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Many research questions in public health and medicine concern sustained interventions in populations defined by substantive priorities. Existing methods to answer such questions typically require a measured covariate set sufficient to control confounding, which can be questionable in observational studies. Differences‐in‐differences rely instead on the parallel trends assumption, allowing for some types of time‐invariant unmeasured confounding. However, most existing difference‐in‐differences implementations are limited to point treatments in restricted subpopulations. We derive identification results for population effects of sustained treatments under parallel trends assumptions. In particular, in settings where all individuals begin follow‐up with exposure status consistent with the treatment plan of interest but may deviate at later times, a version of Robins' g‐formula identifies the intervention‐specific mean under stable unit treatment value assumption, positivity, and parallel trends. We develop consistent asymptotically normal estimators based on inverse‐probability weighting, outcome regression, and a double robust estimator based on targeted maximum likelihood. Simulation studies confirm theoretical results and support the use of the proposed estimators at realistic sample sizes. As an example, the methods are used to estimate the effect of a hypothetical federal stay‐at‐home order on all‐cause mortality during the COVID‐19 pandemic in spring 2020 in the United States. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Studies of social networks provide unique opportunities to assess the causal effects of interventions that may impact more of the population than just those intervened on directly. Such effects are sometimes called peer or spillover effects, and may exist in the presence of interference, that is, when one individual's treatment affects another individual's outcome. Randomization‐based inference (RI) methods provide a theoretical basis for causal inference in randomized studies, even in the presence of interference. In this article, we consider RI of the intervention effect in the eX‐FLU trial, a randomized study designed to assess the effect of a social distancing intervention on influenza‐like‐illness transmission in a connected network of college students. The approach considered enables inference about the effect of the social distancing intervention on the per‐contact probability of influenza‐like‐illness transmission in the observed network. The methods allow for interference between connected individuals and for heterogeneous treatment effects. The proposed methods are evaluated empirically via simulation studies, and then applied to data from the eX‐FLU trial. [ABSTRACT FROM AUTHOR]

Interference, the dependency of an individual's potential outcome on the exposure of other individuals, is a common occurrence in medicine and public health. Recently, targeted maximum likelihood estimation (TMLE) has been extended to settings of interference, including in the context of estimation of the mean of an outcome under a specified distribution of exposure, referred to as a policy. This paper summarizes how TMLE for independent data is extended to general interference (network-TMLE). An extensive simulation study is presented of network-TMLE, consisting of four data generating mechanisms (unit-treatment effect only, spillover effects only, unit-treatment and spillover effects, infection transmission) in networks of varying structures. Simulations show that network-TMLE performs well across scenarios with interference, but issues manifest when policies are not well-supported by the observed data, potentially leading to poor confidence interval coverage. Guidance for practical application, freely available software, and areas of future work are provided. [ABSTRACT FROM AUTHOR]

In the analysis of observational studies, inverse probability weighting (IPW) is commonly used to consistently estimate the average treatment effect (ATE) or the average treatment effect in the treated (ATT). The variance of the IPW ATE estimator is often estimated by assuming that the weights are known and then using the so-called "robust" (Huber-White) sandwich estimator, which results in conservative standard errors (SEs). Here we show that using such an approach when estimating the variance of the IPW ATT estimator does not necessarily result in conservative SE estimates. That is, assuming the weights are known, the robust sandwich estimator may be either conservative or anticonservative. Thus, confidence intervals for the ATT using the robust SE estimate will not be valid, in general. Instead, stacked estimating equations which account for the weight estimation can be used to compute a consistent, closed-form variance estimator for the IPW ATT estimator. The 2 variance estimators are compared via simulation studies and in a data analysis of the association between smoking and gene expression. [ABSTRACT FROM AUTHOR]

