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To describe longitudinal outcomes and predictors of cognitive outcomes in children with HIV in Zambia.Multiple studies have shown that children with HIV are at risk for impaired cognition. However, there are limited data on longitudinal cognitive outcomes in children with HIV.We conducted a prospective cohort study of 208 perinatally infected children with HIV ages 8-17 years, all treated with antiretroviral therapy, and 208 HIV-exposed uninfected controls. Participants were followed for 2 years. Cognition was assessed with a custom NIH Toolbox Cognition Battery, and tests were combined to generate a Summary Cognition Score (SCS). The contribution of potential risk factors to outcomes was explored using regression models and group-based trajectory modeling.HIV was strongly associated with lower SCS at baseline [β-14, 95% confidence interval (CI): -20 to -7, P0.001]. Change scores over time were similar between groups, but poorer average performance in children with HIV persisted at the 2-year follow-up visit (adjusted β = -11, 95% CI: -22 to -0.3, P = 0.04). Other than HIV, the strongest predictors of baseline SCS included socioeconomic status index (β =3, 95% CI: 1, 5, P = 0.004), history of growth stunting (β=-14, 95% CI: -23 to -6, P = 0.001), history of CD4 count below 200 (β = -19, 95% CI: -35 to -2, P = 0.02), and history of World Health Organization stage 4 disease (β = -10, 95% CI: -19 to -0.2, P = 0.04). In the group-based trajectory model, HIV+ status predicted membership in the lowest performing trajectory group (odds ratio 2.5, 95% CI: 1.2 to 5.1, P = 0.01).Children with HIV are at risk of poor cognitive outcomes, despite chronic treatment with antiretroviral therapy.

PDF file - 1288K, Distribution of genes with FPKM > 1. Genes are binned into deciles of percentage of samples in which the FPKM was > 1. Thus for a gene with FPKM > 1 in 65% of samples, the gene would be included in 60-70% bin. Y-axis is the number of genes in each decile.

PDF file - 2194K, RNAseq data from the IGFBP3 gene in the IGV browser for representative FFPE samples (top four tracks) and TCGA prostate samples (bottom three tracks) showing intronic reads.

XLSX file - 10K, Clinical characteristics of patients analyzed by RNAseq.

XLSX file - 42K, Set of 894 genes with a univariate CoxPH q-value < 0.10 that were subjected to pathway enrichment and upstream analyses using Ingenuity Pathway Analysis (IPA).

XLSX file - 28K, RNA-QC, sequencing, and clinical metadata on the 106 samples sequenced in this study.

XLSX file - 14K, Set of most significantly enriched biological functions as deterermined by IPA analysis based on the gene list in Supplementary Table 5.

XLSX file - 9K, Summary of sequencing statistics from RNAseq analysis of 106 FFPE RNA samples.

PDF file - 766K, TaqMan validation of RNAseq data. Taqman Fold Change was calculated for three genes (PTN, SYNM, and TMSB10) and plotted against FPKM values.

XLSX file - 15K, Set of most significantly enriched canonical pathways as deterermined by IPA analysis based on the gene list in Supplementary Table 5.

XLSX file - 9K, Prediction Model based on Clinical Variables alone, namely, tGleason score, Log(prePSA + ), pStage, Surgical Margin Status, and Age.

XLSX file - 33K, Set of 304 genes differentially expressed between Gleason 3+4 pattern and Gleason 4+3 pattern patients based on DEseq analysis (p < 0.05).

PDF file - 1172K, Log2 FPKM+1 values are plotted for the six samples that were sequenced in duplicate. Plots include data for the 5265 detected genes used in the biomarker analysis. R-squared values are indicated for the best fit linear curve for each duplicate sample.

As this is more of a reference article, I chose not to have an abstract similar to the paper I wrote in 2016 regarding flat feet in the military.

