreases in claims-based frailty. Older adults whose frailty phenotype improved over time had a lower baseline claims-based frailty score than those who experienced stable or worsening frailty., Conclusions: Older adults who experienced a frailty phenotype worsening over 3 years experienced concurrent increases in the Faurot frailty index. Our results suggest that claims data may be used to identify clinically meaningful worsening in frailty., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Comparisons of treatments, interventions, or exposures are of central interest in epidemiology, but direct comparisons are not always possible due to practical or ethical reasons. Here, we detail a fusion approach to compare treatments across studies. The motivating example entails comparing the risk of the composite outcome of death, AIDS, or greater than a 50% CD4 cell count decline in people with HIV when assigned triple versus mono antiretroviral therapy, using data from the AIDS Clinical Trial Group (ACTG) 175 (mono versus dual therapy) and ACTG 320 (dual versus triple therapy). We review a set of identification assumptions and estimate the risk difference using an inverse probability weighting estimator that leverages the shared trial arms (dual therapy). A fusion diagnostic based on comparing the shared arms is proposed that may indicate violation of the identification assumptions. Application of the data fusion estimator and diagnostic to the ACTG trials indicates triple therapy results in a reduction in risk compared to monotherapy in individuals with baseline CD4 counts between 50 and 300 cells/mm3. Bridged treatment comparisons address questions that none of the constituent data sources could address alone, but valid fusion-based inference requires careful consideration of the underlying assumptions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Radon is a known cause of lung cancer. Protective standards for radon exposure are derived largely from studies of working populations that are prone to healthy worker survivor bias. This bias can lead to under-protection of workers and is a key barrier to understanding health effects of many exposures. We apply inverse probability weighting to study a set of hypothetical exposure limits among 4,137 male, White and American Indian radon-exposed uranium miners in the Colorado Plateau followed from 1950 to 2005. We estimate cumulative risk of lung cancer through age 90 under hypothetical occupational limits. We estimate that earlier implementation of the current US Mining Safety and Health Administration annual standard of 4 working level months (implemented here as a monthly exposure limit) could have reduced lung cancer mortality from 16/100 workers to 6/100 workers (95% confidence intervals: 3/100, 8/100), in contrast with previous estimates of 10/100 workers. Our estimate is similar to that among contemporaneous occupational cohorts. Inverse probability weighting is a simple and computationally efficient way address healthy worker survivor bias in order to contrast health effects of exposure limits and estimate the number of excess health outcomes under exposure limits at work., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Understanding the potential for, direction, and magnitude of uncontrolled confounding is critical for generating informative real-world evidence. Many sensitivity analyses are available to assess robustness of study results to residual confounding, but it is unclear how researchers are using these methods. We conducted a systematic review of published active comparator cohort studies of drugs or biologics to summarize use of sensitivity analyses aimed at assessing uncontrolled confounding from an unmeasured variable. We reviewed articles in five medical and seven epidemiologic journals published between January 1, 2017, and June 30, 2022. We identified 158 active comparator cohort studies, 76 from medical and 82 from epidemiologic journals. Residual, unmeasured, or uncontrolled confounding was noted as a potential concern in 93% of studies, but only 84 (53%) implemented one or more sensitivity analysis to assess uncontrolled confounding from an unmeasured variable. The most common analyses were E-values among medical journal articles (21%) and restriction on measured variables among epidemiologic journal articles (22%). Researchers must rigorously consider the role of residual confounding in their analyses and the best sensitivity analyses for assessing this potential bias., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Intimate care products may contain substances associated with increased risk of hormone-related cancers. The relationship between genital talc use and ovarian cancer, in particular, has been well studied, but concerns about recall bias and exposure misclassification have precluded conclusions. We examined the association between intimate care products and female hormone-related cancers, accounting for potential biases, using data from a US-based cohort study., Methods: The Sister Study enrolled 50,884 women who had a sister with breast cancer. Data on genital talc use and douching were collected at enrollment (2003-2009) and follow-up (2017-2019). We used Cox proportional hazards models to estimate hazard ratios (HRs) for associations between intimate care product use and breast, ovarian, and uterine cancers. To account for potential exposure misclassification and recall bias, we conducted quantitative bias analyses under various exposure reassignment assumptions., Results: Across considered scenarios, 41%-64% of participants douched and 35%-56% used genital talc. In models adjusted for exposure misclassification, genital talc use was positively associated with ovarian cancer (HR range, 1.17-3.34) Frequent douching and douching during young adulthood were positively associated with ovarian cancer, but neither douching nor talc was associated with breast or uterine cancer. Differential reporting of talc use by cases and noncases likely produces positive biases, but correcting for error still resulted in HRs above 1.0. For example, HR, 1.40 (95% CI, 1.04 to 1.89) when 25% of exposed cases and 10% of unexposed noncases had talc status reassigned., Conclusion: Although results show how differential recall would upwardly bias estimates, corrected results support a positive association between use of intimate care products, including genital talc, and ovarian cancer.