Inverse probability of treatment weights (IPTWs) are commonly used to control for confounding when estimating causal effects of point exposures from observational data. When planning a study that will be analyzed with IPTWs, determining the required sample size for a given level of statistical power is challenging because of the effect of weighting on the variance of the estimated causal means. This paper considers the utility of the design effect to quantify the effect of weighting on the precision of causal estimates. The design effect is defined as the ratio of the variance of the causal mean estimator divided by the variance of a naïve estimator if, counter to fact, no confounding had been present and weights were not needed. A simple, closed‐form approximation of the design effect is derived that is outcome invariant and can be estimated during the study design phase. Once the design effect is approximated for each treatment group, sample size calculations are conducted as for a randomized trial, but with variances inflated by the design effects to account for weighting. Simulations demonstrate the accuracy of the design effect approximation, and practical considerations are discussed. [ABSTRACT FROM AUTHOR]

Assessing population‐level effects of vaccines and other infectious disease prevention measures is important to the field of public health. In infectious disease studies, one person's treatment may affect another individual's outcome, that is, there may be interference between units. For example, the use of bed nets to prevent malaria by one individual may have an indirect effect on other individuals living in close proximity. In some settings, individuals may form groups or clusters where interference only occurs within groups, that is, there is partial interference. Inverse probability weighted estimators have previously been developed for observational studies with partial interference. Unfortunately, these estimators are not well suited for studies with large clusters. Therefore, in this paper, the parametric g‐formula is extended to allow for partial interference. G‐formula estimators are proposed for overall effects, effects when treated, and effects when untreated. The proposed estimators can accommodate large clusters and do not suffer from the g‐null paradox that may occur in the absence of interference. The large sample properties of the proposed estimators are derived assuming no unmeasured confounders and that the partial interference takes a particular form (referred to as 'weak stratified interference'). Simulation studies are presented demonstrating the finite‐sample performance of the proposed estimators. The Demographic and Health Survey from the Democratic Republic of the Congo is then analyzed using the proposed g‐formula estimators to assess the effects of bed net use on malaria. [ABSTRACT FROM AUTHOR]

AbstractInterference occurs when a unit’s treatment (or exposure) affects another unit’s outcome. In some settings, units may be grouped into clusters such that it is reasonable to assume that interference, if present, only occurs between individuals in the same cluster, that is, there is clustered interference. Various causal estimands have been proposed to quantify treatment effects under clustered interference from observational data, but these estimands either entail treatment policies lacking real-world relevance or are based on parametric propensity score models. Here, we propose new causal estimands based on modification of the propensity score distribution which may be more relevant in many contexts and are not based on parametric models. Nonparametric sample splitting estimators of the new estimands are constructed, which allow for flexible data-adaptive estimation of nuisance functions and are consistent, asymptotically normal, and efficient, converging at the usual parametric rate. Simulations show the finite sample performance of the proposed estimators. The proposed methods are applied to evaluate the effect of water, sanitation, and hygiene facilities on diarrhea among children in Senegal. Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work. [ABSTRACT FROM AUTHOR]

We consider nonparametrically estimating the joint distribution of a survival time and mark variable, where the survival time is subject to right censoring and the mark variable is only observed when the survival time is not censored. The possibility of dependent censoring is allowed for using inverse probability of censoring weights. The proposed estimator is shown to be consistent and asymptotically normal. Finite sample behavior of the proposed methods are investigated via simulation study. Finally, we illustrate the nonparametric estimator from a recent HIV vaccine efficacy trial. [ABSTRACT FROM AUTHOR]