Sequential, multiple assignment, randomized trials (SMARTs) compare sequences of treatment decision rules called dynamic treatment regimes (DTRs). In particular, the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) SMART aimed to determine the best DTRs for patients with a substance use disorder. While many authors have focused on a single pairwise comparison, addressing the main goal involves comparisons of >2 DTRs. For complex comparisons, there is a paucity of methods for binary outcomes. We fill this gap by extending the multiple comparisons with the best (MCB) methodology to the Bayesian binary outcome setting. The set of best is constructed based on simultaneous credible intervals. A substantial challenge for power analysis is the correlation between outcome estimators for distinct DTRs embedded in SMARTs due to overlapping subjects. We address this using Robins’ G-computation formula to take a weighted average of parameter draws obtained via simulation from the parameter posteriors. We use non-informative priors and work with the exact distribution of parameters avoiding unnecessary normality assumptions and specification of the correlation matrix of DTR outcome summary statistics. We conduct simulation studies for both the construction of a set of optimal DTRs using the Bayesian MCB procedure and the sample size calculation for two common SMART designs. We illustrate our method on the ENGAGE SMART. The R package SMARTbayesR for power calculations is freely available on the Comprehensive R Archive Network (CRAN) repository. An RShiny app is available at https://wilart.shinyapps.io/shinysmartbayesr/.

Mountaintop removal coal mining (MTR) has been a major source of landscape change in the Central Appalachians of the United States (US). Changes in stream hydrology, channel geomorphology and water quality caused by MTR coal mining can lead to severe impairment of stream ecological integrity. The objective of the Clean Water Act (CWA) is to restore and maintain the ecological integrity of the Nation's waters. Sensitive, readily measured indicators of ecosystem structure and function are needed for the assessment of stream ecological integrity. Most CWA assessments rely on structural indicators; inclusion of functional indicators could make these assessments more holistic and effective. The goals of this study were: (1) test the efficacy of selected carbon (C) and nitrogen (N) cycling and microbial structural and functional indicators for assessing MTR coal mining impacts on streams; (2) determine whether indicators respond to impacts in a predictable manner; and (3) determine if functional indicators are less likely to change than are structural indicators in response to stressors associated with MTR coal mining. The structural indicators are water quality and sediment organic matter concentrations, and the functional indicators relate to microbial activity and biofilm production. Seasonal measurements were conducted over the course of a year in streams draining small MTR-impacted and forested watersheds in the Twentymile Creek watershed of West Virginia (WV). Five of the eight structural parameters measured had significant responses, with all means greater in the MTR-impacted streams than in the forested streams. These responses resulted from changes in source or augmentation of the original source of the C and N structural parameters because of MTR coal mining. Nitrate concentration and the stable carbon isotopic ratio of dissolved inorganic carbon were the most effective indicators evaluated in this study. Only three of the fourteen functional indicators measured had significant responses to MTR coal mining, with all means greater in the forested streams than in the MTR-impacted streams. These results suggest that stressors associated with MTR coal mining caused reduction in some aspects of microbial cycling, but resource subsidies may have counterbalanced some of the inhibition leading to no observable change in most of the functional indicators. The detritus base, which is thought to confer functional stability, was likely sustained in the MTR-impacted streams by channel storage and/or leaf litter inputs from their largely intact riparian zones. Overall, our results largely support the hypothesis that certain functional processes are more resistant to stress induced change than structural properties but also suggest the difficulty of identifying suitable functional indicators for ecological integrity assessment.

Background:To facilitate advances in spinal muscular atrophy therapeutic research, it is important to determine the impact and prevalence of symptoms experienced by children with spinal muscular atrophy. Methods: We conducted qualitative interviews with caregivers of children with spinal muscular atrophy. From these interviews, we generated a survey inquiring about 260 symptoms of importance grouped into 17 symptomatic themes. Results: Sixteen caregivers of children with spinal muscular atrophy aged from 4 months to 12 years participated in initial interviews, and 77 caregivers completed the survey. Higher symptom prevalence was associated with spinal muscular atrophy type, SMN2 copy number, and functional status. Hip, thigh, or knee weakness had the greatest reported impact on the lives of children with spinal muscular atrophy. Conclusions: This research provides one of the largest data sets regarding disease burden in children with spinal muscular atrophy. The most prevalent symptoms are not identical to those with the greatest impact. This unique insight into the most impactful symptoms will help focus therapeutic development in spinal muscular atrophy.