Purpose: Emotional and functional well-being (EWB and FWB) are important components of mental health and quality of life. This study aims to evaluate long-term EWB and FWB in breast cancer (BC) survivors., Methods: The Carolina Breast Cancer Study Phase 3 oversampled Black and younger (< 50 years in age) women so that they each represent approximately 50% of the study population and assessed participants' EWB and FWB with the Functional Assessment of Cancer Therapy-Breast (FACT-B) at 5- (baseline), 25-, and 84-months post diagnosis. Multinomial logit models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic and clinical characteristics and well-being change relative to baseline., Results: Among 2,781 participants with BC, average EWB and FWB improved with time since diagnosis. Persistent FWB decrements were associated with Black race [OR 1.4 (95% CI 1.2-1.7) and 1.3 (95% CI 1.1-1.6), at 25-months and 84-months respectively], older age [OR 1.4 (95% CI 1.1-1.7) and 1.5 (95% CI 1.2-1.8), respectively], no chemotherapy, and recurrence [OR 2.9 (95% CI 1.8-4.8) and 3.1 (95% CI 2.1-4.6), respectively]. EWB decrements were associated with advanced stage and recurrence. Decrements in combined (FWB+EWB) well-being were associated with recurrence at both follow-up survey timepoints [ORs 4.7 (95% CI 2.7-8.0) and 4.3 (95% CI 2.8-6.6), respectively]., Conclusions: Long-term well-being varies by demographics and clinical features, with Black women and women with aggressive disease at greatest risk of long-term decrements., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Generalized (g-) computation is a useful tool for causal inference in epidemiology. However, in settings when the outcome is a survival time subject to right censoring, the standard pooled logistic regression approach to g-computation requires arbitrary discretization of time, parametric modeling of the baseline hazard function, and the need to expand one's dataset. We illustrate a semiparametric Breslow estimator for g-computation with time-fixed treatments and survival outcomes that is not subject to these limitations., Methods: We compare performance of the Breslow g-computation estimator to the pooled logistic g-computation estimator in simulations and illustrate both approaches to estimate the effect of a 3-drug vs 2-drug antiretroviral therapy regimen among people with HIV., Results: In simulations, both approaches performed well at the end of follow-up. The pooled logistic approach was biased at times between the endpoints of the discrete time intervals used, while the Breslow approach was not. In the example, both approaches estimated a 1-year risk difference of about 6 % in favor of the 3-drug regimen, but the shape of the survival curves differed., Conclusions: The Breslow g-computation estimator of counterfactual risk functions does not rely on strong parametric assumptions about the time-to-event distribution or onerous dataset expansions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessie K. Edwards reports financial support was provided by National Institutes of Health. Jessie K. Edwards reports a relationship with The University of North Carolina at Chapel Hill that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In 2017, Blantyre district had the highest adult HIV prevalence in Malawi (17.7%) and lowest viral suppression (60%). In response, the Ministry of Health expanded prevention and treatment services. We assessed whether outreach to social venues could identify individuals with increased HIV acquisition risk or with unsuppressed HIV not currently reached by clinic-based services., Methods: We conducted a cross-sectional bio-behavioral survey in Blantyre, Malawi, from January to March 2022. We visited social venues where people meet new sexual partners and government clinics providing HIV testing or STI screening. Participants aged > 15 years were interviewed, and tested for HIV infection if not on ART. HIV recency tests were performed on those testing positive, and dried blood spots (DBS) was collected to quantify viral load and also to identify acute infection in those with HIV- results., Results: HIV prevalence (18.5% vs 8.3%) and unsuppressed HIV infection (3.9% vs 1.7%) were higher among venue-recruited (n=1802) compared with clinic-recruited participants(n=2313). Among PLHIV at both clinics (n=199) and venues (n=289), 79% were virally suppressed. Few had acute(n=1) or recent infection(n=8). Among women, HIV prevalence was four times higher (38.9% venue vs 8.9% clinic). At clinics, PLHIV reporting visiting venues were less likely to be suppressed (54.6 vs 82.6%). More men at venues than at clinics reported paying for sex (49% vs 30%) or having multiple sex partners in the past 4 weeks (32% vs 16%)., Conclusions: Enhanced venue-based prevention and testing for men and women could reduce treatment lapses, HIV treatment outcomes and reduce onward transmission., Competing Interests: Conflicts of Interest and Source of Funding: The authors declare no competing interest. The study reported in this publication was supported by the MeSH Consortium at UNC Project Malawi and London School of Hygiene & Tropical Medicine-UK, which is funded by the Bill & Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of funders., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Influenza vaccination is recommended for Australians 18+ years old with medical risk factors, but coverage is suboptimal. We aimed to examine whether automatic, opportunistic patient reminders (SMS and/or printed) before appointments with a general practitioner increased influenza vaccination uptake., Methods: This clustered non-randomised feasibility study in Australian general practice included patients aged 18-64 years with at least one medical risk factor attending participating practices between May and September 2021. Software installed at intervention practices identified unvaccinated eligible patients when they booked an appointment, sent vaccination reminders (SMS on booking and 1 h before appointments), and printed automatic reminders on arrival. Control practices provided usual care. Clustered analyses adjusted for sociodemographic differences among practices were performed using logistic regression., Results: A total of 12,786 at-risk adults attended 16 intervention practices (received reminders = 4066; 'internal control' receiving usual care = 8720), and 5082 individuals attended eight control practices. Baseline influenza vaccination uptake (2020) was similar in intervention and control practices (∼34%). After the intervention, uptake was similar in all groups (control practices = 29.3%; internal control = 30.0%; intervention = 31.6% (p-value = 0.203). However, SMS 1 h before appointments increased vaccination coverage (39.3%, adjusted OR = 1.65; 95%CI 1.20;2.27; number necessary to treat = 13), especially when combined with other reminder forms. That effect was more evident among adults with chronic respiratory, rheumatologic, or inflammatory bowel disease., Conclusion: These findings indicate that automated SMS reminders delivered at proximate times to appointments are a low-cost strategy to increase influenza vaccination among adults at higher risk of severe disease attending Australian general practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite increasing morbidity and mortality from non-communicable diseases (NCD) globally, health systems in low- and middle-income countries (LMICs) have limited capacity to address these chronic conditions, particularly in sub-Saharan Africa (SSA). There is an urgent need, therefore, to respond to NCDs in SSA, beginning by applying lessons learned from the first global response to any chronic disease-HIV-to tackle the leading cardiometabolic killers of people living with HIV (PLHIV). We have developed a feasible and acceptable package of evidence-based interventions and a multi-faceted implementation strategy, known as "TASKPEN," that has been adapted to the Zambian setting to address hypertension, diabetes, and dyslipidemia. The TASKPEN multifaceted implementation strategy focuses on reorganizing service delivery for integrated HIV-NCD care and features task-shifting, practice facilitation, and leveraging HIV platforms for NCD care. We propose a hybrid type II effectiveness-implementation stepped-wedge cluster randomized trial to evaluate the effects of TASKPEN on clinical and implementation outcomes, including dual control of HIV and cardiometabolic NCDs, as well as quality of life, intervention reach, and cost-effectiveness., Methods: The trial will be conducted in 12 urban health facilities in Lusaka, Zambia over a 30-month period. Clinical outcomes will be assessed via surveys with PLHIV accessing routine HIV services, and a prospective cohort of PLHIV with cardiometabolic comorbidities nested within the larger trial. We will also collect data using mixed methods, including in-depth interviews, questionnaires, focus group discussions, and structured observations, and estimate cost-effectiveness through time-and-motion studies and other costing methods, to understand implementation outcomes according to Proctor's Outcomes for Implementation Research, the Consolidated Framework for Implementation Research, and selected dimensions of RE-AIM., Discussion: Findings from this study will be used to make discrete, actionable, and context-specific recommendations in Zambia and the region for integrating cardiometabolic NCD care into national HIV treatment programs. While the TASKPEN study focuses on cardiometabolic NCDs in PLHIV, the multifaceted implementation strategy studied will be relevant to other NCDs and to people without HIV. It is expected that the trial will generate new insights that enable delivery of high-quality integrated HIV-NCD care, which may improve cardiovascular morbidity and viral suppression for PLHIV in SSA. This study was registered at ClinicalTrials.gov (NCT05950919)., (© 2024. The Author(s).)