Published associations between combined oral contraceptive use and uterine fibroid development have lacked prospective imaging with ultrasound to distinguish between incident and prevalent fibroids. The Study of Environment, Lifestyle, and Fibroids prospectively followed fibroid-free, African-American women (the group with the highest disease burden in the U.S.) to identify incident cases. We examined associations between combined oral contraceptive use and the 40-month cumulative risk of fibroids. History of hormonal contraceptive use was collected via telephone interview at enrollment. Fibroid identification was performed using transvaginal ultrasonography at enrollment, and at 20 and 40-months of follow-up. Inverse probability weights for exposures and censoring were used to construct weighted risk ratios (wRR) and weighted risk different (wRD) estimators which control for differences in fibroid risk factors between exposure groups. In addition, unweighted fully adjusted log-binomial regression models (aRR) were run for comparison. Of the 1,308 participants in the analysis sample, 70% had used combined oral contraceptives and 17% developed fibroids by 40 months. We observed an inverse association between ever use of combined oral contraceptives and cumulative fibroid incidence (wRR: 0.78; 95% Confidence Interval (CI): 0.60, 1.00; wRD: -0.05, 95% CI: -0.11, 0; aRR: 0.76, 95% CI: 0.60, 0.98). Fibroid incidence was greater in participants who started using combined oral contraceptives after age 17 years than among younger initiators, though the restriction to ever-users made this estimate less precise (wRR: 1.25; 95% CI: 0.89, 1.76; wRD: 0.04, 95% CI: -0.02, 0.10). No consistent patterns of fibroid incidence were seen among ever-users for duration of, or years since, last combined oral contraceptives use. [ABSTRACT FROM AUTHOR]

We sought to examine cervical cancer screening barriers by sexual orientation among low-income women in North Carolina. The MyBodyMyTest-3 Trial recruited low-income women (< 250% of federal poverty level) aged 25–64 years who were 1+ year overdue for cervical cancer screening. We compared perceptions of cervical cancer screening among those who self-identified as lesbian, gay, bisexual, or queer (LGBQ; n = 70) to straight/heterosexual women (n = 683). For both LGBQ and straight respondents, the greatest barriers to screening were lack of health insurance (63% and 66%) and cost (49% and 50%). LGBQ respondents were more likely than straight respondents to report forgetting to screen (16% vs. 8%, p =.05), transportation barriers (10% vs. 2%, p =.001), and competing mental or physical health problems (39% vs. 27%, p =.10). Addressing access remains important for improving cervical cancer screening among those under-screened. For LGBQ women, additional attention may be needed for reminders, co-occurring health needs, and transportation barriers. [ABSTRACT FROM AUTHOR]

Estimating population‐level effects of a vaccine is challenging because there may be interference, that is, the outcome of one individual may depend on the vaccination status of another individual. Partial interference occurs when individuals can be partitioned into groups such that interference occurs only within groups. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to draw inference about causal effects of an exposure or treatment. Tchetgen Tchetgen and VanderWeele proposed a modified IPW estimator for causal effects in the presence of partial interference. Motivated by a cholera vaccine study in Bangladesh, this paper considers an extension of the Tchetgen Tchetgen and VanderWeele IPW estimator to the setting where the outcome is subject to right censoring using inverse probability of censoring weights (IPCW). Censoring weights are estimated using proportional hazards frailty models. The large sample properties of the IPCW estimators are derived, and simulation studies are presented demonstrating the estimators' performance in finite samples. The methods are then used to analyze data from the cholera vaccine study. [ABSTRACT FROM AUTHOR]

High-dimensional low sample size (HDLSS) data sets frequently emerge in many biomedical applications. The direction-projection-permutation (DiProPerm) test is a two-sample hypothesis test for comparing two high-dimensional distributions. The DiProPerm test is exact, i.e., the type I error is guaranteed to be controlled at the nominal level for any sample size, and thus is applicable in the HDLSS setting. This paper discusses the key components of the DiProPerm test, introduces the diproperm R package, and demonstrates the package on a real-world data set. [ABSTRACT FROM AUTHOR]