ObjectiveTo re-evaluate the longitudinal progression of stroke-induced homonymous visual field defects using strictly automated perimetry (Zeiss Humphrey Systems), rigorous inclusion/exclusion criteria, and quantitative analyses.MethodsA retrospective chart review of stroke patients diagnosed with “homonymous hemianopia”, who underwent monocular Humphrey visual field (HVF) perimetry using the 24-2 SITA standard pattern from 2011-2019, was conducted at a large US academic medical center. Reliable tests (ResultsOf 532 patients with “homonymous hemianopia”, sequential, reliable HVFs were only available for 36 patients in the right eye, and 30 patients in the left eye, ranging from 7 days to 58 months post-stroke. Both PMD and deficit area improved early, within the first 3 months post-stroke; however, this was followed by a subsequent decline in performance >1 year post-stroke. Changes were similar between eyes.ConclusionWe discovered that a large portion of occipital stroke patients do not receive comprehensive ophthalmologic follow-up and, even then, only a fraction of HVFs performed are reliable enough for rigorous analysis. Nonetheless, reliable HVFs in such patients confirmed early visual improvement after stroke, consistent with prior reports. However, in contrast with prior, qualitative reports, there was no stability of the deficit beyond 6 months post-stroke; instead, gradual worsening erased the initial spontaneous improvement, especially >1 year post-stroke.

The ability to maintain an absolute, submaximal torque level during fatiguing contractions is controlled, in part, by the recruitment of larger motor units. These motor units are commonly identified based on greater action potential peak-to-peak amplitude values. It is unclear, however, if motor unit action potential (MUAP) amplitude values during low torque, fatiguing contractions reach similar levels as those observed during non-fatigued, high torque contractions. To establish a clearer understanding of motor unit control during fatigue, we compared MUAP amplitude during 50 and 80% maximum voluntary contraction (MVC) torque contractions and at the beginning, middle, and end of a 30% MVC fatigue protocol. Eleven untrained men (mean age = 24 years) performed isometric contractions at 50 and 80% MVC, followed by repeated contractions at 30% MVC. Surface electromyographic (EMG) signals were detected from the vastus lateralis and decomposed to quantify the peak-to-peak amplitude of individual MUAPs. A two-level multilevel model was estimated, allowing examination of simultaneous measures of MUAP amplitude within participants and controlling for the dependence between measures within participants. Results from the multilevel analyses suggested that there were not statistically significant differences in MUAP amplitude between 80% MVC and end fatigue. Separate repeated-measures analyses of variance indicated that there were not statistically significant mean differences in greatest MUAP or surface EMG amplitude between 80% MVC and end fatigue. MUAP and surface EMG amplitude values during a 30% MVC fatiguing protocol appear to be comparable to those observed during a non-fatigued 80% MVC condition.

Background The KwaZulu-Natal (KZN) province of South Africa has the highest prevalence of HIV infection in the world. Viral load (VL) testing is a crucial tool for clinical and programmatic monitoring. Within uMkhanyakude district, VL suppression rates were 91% among patients with VL data; however, VL performance rates averaged only 38·7%. The objective of this study was to determine if enhanced clinic processes and community outreach could improve VL monitoring within this district. Methods A packaged intervention was implemented at three rural clinics in the setting of the KZN HIV AIDS Drug Resistance Surveillance Study. This included file hygiene, outreach, a VL register and documentation revisions. Chart audits were used to assess fidelity. Outcome measures included percentage VL performed and suppressed. Each rural clinic was matched with a peri-urban clinic for comparison before and after the start of each phase of the intervention. Monthly sample proportions were modelled using quasi-likelihood regression methods for over-dispersed binomial data. Results Mkuze and Jozini clinics increased VL performance overall from 33·9% and 35·3% to 75·8% and 72·4%, respectively which was significantly greater than the increases in the comparison clinics (RR 1·86 and 1·68, p p Conclusions The packaged intervention improved VL performance and suppression rates overall but was significant in Mkuze and Jozini. Larger sustained efforts will be needed to have a similar impact throughout the province.