Background: Frailty is an aging-related syndrome of reduced physiological reserve to maintain homeostasis. The Faurot frailty index has been validated as a Medicare claims-based proxy for predicting frailty using billing information from a user-specified ascertainment window., Objectives: We assessed the validity of the Faurot frailty index as a predictor of the frailty phenotype and 1-year mortality using varying frailty ascertainment windows., Research Design: We identified older adults (66+ y) in Round 5 (2015) of the National Health and Aging Trends Study with Medicare claims linkage. Gold standard frailty was assessed using the frailty phenotype. We calculated the Faurot frailty index using 3, 6, 8, and 12 months of claims prior to the survey or all-available lookback. Model performance for each window in predicting the frailty phenotype was assessed by quantifying calibration and discrimination. Predictive performance for 1-year mortality was assessed by estimating risk differences across claims-based frailty strata., Results: Among 4253 older adults, the 6 and 8-month windows had the best frailty phenotype calibration (calibration slopes: 0.88 and 0.87). All-available lookback had the best discrimination (C-statistic=0.780), but poor calibration. Mortality associations were strongest using a 3-month window and monotonically decreased with longer windows. Subgroup analyses revealed worse performance in Black and Hispanic individuals than counterparts., Conclusions: The optimal ascertainment window for the Faurot frailty index may depend on the clinical context, and researchers should consider tradeoffs between discrimination, calibration, and mortality. Sensitivity analyses using different durations can enhance the robustness of inferences. Research is needed to improve prediction across racial and ethnic groups., Competing Interests: T.S. receives salary support from the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Takeda, AbbVie, Boehringer Ingelheim, As tellas, and Sarepta) and from a generous contribution from Dr. Nancy A. Dreyer to the Department of Epidemiology, University of North Carolina at Chapel Hill. T.S. does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, and Novo Nordisk. J.L.L. receives research support from Roche to the University of North Carolina; her spouse was formerly employed by GlaxoSmithKline and previously owned stock in the company. K.R-H. receives research support unrelated to this work from Pfizer Global Medical Foundation to the University of North Carolina. D.H.K. received personal fees from Alosa Health and VillageMD for unrelated work. The remaining authors, J.K.E., K.R.F., and E.D.D., declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: People with suspected malaria may harbor Plasmodium falciparum undetected by rapid diagnostic test (RDT). The impact of these subpatent infections on the risk of developing clinical malaria is not fully understood., Methods: We analyzed subpatent P. falciparum infections using a longitudinal cohort in a high-transmission site in Kenya. Weighted Kaplan-Meier models estimated the risk difference (RD) for clinical malaria during the 60 days following a symptomatic subpatent infection. Stratum-specific estimates by age and transmission season assessed modification., Results: Over 54 months, we observed 1128 symptomatic RDT-negative suspected malaria episodes, of which 400 (35.5%) harbored subpatent P. falciparum. Overall, the 60-day risk of developing clinical malaria was low following all episodes (8.6% [95% confidence interval, 6.7%-10.4%]). In the low-transmission season, the risk of clinical malaria was slightly higher in those with subpatent infection, whereas the opposite was true in the high-transmission season (low-transmission season RD, 2.3% [95% confidence interval, .4%-4.2%]; high-transmission season RD, -4.8% [-9.5% to -.05%])., Conclusions: The risk of developing clinical malaria among people with undetected subpatent infections is low. A slightly elevated risk in the low-transmission season may merit alternate management, but RDTs identify clinically relevant infections in the high-transmission season., Competing Interests: Potential conflicts of interest. S. M. T. reports receiving speaker compensation from Abbott Laboratories. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: While noninferiority of tenofovir alafenamide and emtricitabine (TAF/FTC) as preexposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) has been shown, interest remains in its efficacy relative to placebo. We estimate the efficacy of TAF/FTC PrEP versus placebo for the prevention of HIV infection., Methods: We used data from the DISCOVER and iPrEx trials to compare TAF/FTC to placebo. DISCOVER was a noninferiority trial conducted from 2016 to 2017. iPrEx was a placebo-controlled trial conducted from 2007 to 2009. Inverse probability weights were used to standardize the iPrEx participants to the distribution of demographics and risk factors in the DISCOVER trial. To check the comparison, we evaluated whether risk of HIV infection in the shared tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) arms was similar., Results: Notable differences in demographics and risk factors occurred between trials. After standardization, the difference in risk of HIV infection between the TDF/FTC arms was near zero. The risk of HIV with TAF/FTC was 5.8 percentage points lower (95% confidence interval [CI], -2.0% to -9.6%) or 12.5-fold lower (95% CI, .02 to .31) than placebo standardized to the DISCOVER population., Conclusions: There was a reduction in HIV infection with TAF/FTC versus placebo across 96 weeks of follow-up., Clinical Trials Registration: NCT02842086 and NCT00458393., Competing Interests: Potential conflicts of interest. D. V. G. has accepted funds from Gilead Sciences. M. D., M. L. M., and Y. S. are employees of Gilead Sciences and hold stock interest in the company. A. A. A. has received consulting fees from Merck and Gilead; and research funding to her institution from Merck and Gilead. J. J. E. is an ad hoc consultant to Gilead Sciences and ViiV Healthcare. University of North Carolina at Chapel Hill receives clinical research funding from ViiV Healthcare and Gilead Science for studies on which J. J. E. is an investigator. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The World Health Organization Africa region has high regional hepatitis B virus (HBV) prevalence, and evidence suggests more frequent horizontal HBV transmission than other regions. Context-specific epidemiological studies are needed to inform additional HBV prevention measures., Methods: In the cross-sectional Horizontal and Vertical Transmission of Hepatitis B (HOVER-HBV) study, we introduced HBV surface antigen (HBsAg) screening alongside existing HIV screening as part of routine antenatal care in high-volume maternity clinics in Kinshasa, Democratic Republic of Congo. We recruited households of pregnant women ("index mothers") who were HBsAg-positive and HBsAg-negative, defining households as index-positive and index-negative, respectively. Household members underwent HBsAg testing and an epidemiological survey. We evaluated HBsAg prevalence and potential transmission correlates., Results: We enrolled 1006 participants from 200 households (100 index-positive, 100 index-negative) across Kinshasa. HBsAg-positivity prevalence was more than twice as high in index-positive households (5.0% [95% confidence interval {CI}, 2.8%-7.1%]) as in index-negative households (1.9% [95% CI, .6%-3.2%]). HBsAg-positivity prevalence was 3.3 (95% CI, .9-11.8) times as high among direct offspring in index-positive versus index-negative households. Factors associated with HBsAg positivity included older age, marriage, and having multiple recent partners or any new sexual partners among index mothers; and older age, lower household wealth, sharing nail clippers, and using street salons among offspring in index-positive households., Conclusions: Vertical and horizontal HBV transmission within households is ongoing in Kinshasa. Factors associated with infection reveal opportunities for HBV prevention efforts, including perinatal prevention, protection during sexual contact, and sanitation of shared personal items., Competing Interests: Potential conflicts of interest. J. B. P. and P. T. report nonfinancial support from Abbott Laboratories (donation of hepatitis B laboratory testing and reagents for other studies), and J. B. P. reports consulting for Zymeron Corporation, all outside the submitted work. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Approaches to address measurement error frequently rely on validation data to estimate measurement error parameters (e.g., sensitivity and specificity). Acquisition of validation data can be costly, thus secondary use of existing data for validation is attractive. To use these external validation data, however, we may need to address systematic differences between these data and the main study sample. Here, we derive estimators of the risk and the risk difference that leverage external validation data to account for outcome misclassification. If misclassification is differential with respect to covariates that themselves are differentially distributed in the validation and study samples, the misclassification parameters are not immediately transportable. We introduce two ways to account for such covariates: (1) standardize by these covariates or (2) iteratively model the outcome. If conditioning on a covariate for transporting the misclassification parameters induces bias of the causal effect (e.g., M-bias), the former but not the latter approach is biased. We provide proof of identification, describe estimation using parametric models, and assess performance in simulations. We also illustrate implementation to estimate the risk of preterm birth and the effect of maternal HIV infection on preterm birth. Measurement error should not be ignored and it can be addressed using external validation data via transportability methods., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

While randomized controlled trials (RCTs) are critical for establishing the efficacy of new therapies, there are limitations regarding what comparisons can be made directly from trial data. RCTs are limited to a small number of comparator arms and often compare a new therapeutic to a standard of care which has already proven efficacious. It is sometimes of interest to estimate the efficacy of the new therapy relative to a treatment that was not evaluated in the same trial, such as a placebo or an alternative therapy that was evaluated in a different trial. Such dual-study comparisons are challenging because of potential differences between trial populations that can affect the outcome. In this article, two bridging estimators are considered that allow for comparisons of treatments evaluated in different trials, accounting for measured differences in trial populations. A "multi-span" estimator leverages a shared arm between two trials, while a "single-span" estimator does not require a shared arm. A diagnostic statistic that compares the outcome in the standardized shared arms is provided. The two estimators are compared in simulations, where both estimators demonstrate minimal empirical bias and nominal confidence interval coverage when the identification assumptions are met. The estimators are applied to data from the AIDS Clinical Trials Group 320 and 388 to compare the efficacy of two-drug vs four-drug antiretroviral therapy on CD4 cell counts among persons with advanced HIV. The single-span approach requires weaker identification assumptions and was more efficient in simulations and the application., (© 2023 John Wiley & Sons Ltd.)

Background: Severe skin and soft tissue infections related to injection drug use have increased in concordance with a shift to heroin and illicitly manufactured fentanyl. Opioid agonist therapy medications (methadone and buprenorphine) may improve long-term outcomes by reducing injection drug use. We aimed to examine the association of medication use with mortality among people with opioid use-related skin or soft tissue infections., Methods: An observational cohort study of Medicaid enrollees aged 18 years or older following their first documented medical encounters for opioid use-related skin or soft tissue infections during 2007-2018 in North Carolina. The exposure was documented medication use (methadone or buprenorphine claim) in the first 30 days following initial infection compared with no medication claim. Using Kaplan-Meier estimators, we examined the difference in 3-year incidence of mortality by medication use, weighted for year, age, comorbidities, and length of hospital stay., Results: In this sample, there were 13,286 people with opioid use-related skin or soft tissue infections. The median age was 37 years, 68% were women, and 78% were white. In Kaplan-Meier curves for the total study population, 12 of every 100 patients died during the first 3 years. In weighted models, for every 100 people who used medications, there were four fewer deaths over 3 years (95% confidence interval = 2, 6)., Conclusion: In this study, people with opioid use-related skin and soft tissue infections had a high risk of mortality following their initial healthcare visit for infections. Methadone or buprenorphine use was associated with reductions in mortality., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Loop diuretics are a standard pharmacologic therapy in heart failure (HF) management. Although furosemide is most frequently used, torsemide and bumetanide are increasingly prescribed in clinical practice, possibly because of superior bioavailability. Few real-world comparative effectiveness studies have examined outcomes across all 3 loop diuretics. The study goal was to compare the effects of loop diuretic prescribing at HF hospitalization discharge on mortality and HF readmission. We identified patients in Medicare claims data initiating furosemide, torsemide, or bumetanide after an index HF hospitalization from 2007 to 2017. We estimated 6-month risks of all-cause mortality and a composite outcome (HF readmission or all-cause mortality) using inverse probability of treatment weighting to adjust for relevant confounders. We identified 62,632 furosemide, 1,720 torsemide, and 2,389 bumetanide initiators. The 