People living with HIV on antiretroviral therapy often have undetectable virus levels by standard assays, but "latent" HIV still persists in viral reservoirs. Eliminating these reservoirs is the goal of HIV cure research. The quantitative viral outgrowth assay (QVOA) is commonly used to estimate the reservoir size, that is, the infectious units per million (IUPM) of HIV-persistent resting CD4+ T cells. A new variation of the QVOA, the ultra deep sequencing assay of the outgrowth virus (UDSA), was recently developed that further quantifies the number of viral lineages within a subset of infected wells. Performing the UDSA on a subset of wells provides additional information that can improve IUPM estimation. This paper considers statistical inference about the IUPM from combined dilution assay (QVOA) and deep viral sequencing (UDSA) data, even when some deep sequencing data are missing. Methods are proposed to accommodate assays with wells sequenced at multiple dilution levels and with imperfect sensitivity and specificity, and a novel bias-corrected estimator is included for small samples. The proposed methods are evaluated in a simulation study, applied to data from the University of North Carolina HIV Cure Center, and implemented in the open-source R package SLDeepAssay. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Endoscopic healing has been associated with improved long-term clinical outcomes in inflammatory bowel disease (IBD) and is a recommended target for treatment. Evidence is limited regarding real-world uptake and patterns of treat-to-target monitoring to assess endoscopic healing after treatment initiation. We aimed to estimate the proportion of patients in the Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) who received colonoscopy in the 3-15 months after starting a new IBD treatment. METHODS: We identified SPARC IBD patients who initiated a new biologic (infliximab, adalimumab, certolizumab pegol, golimumab, vedolizumab, and ustekinumab) or tofacitinib. We estimated the proportion of patients who received colonoscopies in the 3-15 months after IBD treatment initiation and described use by patient subgroups. RESULTS: Among 1,708 eligible initiations from 2017 to 2022, the most common medications were ustekinumab (32%), infliximab (22%), vedolizumab (20%), and adalimumab (16%). The median patient age was 38 years, with 66% Crohn's disease; 55% were female, and 12% were non-White. In the 3-15 months after medication initiation, 49.3% (95% confidence interval 46.2%-52.5%) of initiations were followed by a colonoscopy. Colonoscopy use was similar between ulcerative colitis and Crohn's disease, but was higher among male patients, those older than 40 years, and those who received colonoscopy within 3 months of initiation. Colonoscopy use varied between study sites, from 26.6% (15.0%-38.3%) to 63.2% (54.5%-72.0%). DISCUSSION: Approximately half of SPARC IBD patients received colonoscopy in the 3-15 months after initiation to a new IBD treatment, suggesting a low uptake of treat-to-target colonoscopy for the assessment of mucosal healing in real-world clinical practice. The variation in colonoscopy use between study sites suggests a lack of consensus and a need for more robust evidence around whether or not the practice of routine monitoring colonoscopy is associated with improved patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Underscreened, low-income, and uninsured or publicly insured women in the United States bear a greater burden of cervical cancer morbidity and mortality and may face unique barriers that preclude screening adherence. Methods: Participants were 710 My Body My Test-3 clinical trial participants who were publicly insured or uninsured with incomes ≤250% of the U.S. Federal Poverty Level, aged 25–64 years, and not up to date on cervical cancer screening as per national guidelines. Using Health Belief Model constructs, we assessed screening-related knowledge, perceptions, and behaviors—overall and stratified by race and ethnicity—and estimated associations with past-year attempted screening using multivariable regression models. Results: Overall, knowledge was low about the human papillomavirus, purpose of a Pap test, and recommended screening interval. Perceived severity of cervical cancer was high (3.63 on a 4-point scale). Black and Latina/Hispanic women were more likely to perceive screening as lowering their risk of cervical cancer than White women. Black women reported lower perceived risk of cervical cancer compared with White women (p = 0.03), but Black women were more likely to have sought screening in the past year (p = 0.01). Having at least three doctor visits in the past year was associated with a screening attempt. Greater perceived risk of cervical cancer, more positive perceptions of screening, and feeling more nervousness about screening were also associated with a screening attempt (all p < 0.05). Conclusions: Addressing knowledge gaps and misconceptions about cervical cancer screening and leveraging positive perceptions of screening may improve screening uptake and adherence among diverse underscreened U.S. women. Clinical Trial Registration Number: NCT02651883. [ABSTRACT FROM AUTHOR]

The authors offer a response to the article "Invited Commentary: Combining Information to Answer Epidemiologic Questions about a Target Population" by I. J. Dahabreh. They talk about the data combined in fusion study designs, case on estimating a misclassified and transported proportion, and introduction of the oncept of learning functions.