OBJECTIVE: Interactions between enzyme-inducing anti-seizure medications (EI-ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co-usage of ARVs and EI-ASMs is associated with ARV-resistant HIV among people living with HIV in Zambia. METHODS: Eligible participants were ≥18 years of age, concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data was obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVL), and HIV genotype and resistance profile in participants with a pVL> 1000 copies/ml were obtained. Pearson’s test of independence was used to determine whether treatment with EI-ASM was associated with pVL>1000/mL copies. RESULTS: Of 50 participants, 41 (82%) were on carbamazepine (37 on monotherapy), all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a TDF/3TC backbone. The majority (94%) were on a stable ARV regimen for > 6 months. Median CD4 nadir was 205 (IQR 88–389) cells/mm3, and 60% of participants had commenced ARVs treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm(3) (SD 226.3). Seven participants (14%) had a CD4 count1000 copies/mL, all were on carbamazepine. Three participants with elevated pVL had a CD4 count < 200 cells/mm(3). None had documented adherence concerns by providers; however, 2 had events concerning for clinical failure. HIV genotype testing showed mutations in 3 participants. Carbamazepine was not found to correlate with elevated pVL (p=0.58). SIGNIFICANCE: EI-ASMs are commonly used in sub-Saharan Africa. Despite concurrent use of EI-ASMs and ARVs, the majority of participants showed CD4 counts > 200 cells/mm3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV.

The National Institutes of Health requires data and safety monitoring boards (DSMBs) for all phase III clinical trials. The National Heart, Lung and Blood Institute requires DSMBs for all clinical trials involving more than one site and those involving cooperative agreements and contracts. These policies have resulted in the establishment of DSMBs for many implementation trials, with little consideration regarding the appropriateness of DSMBs and/or key adaptations needed by DSMBs to monitor data quality and participant safety. In this perspective, we review the unique features of implementation trials and reflect on key questions regarding the justification for DSMBs and their potential role and monitoring targets within implementation trials.

Linked foraging and bioenergetics models allow for increased understanding of fish growth potential and behavior by incorporating prey availability coupled to environmental conditions including temperature and prey visibility. To inform our understanding of growth and vertical migration patterns of Chinook salmon (Oncorhynchus tshawytscha) inhabiting lentic ecosystems, we linked foraging and bioenergetics models to create GrowChinook ( http://growchinook.fw.oregonstate.edu/ ). This multimodel design and optimization routine has broad applications in examining growth potential and predicting habitat use in stratified environments. We demonstrate the use of GrowChinook for the spring–summer rearing period in three Willamette River basin reservoirs, Oregon, USA. These reservoirs support juvenile spring Chinook salmon that exhibit a novel reservoir-reared life history that includes larger juvenile fish compared with nearby stream-reared subyearlings. Model outputs of predicted growth and depth use patterns based on observed prey distributions and environmental conditions were corroborated by observed empirical size and growth data from other years. Our simulations support diel vertical migration as a tactic that increases growth potential and contribute to understanding juvenile Chinook salmon growth in stratified systems.

Doubly robust (DR) estimators are an important class of statistics derived from a theory of semiparametric efficiency. They have become a popular tool in causal inference, including applications to dynamic treatment regimes. The doubly robust estimators for the mean response to a dynamic treatment regime may be conceived through the augmented inverse probability weighted (AIPW) estimating function, defined as the sum of the inverse probability weighted (IPW) estimating function and an augmentation term. The IPW estimating function of the causal estimand via marginal structural model is defined as the complete-case score function for those subjects whose treatment sequence is consistent with the dynamic regime in question divided by the probability of observing the treatment sequence given the subject's treatment and covariate histories. The augmentation term is derived by projecting the IPW estimating function onto the nuisance tangent space and has mean-zero under the truth. The IPW estimator of the causal estimand is consistent if (i) the treatment assignment mechanism is correctly modeled and the AIPW estimator is consistent if either (i) is true or (ii) nested functions of intermediate and final outcomes are correctly modeled. Hence, the AIPW estimator is doubly robust and, moreover, the AIPW is semiparametric efficient if both (i) and (ii) are true simultaneously. Unfortunately, DR estimators can be inferior when either (i) or (ii) is true and the other false. In this case, the misspecified parts of the model can have a detrimental effect on the variance of the DR estimator. We propose an improved DR estimator of causal estimand in dynamic treatment regimes through a technique originally developed by [4] which aims to mitigate the ill-effects of model misspecification through a constrained optimization. In addition to solving a doubly robust system of equations, the improved DR estimator simultaneously minimizes the asymptotic variance of the estimator under a correctly specified treatment assignment mechanism but misspecification of intermediate and final outcome models. We illustrate the desirable operating characteristics of the estimator through Monte Carlo studies and apply the methods to data from a randomized study of integrilin therapy for patients undergoing coronary stent implantation. The methods proposed here are new and may be used to further improve personalized medicine, in general.