6-month adjusted all-cause mortality risk was lowest for torsemide (13.2%), followed by furosemide (14.5%) and bumetanide (15.6%). The 6-month composite outcome risk was 21.4% for torsemide, 24.7% for furosemide, and 24.9% for bumetanide. Compared with furosemide, the 6-month all-cause mortality risk was 1.3% (95% confidence interval [CI]: -3.7, 1.0) lower for torsemide and 1.0% (95% CI: -1.2, 3.2) higher for bumetanide, and the 6-month composite outcome risk was 3.3% (95% CI: -6.3, -0.3) lower for torsemide and 0.2% (95% CI: -2.5, 2.9) higher for bumetanide. In conclusion, the findings suggested that the first prescribed loop diuretic following HF hospitalization is associated with clinically important differences in morbidity in older patients receiving torsemide, bumetanide, or furosemide. These differences were consistent for the effect of all-cause mortality alone, but were not statistically significant., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Studies designed to estimate the effect of an action in a randomized or observational setting often do not represent a random sample of the desired target population. Instead, estimates from that study can be transported to the target population. However, transportability methods generally rely on a positivity assumption, such that all relevant covariate patterns in the target population are also observed in the study sample. Strict eligibility criteria, particularly in the context of randomized trials, may lead to violations of this assumption. Two common approaches to address positivity violations are restricting the target population and restricting the relevant covariate set. As neither of these restrictions is ideal, we instead propose a synthesis of statistical and simulation models to address positivity violations. We propose corresponding g-computation and inverse probability weighting estimators. The restriction and synthesis approaches to addressing positivity violations are contrasted with a simulation experiment and an illustrative example in the context of sexually transmitted infection testing uptake. In both cases, the proposed synthesis approach accurately addressed the original research question when paired with a thoughtfully selected simulation model. Neither of the restriction approaches was able to accurately address the motivating question. As public health decisions must often be made with imperfect target population information, model synthesis is a viable approach given a combination of empirical data and external information based on the best available knowledge., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Higher-order evidence is evidence about evidence. Epidemiologic examples of higher-order evidence include the settings where the study data constitute first-order evidence and estimates of misclassification comprise the second-order evidence (e.g., sensitivity, specificity) of a binary exposure or outcome collected in the main study. While sampling variability in higher-order evidence is typically acknowledged, higher-order evidence is often assumed to be free of measurement error (e.g., gold standard measures). Here we provide two examples, each with multiple scenarios where second-order evidence is imperfectly measured, and this measurement error can either amplify or attenuate standard corrections to first-order evidence. We propose a way to account for such imperfections that requires third-order evidence. Further illustrations and exploration of how higher-order evidence impacts results of epidemiologic studies is warranted., (© 2023. Springer Nature B.V.)

Background: Incarceration is associated with negative impacts on mental health. Probation, a form of community supervision, has been lauded as an alternative. However, the effect of probation versus incarceration on mental health is unclear. Our objective was to estimate the impact on mental health of reducing sentencing severity at individuals' first adult criminal-legal encounter., Methods: We used the US National Longitudinal Survey on Youth 1997, a nationally representative dataset of youth followed into their mid-thirties. Restricting to those with an adult encounter (arrest, charge alone or no sentence, probation, incarceration), we used parametric g-computation to estimate the difference in mental health at age 30 (Mental Health Inventory-5) if (1) everyone who received incarceration for their first encounter had received probation and (2) everyone who received probation had received no sentence., Results: Among 1835 individuals with adult encounters, 19% were non-Hispanic Black and 65% were non-Hispanic White. Median age at first encounter was 20. Under hypothetical interventions to reduce sentencing, we did not see better mental health overall (Intervention 1, incarceration to probation: RD = -0.01; CI = -0.02, 0.01; Intervention 2, probation to no sentence: RD = 0.00; CI = -0.01, 0.01) or when stratified by race., Conclusion: Among those with criminal-legal encounters, hypothetical interventions to reduce sentencing, including incremental sentencing reductions, were not associated with improved mental health. Future work should consider the effects of preventing individuals' first criminal-legal encounter., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Mortality remains elevated among Black versus White adults receiving human immunodeficiency virus (HIV) care in the United States. We evaluated the effects of hypothetical clinic-based interventions on this mortality gap., Methods: We computed 3-year mortality under observed treatment patterns among >40 000 Black and >30 000 White adults entering HIV care in the United States from 1996 to 2019. We then used inverse probability weights to impose hypothetical interventions, including immediate treatment and guideline-based follow-up. We considered 2 scenarios: "universal" delivery of interventions to all patients and "focused" delivery of interventions to Black patients while White patients continued to follow observed treatment patterns., Results: Under observed treatment patterns, 3-year mortality was 8% among White patients and 9% among Black patients, for a difference of 1 percentage point (95% confidence interval [CI], .5-1.4). The difference was reduced to 0.5% under universal immediate treatment (95% CI, -.4% to 1.3%) and to 0.2% under universal immediate treatment combined with guideline-based follow-up (95% CI, -1.0% to 1.4%). Under the focused delivery of both interventions to Black patients, the Black-White difference in 3-year mortality was -1.4% (95% CI, -2.3% to -.4%)., Conclusions: Clinical interventions, particularly those focused on enhancing the care of Black patients, could have significantly reduced the mortality gap between Black and White patients entering HIV care from 1996 to 2019., Competing Interests: Potential  conflicts of interest. L. C. Z. reports grants from NIH, predoctoral fellowship funding from ViiV Healthcare, and consulting fees and travel support from Carelon. S. R. C. reports grants from NIH. J. J. E. reports grants from NIH, ViiV Healthcare, Gilead Sciences, and Janssen; consulting fees from ViiV Healthcare, Gilead Sciences, and Merck & Co; and