"Fusion" study designs combine data from different sources to answer questions that could not be answered (as well) by subsets of the data. Studies that augment main study data with validation data, as in measurement-error correction studies or generalizability studies, are examples of fusion designs. Fusion estimators, here solutions to stacked estimating functions, produce consistent answers to identified research questions using data from fusion designs. In this paper, we describe a pair of examples of fusion designs and estimators, one where we generalize a proportion to a target population and one where we correct measurement error in a proportion. For each case, we present an example motivated by human immunodeficiency virus research and summarize results from simulation studies. Simulations demonstrate that the fusion estimators provide approximately unbiased results with appropriate 95% confidence interval coverage. Fusion estimators can be used to appropriately combine data in answering important questions that benefit from multiple sources of information. [ABSTRACT FROM AUTHOR]

• We found relatively low rates of recombinant zoster vaccine (RZV) series initiation. • There were lower rates of RZV initiation among men, those living in rural areas and in the Northeast and the South, and those of younger age. • Initiation rates differed by immune function (higher among immunocompromised). • Among initiators, overall RZV series completion was high. • This information can be used for targeting efforts to increase vaccine uptake. The Centers for Disease Control and Prevention (CDC) recommends recombinant zoster vaccination (RZV) for adults ≥ 50 years to prevent herpes zoster (HZ) and its sequelae. Initially, no distinct recommendation was made for immunocompromised adults, who experience higher HZ rates and more severe outcomes. We characterized receipt of first RZV dose (initiation) and both doses (completion) over time, and the impact of immune function on RZV uptake among adults aged 50–64 years in the United States. We identified RZV claims from the IBM MarketScan database between 1/1/2018 and 12/31/2019. We characterized immunocompromised enrollees as having malignancy, HIV, solid organ transplant, primary immunosuppression, or medication-induced immunosuppression using inpatient, outpatient, and prescription claims in the 6 months prior to study start. We evaluated patterns of vaccine uptake by demographic and healthcare access characteristics and immune status. The cumulative incidence of RZV initiation during the study period was 10.0%. Incidence increased with age and number of medical office visits, and was higher among women, urban residents, high-deductible insurance beneficiaries, and those who were immunocompromised compared to immunocompetent. Among immunocompromised adults, RZV initiation was highest among those with HIV and primary immunodeficiencies. Of those who initiated RZV, 89.5% received both doses. RZV completion was highest among those who received the first dose at a pharmacy. Most enrollees (88.6%) who completed RZV vaccination did so within the recommended dosing schedule. RZV uptake was low in the two years since the CDC recommendation, and differed by demographic, healthcare access, and clinical characteristics. Initiation rates were higher among immunocompromised adults compared to immunocompetent adults, despite no CDC recommendation for vaccination in these groups during the study period. The CDC has since recommended RZV for immunocompromised individuals, and our findings may inform efforts to increase RZV uptake in individuals at higher risk of severe disease. [ABSTRACT FROM AUTHOR]

Serial limiting dilution (SLD) assays are a widely used tool in many areas of public health research to measure the concentration of target entities. This concentration can be estimated via maximum likelihood. Asymptotic as well as exact inference methods have been proposed for hypothesis testing and confidence interval construction in this one-sample problem. However, in many scientific applications, it may be of interest to compare the concentration of target entities between a pair of samples and construct valid confidence intervals for the difference in concentrations. In this paper, an exact, computationally efficient inferential procedure is proposed for hypothesis testing and confidence interval construction in the two-sample SLD assay problem. The proposed exact method is compared to an approach based on asymptotic approximations in simulation studies. The methods are illustrated using data from the University of North Carolina HIV Cure Center. [ABSTRACT FROM AUTHOR]