This paper reports the results of a randomized controlled trial (RCT) to assess the efficacy of Nexus, a telehealth delivered intervention that combines Couples' HIV counseling and testing (CHTC) with home-based HIV-testing, examining the impact of the intervention on the couples' formation and adherence to safer sexual agreements. Between 2016 and 2018, 424 couples were recruited online from the U.S and randomized to the intervention arm (a telehealth delivered CHTC session with two home HIV-testing kits) or a control arm (two home HIV-testing kits), with study assessments at baseline, 3 and 6 months. Outcomes were the formation and adherence to safer sexual agreements, dyadic discordance in sexual agreements, breakage of sexual agreements, and perceptions of PrEP. Couples in the intervention arm had significantly greater odds of reporting a safer sexual agreement (3 months OR 1.87, p-value 0.005, and 6 months OR 1.84, p-value 0.007), lower odds of reporting discordant sexual agreements at 6 months (OR 0.62, p-value 0.048), and a significantly lower odds of reporting breaking their sexual agreement (3 months OR 0.51, p-value 0.035, and 6 months OR 0.23, p-value 0.000). By 6 months, couples in the intervention arm were less likely to say PrEP was beneficial to one (RRR 0.33, P = 0.000) or both of them (RRR 0.29, P = 0.000) than being beneficial to neither of the partners. The high levels of acceptability and efficacy of the intervention demonstrate strong potential for the scale-up of this efficacious intervention that is delivered through a low-cost telehealth platform.

Screening for chronic diseases, such as cancer, is an important public health priority, but traditionally only the frequency or rate of screening has received attention. In this work, we study the importance of adhering to recommended screening policies and develop new methodology to better optimize screening policies when adherence is imperfect. We consider a progressive disease model with four states (healthy, undetectable preclinical, detectable preclinical, clinical), and overlay this with a stochastic screening-behavior model using the theory of renewal processes that allows us to capture imperfect adherence to screening programs in a transparent way. We show that decreased adherence leads to reduced efficacy of screening programs, quantified here using elements of the lead time distribution (i.e., the time between screening diagnosis and when diagnosis would have occurred clinically in the absence of screening). Under the assumption of an inverse relationship between prescribed screening frequency and individual adherence, we show that the optimal screening frequency generally decreases with increasing levels of non-adherence. We apply this model to an example in breast cancer screening, demonstrating how accounting for imperfect adherence affects the recommended screening frequency.

Introduction Tenofovir diphosphate (TFV‐DP) in dried blood spots (DBS), a measure of cumulative antiretroviral therapy (ART) adherence, is associated with viral suppression and predicts future viremia in persons with HIV (PWH). However, its utility to identify those at risk for virologic failure (VF) and drug resistance is unknown. To address this, we aimed to establish the association between this adherence biomarker and VF with drug resistance in a cohort of PWH initiating first‐line ART in KwaZulu‐Natal, South Africa. Methods PWH initiating TFV disoproxil fumarate (TDF)‐based ART within a parent prospective cohort were evaluated. Using a nested design, DBS for TFV‐DP were collected from cases who developed VF (HIV‐1 RNA ≥1000 copies/ml) after ≥5 months on ART versus controls, matched 1:2 by site, age, gender, race and ART duration. Cases were categorized as having VF with or without resistance using genotyping. One‐way analysis of variance (ANOVA) was used to compare TFV‐DP for controls, cases with VF and resistance, and cases with VF without resistance. Data are presented as mean (standard deviation, SD) or geometric mean [95% confidence interval, 95% CI]. Results and discussion One thousand participants were enrolled in the parent study between 2014 and 2016, of which 288 (29%) had DBS available. Of these, 94 (33%) were cases and 194 (67%) were controls; 59% were women. Mean age of our population was 33 (SD 8) years. Genotyping was available in 50 (53%) of the 94 cases. Geometric mean TFV‐DP in DBS from controls was 708 [95% CI; 647–773] fmol/punch, which was higher compared to participants having VF with resistance (n = 36), 386 [95% CI; 241–617] fmol/punch and VF without resistance (n = 14), 61 [95% CI; 22–164] fmol/punch; p