participation in a data and safety and monitoring board (DSMB) for TAIMED. A. A. A. reports grants from NIH, Merck & Co, and Gilead Sciences; consulting fees from Merck & Co and Gilead Sciences; participation in DSMBs for ACTIV 6 and RECOVER; and a leadership role in the Infectious Diseases Society of America. K. N. A. reports grants from NIH, royalties from Coursera, consulting fees from TrioHealth Inc and the All of Us Research Program, and travel support from the International Workshop on HIV and Hepatitis Observational Databases. V. C. M. reports grants from NIH, Emory University, Lilly, Gilead Sciences, ViiV Healthcare, CDC, and the Department of Veterans Affairs; honoraria from Medscape/WebMD/ViiV, Integritas, and Lilly; travel support from NIH; and service as Study Section Chair and participation in a DSMB for NIH. M. J. G. reports grants from NIH and participation on advisory boards for Merck & Co, Gilead Sciences, and ViiV Healthcare. M. A. H. reports grants from NIH, Gilead Sciences, and CDC. P. F. R. reports consulting fees from Gilead Sciences and Janssen. P. K. reports grants from NIH. RDM reports grants from NIH. J. K. E. reports grants from NIH and travel support from and a leadership position in the Society for Epidemiologic Research. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: When competing events occur, there are two main options for handling them analytically that invoke different assumptions: 1) censor person-time after a competing event (which is akin to assuming they could be prevented) to calculate a conditional risk; or 2) do not censor them (allow them to occur) to calculate an unconditional risk. The choice of estimand has implications when weighing the relative frequency of a beneficial outcome and an adverse outcome in a risk-benefit analysis., Recent Findings: We review the assumptions and interpretations underlying the two main approaches to analyzing competing risks. Using a popular metric in risk-benefit analyses, the Benefit-Risk Ratio, and a toy dataset, we demonstrated that conclusions about whether a treatment was more beneficial or more harmful can depend on whether one uses conditional or unconditional risks., Summary: We argue that unconditional risks are more relevant to decision-making about exposures with competing outcomes than conditional risks., Competing Interests: Dr. Zalla reports grants from NIH during the conduct of the study, other grants from Viiv Healthcare, and personal fees from Carelon, outside the submitted work. Mr. Joseph reports personal fees from Takeda Pharmaceuticals, outside the submitted work. Other authors have no conflicts of interest to report.

Competing Interests: The authors report no conflicts of interest.

Purpose: Model-based forecasts of population size, deaths, and age distribution of people with HIV (PWH) are helpful for public health and clinical services planning but are influenced by subgroup-specific heterogeneities and changes in mortality rates., Methods: Using an agent-based simulation of PWH in the United States, we examined the impact of distinct approaches to parametrizing mortality rates on forecasted epidemiology of PWH on antiretroviral treatment (ART). We first estimated mortality rates among (1) all PWH, (2) sex-specific, (3) sex-and-race/ethnicity-specific, and (4) sex-race/ethnicity-and-HIV-acquisition-risk-specific subgroups. We then assessed each scenario by (1) allowing unrestricted reductions in age-specific mortality rates over time and (2) restricting the mortality rates among PWH to subgroup-specific mortality thresholds from the general population., Results: Among the eight scenarios examined, those lacking subgroup-specific heterogeneities and those allowing unrestricted reductions in future mortality rates forecasted the lowest number of deaths among all PWH and 9 of the 15 subgroups through 2030. The forecasted overall number and age distribution of people with a history of injection drug use were sensitive to inclusion of subgroup-specific mortality rates., Conclusions: Our results underscore the potential risk of underestimating future deaths by models lacking subgroup-specific heterogeneities in mortality rates, and those allowing unrestricted reductions in future mortality rates., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Parastu Kasaie reports financial support was provided by National Institutes of Health. Keri Althof reports financial support was provided by National Institutes of Health. Emily Hyle reports financial support was provided by National Institutes of Health. Lauren Zalla reports financial support was provided by National Institutes of Health. Anthony Fojo reports financial support was provided by National Institutes of Health. Emily Hyle reports financial support was provided by Massachusetts General Hospital. Keri Althoff reports a relationship with TrioHealth that includes: board membership. KNA reports serving on the Scientific Advisory Board for TrioHealth Inc. and as a consultant to the All of Us Study (National Institutes of Health). PFR reports serving as a consultant for Gilead and Janssen Pharmaceuticals. Kelly Gebo is a consultant for Teach for America and the Aspen Institute and was an unpaid representative to a scientific Advisory Board for Pfizer. LCZ reports serving as a consultant for Carelon. None of these have direct relation to, or impact on, the findings presented here. All other authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inverse probability weighting can be used to correct for missing data. New estimators for the weights in the nonmonotone setting were introduced in 2018. These estimators are the unconstrained maximum likelihood estimator (UMLE) and the constrained Bayesian estimator (CBE), an alternative if UMLE fails to converge. In this work we describe and illustrate these estimators, and examine performance in simulation and in an applied example estimating the effect of anemia on spontaneous preterm birth in the Zambia Preterm Birth Prevention Study. We compare performance with multiple imputation (MI) and focus on the setting of an observational study where inverse probability of treatment weights are used to address confounding. In simulation, weighting was less statistically efficient at the smallest sample size and lowest exposure prevalence examined (n = 1500, 15% respectively) but in other scenarios statistical performance of weighting and MI was similar. Weighting had improved computational efficiency taking, on average, 0.4 and 0.05 times the time for MI in R and SAS, respectively. UMLE was easy to implement in commonly used software and convergence failure occurred just twice in >200 000 simulated cohorts making implementation of CBE unnecessary. In conclusion, weighting is an alternative to MI for nonmonotone missingness, though MI performed as well as or better in terms of bias and statistical efficiency. Weighting's superior computational efficiency may be preferred with large sample sizes or when using resampling algorithms. As validity of weighting and MI rely on correct specification of different models, both approaches could be implemented to check agreement of results., (© 2023 John Wiley & Sons Ltd.)