Under-screened women are more likely to be diagnosed with invasive cervical cancer at later stages and have worse survival outcomes. Under- or un-insured women, low-income women, and minoritized groups face barriers to screening. Intention to screen is an indicator of future screening behavior, yet is understudied among low-income, under-screened women. Participants were 710 low-income, uninsured or publicly insured women ages 25–64 years in North Carolina who were not up to date on cervical cancer screening according to national guidelines. Participants were asked about barriers to screening and intention to screen. We estimated reported barriers to cervical cancer screening stratified by race and ethnicity (categorized as White, Black, and Hispanic) and assessed predictors of intention to screen. Sixty-one percent of all participants reported 5 or more barriers to screening. The most commonly reported reasons for not getting screened were lack of insurance (White: 71%, Black: 62%, Hispanic/Latina: 63%) and cost (White: 55%, Black: 44%, Hispanic/Latina: 61%). Women were more likely to have an intention to screen if they reported "it was not hard to get screening" (OR: 1.47 (1.00, 2.15)). Older women reported being less likely to intend to screen. Black women reported being more likely to intend to screen than White women. Lack of health insurance and cost were frequently reported barriers to cervical cancer screening. Increasing knowledge of affordable clinics and expanding access to Medicaid may reduce barriers and increase cervical cancer screening uptake. [ABSTRACT FROM AUTHOR]

Controlled drug delivery systems can provide sustained release profiles, favorable pharmacokinetics, and improved patient adherence. Here, a reservoir-style implant comprising a biodegradable polymer, poly(ε-caprolactone) (PCL), was developed to deliver drugs subcutaneously. This work addresses a key challenge when designing these implantable drug delivery systems, namely the accurate prediction of drug release profiles when using different formulations or form factors of the implant. The ability to model and predict the release behavior of drugs from an implant based on their physicochemical properties enables rational design and optimization without extensive and laborious in vitro testing. By leveraging experimental observations, we propose a mathematical model that predicts the empirical parameters describing the drug diffusion and partitioning processes based on the physicochemical properties of the drug. We demonstrate that the model enables an adequate fit predicting empirical parameters close to experimental values for various drugs. The model was further used to predict the release performance of new drug formulations from the implant, which aligned with experimental results for implants exhibiting zero-order release kinetics. Thus, the proposed empirical models provide useful tools to inform the implant design to achieve a target release profile. [ABSTRACT FROM AUTHOR]

This JAMA Guide to Statistics and Methods describes how intention-to-treat, per-protocol, and as-treated approaches to analysis differ with regard to the patient population and treatment assignments and their implications for interpretation of treatment effects in clinical trials. [ABSTRACT FROM AUTHOR]

Background Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious virus isolation in outpatients with coronavirus disease 2019 (COVID-19) has been associated with viral RNA levels and symptom duration, little is known about the host, disease, and viral determinants of infectious virus detection. Methods COVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay. Results Among 204 participants with mild-to-moderate symptomatic COVID-19, the median nasopharyngeal viral RNA was 6.5 (interquartile range [IQR] 4.7–7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (immunoglobulin (Ig)A, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (prevalence ratio [PR] = 0.12, 95% confidence interval [CI]:.04,.36; P  = .00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; P  < .0001) and fewer days since symptom onset (PR = 0.79, 95% CI:.71,.88 per day; P  < .0001). Conclusions The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion. Clinical Trials Registration NCT04405570. [ABSTRACT FROM AUTHOR]

Background: Of new sexually transmitted infections (STIs) in the United States, 50% occur among youth aged 15 to 24 years. Previous studies among youth with HIV (YHIV) do not distinguish STI trends among individuals with perinatally (YPHIV) and nonperinatally (YNPHIV) acquired HIV.Methods: Among 3 Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) studies conducted between 2009 and 2015, we estimated incident diagnoses of trichomonal, bacterial, viral, and overall STIs stratified by sex assigned at birth, mode of HIV acquisition (perinatal [YPHIV] and nonperinatal [YNPHIV]), age (13-17 and 18-24 years), CD4 count (<200, 200-499, and ≥500/μL), and HIV viral load (VL) (<400 and ≥400 copies/mL).Results: Among 3131 YHIV, across the 3 studies, mean (SD) age was 20.6 (2.6) years, 888 (28%) were female, 2498 (80%) had nonperinatal HIV acquisition recorded, and 2298 (73%) were African American/Black. Mean follow-up was 0.9 (0.3) years. Compared with YPHIV, YNPHIV spent less person-time with VL <400 copies/mL (47% vs. 53%) and more time off antiretroviral therapy (49% vs. 15%), and had higher overall STI rates (males, 65.9 vs. 8.5/100 person-years [PY]; females, 54.7 vs. 17.2/100 PY). Among YPHIV, bacterial STIs were higher during person-time spent with VL ≥400 vs. <400 copies/mL (male YPHIV, 10.9 vs. 0.6/100 PY; female YPHIV, 11.2 vs. 2.9/100 PY); no difference was observed among YNPHIV, which may be due to concurrent acquisition of HIV and other STIs and limited follow-up.Conclusions: Compared with YPHIV, YNPHIV spent less time on antiretroviral therapy and virologically suppressed; YNPHIV also had higher STI diagnosis rates. Very high STI diagnosis rates among YHIV, including among those without virologic suppression, highlight the importance of youth-focused efforts to support durable virologic suppression and identify and treat STIs. [ABSTRACT FROM AUTHOR]

Background: Low-income and uninsured people with a cervix (PWC) are at the highest risk of being underscreened for cervical cancer. We evaluated the prevalence of high-risk human papillomavirus (hrHPV) on home self-collected samples, as well as rates of in-clinic follow-up and risk factors associated with hrHPV positivity in this at-risk population.Methods: My Body My Test 3 was conducted between 2016 and 2019 in North Carolina among individuals aged 25 to 64 years, overdue for cervical cancer screening, and with incomes of <250% of the US Federal Poverty Level. Our analytic sample included participants randomized to the self-collection arm who returned self-collected cervicovaginal brush samples for HPV testing (n = 329). Samples were tested for 14 hrHPV types by an HPV RNA assay and further genotyped for HPV-16 and HPV-18/45. We examined behavioral risk factors for hrHPV positivity using logistic regression and between-subject t tests.Results: High-risk HPV RNA prevalence was 16% (n = 52/329) in self-collected samples. Of the hrHPV-positive participants, 24 (46%) presented for in-clinic cervical cancer screening, compared with 56 (20%) of hrHPV-negative participants. Those with ≥2 sexual partners in the past year were twice as likely to be hrHPV positive in adjusted analyses (adjusted odds ratio, 2.00 [95% confidence interval, 1.03-3.88]). High-risk HPV-positive and HPV-negative participants had similar attitudes toward screening, with the exception of hrHPV-positive participants who reported a lower perceived risk of cervical cancer than those who were hrHPV negative (P < 0.05).Conclusion: The hrHPV RNA prevalence was similar to findings in other underscreened PWC in the United States. Efforts to reach underscreened PWC are critical for cervical cancer prevention. Future studies aimed at home self-collection should address methods of increasing clinic attendance and completion of treatment among those with HPV-positive results. [ABSTRACT FROM AUTHOR]

Background: Despite screening's effectiveness in reducing cervical cancer incidence and mortality, disparities in cervical cancer screening uptake remain, with lower rates documented among uninsured and low-income individuals. We examined perceived financial barriers to, and the perceived cost burden of, cervical cancer screening. Materials and Methods: We surveyed 702 low-income, uninsured or publicly insured women ages 25–64 years in North Carolina, U.S., who were not up to date on cervical cancer screening according to national guidelines. Participants were asked about perceived financial barriers to screening and how much they perceived screening would cost. We used multivariable logistic regression to assess the sociodemographic predictors of perceived financial barriers. Results: Seventy-two percent of participants perceived financial barriers to screening. Screening appointment costs (71%) and follow-up/future treatment costs (44%) were most commonly reported, followed by lost pay due to time missed from work (6%) and transportation costs (5%). In multivariable analysis, being uninsured (vs. publicly insured), younger (25–34 vs. 50–64 years), White (vs. Black), and not reporting income data were associated with perceiving screening costs and future treatment costs as barriers to screening. Participants reported wide-ranging estimates of the perceived out-of-pocket cost of screening ($0–$1300), with a median expected cost of $245. Conclusions: The majority of our sample of low-income women perceived substantial financial barriers to screening, particularly related to screening appointment costs and potential follow-up/future treatment costs. Providing greater cost transparency and access to financial assistance may reduce perceived financial barriers to screening, potentially increasing screening uptake among this underserved population. Clinicaltrials.gov registration number NCT02651883. [ABSTRACT FROM AUTHOR]