Introduction: Little 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., Methods: Using 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., Results: A 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., Conclusions: Implementation 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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Understanding how health inequities develop over time is necessary to inform interventions, but methods for doing so are underutilized. We provide an example of the accumulation of stressful life events using the mean cumulative count (MCC), which estimates the expected number of events per person as a function of time, allowing for censoring and competing events. Data came from the National Longitudinal Survey of Youth 1997, a nationally representative data set. To compare the MCC with standard practice, we present the proportions of persons experiencing 1, 2, and ≥3 stressful events and the cumulative probability of experiencing at least 1 event by the end of follow-up. Our sample included 6,522 individuals aged 18-33 years who were followed for a median of 14 years. Using the MCC, by age 20 years the expected number of encounters was 56 events per 100 participants for Black non-Hispanic persons, 47 per 100 for White non-Hispanic persons, and 50 per 100 for Hispanic persons. By age 33 years, inequities grew to 117, 99, and 108 events per 100 persons, respectively. The MCC revealed that inequities in stressful events accumulate over the course of early adulthood, partially driven by repeat events; this information was not evident from conventional approaches. This method can be used to identify intervention points for disrupting the accumulation of repeat events to improve health equity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We describe an approach to sensitivity analysis introduced by Robins et al (1999), for the setting where the outcome is missing for some observations. This flexible approach focuses on the relationship between the outcomes and missingness, where data can be missing completely at random, missing at random given observed data, or missing not at random. We provide examples from HIV that include the sensitivity of the estimation of a mean and proportion under different missingness mechanisms. The approach illustrated provides a method for examining how the results of epidemiologic studies might shift as a function of bias due to missing data., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Population-based seroprevalence studies are crucial to understand community transmission of COVID-19 and guide responses to the pandemic. Seroprevalence is typically measured from diagnostic tests with imperfect sensitivity and specificity. Failing to account for measurement error can lead to biased estimates of seroprevalence. Methods to adjust seroprevalence estimates for the sensitivity and specificity of the diagnostic test have largely focused on estimation in the context of convenience sampling. Many existing methods are inappropriate when data are collected using a complex sample design., Methods: We present methods for seroprevalence point estimation and confidence interval construction that account for imperfect test performance for use with complex sample data. We apply these methods to data from the Chatham County COVID-19 Cohort (C4), a longitudinal seroprevalence study conducted in central North Carolina. Using simulations, we evaluate bias and confidence interval coverage for the proposed estimator compared with a standard estimator under a stratified, three-stage cluster sample design., Results: We obtained estimates of seroprevalence and corresponding confidence intervals for the C4 study. SARS-CoV-2 seroprevalence increased rapidly from 10.4% in January to 95.6% in July 2021 in Chatham County, North Carolina. In simulation, the proposed estimator demonstrates desirable confidence interval coverage and minimal bias under a wide range of scenarios., Conclusion: We propose a straightforward method for producing valid estimates and confidence intervals when data are based on a complex sample design. The method can be applied to estimate the prevalence of other infections when estimates of test sensitivity and specificity are available., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In the Lake Victoria region of East Africa, little is known about delays between tuberculosis (TB) symptom onset and presentation at a clinic. Associations between clinic presentation delay and TB treatment outcomes are also poorly understood. In 2019, we abstracted data from routine TB treatment records for all adults (n = 776) initiating TB treatment in a 6-month period across 12 health facilities near Lake Victoria. We interviewed 301 cohort members and assessed whether they experienced a clinic presentation delay longer than 6 weeks. We investigated potential clinical and demographic correlates of clinic presentation delay and examined the association between clinic presentation delay and an unfavorable TB treatment outcome (death, loss to follow-up, or treatment failure). Clinic presentation delay was common, occurring among an estimated 54.7% (95% CI: 48.9%, 61.2%) of cohort members, though no specific correlates were identified. Clinic presentation delay was slightly associated with unfavorable TB treatment outcomes. The 180-day risk of an unfavorable outcome was 14.2% (95% CI: 8.0%, 20.4%) among those with clinic presentation delay, compared to 12.7% (95% CI: 5.1%, 20.3%) among those presenting earlier. Multi-level community-based interventions may be necessary to reduce clinic presentation delays in communities near Lake Victoria., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mulholland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although the importance of clinical ethics in contemporary clinical environments is established, development of formal clinical ethics services in the Australia health system has, to date, been ad hoc. This study was designed to systematically follow and reflect upon the first 18 months of activity by a newly established service, to examine key barriers and facilitators to establishing a new service in an Australian hospital setting., Methods: HOW THE STUDY WAS PERFORMED AND STATISTICAL TESTS USED: A qualitative case study approach was utilised. The study gathered and analysed data using observations of service committee meetings, document analysis of agendas and minutes, and semi-structured interviews with committee members to generate semantic themes. By interpreting the thematic findings in reference to national capacity building resources, this study also aimed to provide practice-based reflections for other health agencies., Results: THE MAIN FINDINGS: An overarching theme identified in the data was a strong commitment to supporting clinicians facing difficult patient care decisions and navigating difficult discussions with patients and families. Another key theme was the role of the new clinical ethics support service in providing clinicians with a pathway to raise system-wide issues with the organisation Executive. While there was strong clinical engagement, consumer and community participation remained a challenge, as did unresolved governance issues and a need for clearer policy relationship between the service and the organisation. Considering these themes in relation to the national capacity building resources, the study identifies three areas likely to require ongoing development and negotiation. These are: the role of the clinical ethics support service as a link between the workforce and the Executive; the incorporation of consumers and patients; and ethical reasoning. To improve the effectiveness of the service, it is necessary to increase clarity on the service's role at the governance and policy level, as well as develop strategies for engaging consumers, patients and families. Finally, the capacity of the service to reflect on complex cases may be enhanced through explicit discussions of various different ethical frameworks and ways of deliberating., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009-2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) is well tolerated, cost-effective, and yields high sustained virologic response rates, yet it has remained financially inaccessible