Background People who inject drugs (PWID) living with HIV experience inadequate access to antiretroviral treatment (ART) and medication for opioid use disorders (MOUD). HPTN 074 showed that an integrated intervention increased ART use and viral suppression over 52 weeks. To examine durability of ART, MOUD, and HIV viral suppression, participants could re-enroll for an extended follow-up period, during which standard-of-care (SOC) participants in need of support were offered the intervention. Methods Participants were recruited from Ukraine, Indonesia and Vietnam and randomly allocated 3:1 to SOC or intervention. Eligibility criteria included: HIV-positive; active injection drug use; 18-60 years of age; ≥1 HIV-uninfected injection partner; and viral load ≥1,000 copies/mL. Re-enrollment was offered to all available intervention and SOC arm participants, and SOC participants in need of support (off-ART or off-MOUD) were offered the intervention. Results The intervention continuation group re-enrolled 89 participants, and from week 52 to 104, viral suppression (<40 copies/mL) declined from 41% to 29% (estimated 9.4% decrease per year, 95% CI -17.0%; -1.8%). The in need of support group re-enrolled 94 participants and had increased ART (re-enrollment: 55%, week 26: 69%) and MOUD (re-enrollment: 16%, week 26: 25%) use, and viral suppression (re-enrollment: 40%, week 26: 49%). Conclusions Viral suppression declined in year 2 for those who initially received the HPTN 074 intervention and improved maintenance support is warranted. Viral suppression and MOUD increased among in need participants who received intervention during the study extension. Continued efforts are needed for widespread implementation of this scalable, integrated intervention. [ABSTRACT FROM AUTHOR]

We use simple examples to show how the bias and standard error of an estimator depend in part on the type of estimator chosen from among parametric, nonparametric, and semiparametric candidates. We estimated the cumulative distribution function in the presence of missing data with and without an auxiliary variable. Simulation results mirrored theoretical expectations about the bias and precision of candidate estimators. Specifically, parametric maximum likelihood estimators performed best but must be "omnisciently" correctly specified. An augmented inverse probability–weighted (IPW) semiparametric estimator performed best among candidate estimators that were not omnisciently correct. In one setting, the augmented IPW estimator reduced the standard error by nearly 30%, compared with a standard Horvitz-Thompson IPW estimator; such a standard error reduction is equivalent to doubling the sample size. These results highlight the gains and losses that can be incurred when model assumptions are made in any analysis. [ABSTRACT FROM AUTHOR]

Background: The replication-competent human immunodeficiency virus (HIV) reservoir is the major barrier to cure. The quantitative viral outgrowth assay (QVOA), the gold-standard method to quantify replication-competent HIV, is resource intensive, which limits its application in large clinical trials. The intact proviral DNA assay (IPDA) requires minimal cell input relative to QVOA and quantifies both defective and intact proviral HIV DNA, the latter potentially serving as a surrogate marker for replication-competent provirus. However, there are limited cross-sectional and longitudinal data on the relationship between IPDA and QVOA measurements.Methods: QVOA and IPDA measurements were performed on 156 resting CD4 T-cell (rCD4) samples from 83 antiretroviral therapy-suppressed HIV-positive participants. Longitudinal QVOA and IPDA measurements were performed on rCD4 from 29 of these participants.Results: Frequencies of intact, defective, and total proviruses were positively associated with frequencies of replication-competent HIV. Longitudinally, decreases in intact proviral frequencies were strikingly similar to that of replication-competent virus in most participants. In contrast, defective proviral DNA frequencies appeared relatively stable over time in most individuals.Conclusions: Changes in frequencies of IPDA-derived intact proviral DNA and replication-competent HIV measured by QVOA are similar. IPDA is a promising high-throughput approach to estimate changes in the frequency of the replication-competent reservoir. [ABSTRACT FROM AUTHOR]