to many patients., Methods: Participants of the Women's Interagency HIV Study (an observational US cohort) with human immunodeficiency virus (HIV) and HCV (RNA+) reporting no prior hepatitis C treatment were followed for DAA initiation (2015-2019). We estimated risk ratios (RRs) of the relationship between time-varying health insurance status and DAA initiation, adjusting for confounders with stabilized inverse probability weights. We also estimated weighted cumulative incidences of DAA initiation by health insurance status., Results: A total of 139 women (74% Black) were included; at baseline, the median age was 55 years and 86% were insured. Most had annual household incomes ≤$18 000 (85%); advanced liver fibrosis (21%), alcohol use (45%), and recreational drug use (35%) were common. Across 439 subsequent semiannual visits, 88 women (63%) reported DAA initiation. Compared with no health insurance, health insurance increased the likelihood of reporting DAA initiation at a given visit (RR, 4.94; 95% confidence limit [CL], 1.92 to 12.8). At 2 years, the weighted cumulative incidence of DAA initiation was higher among the insured (51.2%; 95% CL, 43.3% to 60.6%) than the uninsured (3.5%; 95% CL, 0.8% to 14.6%)., Conclusions: Accounting for clinical, behavioral, and sociodemographic factors over time, health insurance had a substantial positive effect on DAA initiation. Interventions to increase insurance coverage should be prioritized to increase HCV curative therapy uptake for persons with HIV., Competing Interests: Potential conflicts of interest. A. A. A. reports consultancies with Merck and Gilead, royalties or licenses from Gilead related to consultations, research funding from Merck and Gilead, and nonfinancial interests from roles on the Infectious Diseases Society of America Board of Directors and IAS Governing Council. M. L. A. reports consultancies with Gilead; payment or honoraria from Gilead, Merck, and Discidium Biosciences (paid to author); travel support from Merck; participation on a data and safety monitoring board or advisory board for Senhwa Biosciences; and research funding from AbbVie and NIH. A. S. reports research funding and payment for participation in advisory board meetings from Gilead. P. C. T. reports research funding from Merck, Gilead, and Eli-Lilly (all paid to institution); royalties or licenses from UptoDate (paid to author); honorarium from Vindico CME; and participation on the STAR cohort Scientific Advisory Board and BIRCWH K12 External Scientific Advisory Board. K. W. reports research funding from AbbVie. C. R. reports grants and travel support from NIH (paid to institution). M. P. reports travel/meeting support from NIH (to the author's institution). A. L. F. reports travel support from NIH. J. K. E. reports institutional grants from NIH NIGMS and travel support from the Society for Epidemiologic Research (paid to author). D. F. H. reports additional NIDA salary support as a co-investigator. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Geographic mobility may disrupt continuity of care and contribute to poor clinical outcomes among people receiving treatment for tuberculosis (TB). This may occur especially where health services are not well coordinated across international borders, particularly in lower and middle income country settings. In this work, we describe mobility and the relationship between mobility and unfavorable TB treatment outcomes (i.e., death, loss to follow-up, or treatment failure) among a cohort of adults who initiated TB treatment at one of 12 health facilities near Lake Victoria. We abstracted data from health facility records for all 776 adults initiating TB treatment during a 6-month period at the selected facilities in Kenya, Tanzania, and Uganda. We interviewed 301 cohort members to assess overnight travel outside one's residential district/sub-county. In our analyses, we estimated the proportion of cohort members traveling in 2 and 6 months following initiation of TB treatment, explored correlates of mobility, and examined the association between mobility and an unfavorable TB treatment outcome. We estimated that 40.7% (95% CI: 33.3%, 49.6%) of people on treatment for TB traveled overnight at least once in the 6 months following treatment initiation. Mobility was more common among people who worked in the fishing industry and among those with extra-pulmonary TB. Mobility was not strongly associated with other characteristics examined, however, suggesting that efforts to improve TB care for mobile populations should be broad ranging. We found that in this cohort, people who were mobile were not at increased risk of an unfavorable TB treatment outcome. Findings from this study can help inform development and implementation of mobility-competent health services for people with TB in East Africa., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mulholland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recurrent events-outcomes that an individual can experience repeatedly over the course of follow-up-are common in epidemiologic and health services research. Studies involving recurrent events often focus on time to first occurrence or on event rates, which assume constant hazards over time. In this paper, we contextualize recurrent event parameters of interest using counterfactual theory in a causal inference framework and describe an approach for estimating a target parameter referred to as the mean cumulative count. This approach leverages inverse probability weights to control measured confounding with an existing (and underutilized) nonparametric estimator of recurrent event burden first proposed by Dong et al. in 2015. We use simulations to demonstrate the unbiased estimation of the mean cumulative count using the weighted Dong-Yasui estimator in a variety of scenarios. The weighted Dong-Yasui estimator for the mean cumulative count allows researchers to use observational data to flexibly estimate and contrast the expected number of cumulative events experienced per individual by a given time point under different exposure regimens. We provide code to ease application of this method., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: During the 2010 Deepwater Horizon ( DWH ) disaster, response and cleanup workers were potentially exposed to toxic volatile components of crude oil. However, to our knowledge, no study has examined exposure to individual oil spill-related chemicals in relation to cardiovascular outcomes among oil spill workers., Objectives: Our aim was to investigate the association of several spill-related chemicals [benzene, toluene, ethylbenzene, xylene, n -hexane (BTEX-H)] and total hydrocarbons (THC) with incident coronary heart disease (CHD) events among workers enrolled in a prospective cohort., Methods: Cumulative exposures to THC and BTEX-H across the cleanup period were estimated via a job-exposure matrix that linked air measurement data with self-reported DWH spill work histories. We ascertained CHD events following each worker's last day of cleanup work as the first self-reported physician-diagnosed myocardial infarction (MI) or a fatal CHD event. We estimated hazard ratios (HR) and 95% confidence intervals for the associations of exposure quintiles (Q) with risk of CHD. We applied inverse probability weights to account for bias due to confounding and loss to follow-up. We used quantile g-computation to assess the joint effect of the BTEX-H mixture., Results: Among 22,655 workers with no previous MI diagnoses, 509 experienced an incident CHD event through December 2019. Workers in higher quintiles of each exposure agent had increased CHD risks in comparison with the referent group (Q1) of that agent, with the strongest associations observed in Q5 (range of HR = 1.14 - 1.44 ). However, most associations were nonsignificant, and there was no evidence of exposure-response trends. We observed stronger associations among ever smokers, workers with ≤ high school education, and workers with body mass index < 30   kg / m 2 . No apparent positive association was observed for the BTEX-H mixture., Conclusions: Higher exposures to volatile components of crude oil were associated with modest increases in risk of CHD among oil spill workers, although we did not observe exposure-response trends. https://doi.org/10.1289/EHP11859.