Objectives: HIV virological failure remains a major threat to programme success in sub-Saharan Africa. While HIV drug resistance (HIVDR) and inadequate adherence are the main drivers of virological failure, the individual, clinical and health system characteristics that lead to poor outcomes are not well understood. The objective of this paper is to identify those characteristics among people failing first-line antiretroviral therapy (ART). Methods: We enrolled a cohort of adults in HIV care experiencing virological failure on first-line ART at five sites and used standard statistical methods to characterize them with a focus on three domains: individual/demographic, clinical, and health system, and compared each by country of enrolment. Results: Of 840 participants, 51% were women, the median duration on ART was 3.2 years [interquartile range (IQR) 1.1, 6.4 years] and the median CD4 cell count prior to failure was 281 cells/µL (IQR 121, 457 cells/µL). More than half of participants [53%; 95% confidence interval (CI) 49–56%] stated that they had > 90% adherence and 75% (95% CI 72–77%) took their ART on time all or most of the time. Conversely, the vast majority (90%; 95% CI 86–92%) with a completed genotypic drug resistance test had any HIV drug resistance. This population had high health system use, reporting a median of 3 (IQR 2.6) health care visits and a median of 1 (IQR 1.1) hospitalization in the preceding 6 months. Conclusions: Patients failing first-line ART in sub-Saharan Africa generally report high rates of adherence to ART, have extremely high rates of HIV drug resistance and utilize significant health care resources. Health systems interventions to promptly detect and manage treatment failure will be a prerequisite to establishing control of the HIV epidemic.

Background Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. Objective To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. Design Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499). Setting Ambulatory HIV clinics in the public sector in Uganda and South Africa. Patients Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. Intervention Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. Measurements The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. Results The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. Limitation Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings. Conclusion The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. Primary funding source The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.

An adaptive treatment length strategy is a sequential stage-wise treatment strategy where a subject's treatment begins at baseline and one chooses to stop or continue treatment at each stage provided the subject has been continuously treated. The effects of treatment are assumed to be cumulative and, therefore, the effect of treatment length on clinical endpoint, measured at the end of the study, is of primary scientific interest. At the same time, adverse treatment-terminating events may occur during the course of treatment that require treatment be stopped immediately. Because the presence of a treatment-terminating event may be strongly associated with the study outcome, the treatment-terminating event is informative. In observational studies, decisions to stop or continue treatment depend on covariate history that confounds the relationship between treatment length on outcome. We propose a new risk-set weighted estimator of the mean potential outcome under the condition that time-dependent covariates update at a set of common landmarks. We show that our proposed estimator is asymptotically linear given mild assumptions and correctly specified working models. Specifically, we study the theoretical properties of our estimator when the nuisance parameters are modeled using either parametric or semiparametric methods. The finite sample performance and theoretical results of the proposed estimator are evaluated through simulation studies and demonstrated by application to the Enhanced Suppression of the Platelet Receptor IIb/IIIa with Integrilin Therapy (ESPRIT) infusion trial data.

Political discourses and practices surrounding the current presidential administration are propagating familiar stereotypes of immigrants as “diseases,” “criminals,” and questionably “American.” Em...

Recent concerns about the viability of zoo populations have motivated studies on the historic and current status of animal populations in North American and European zoos. However, these evaluations may not accurately reflect the populations' long-term viability in the decades to come. Here, we assessed the projected future status of North American zoo populations by conducting standardized population viability analyses (PVAs) for 137 cooperative breeding programs. We summarized PVA results to describe patterns in viability across populations, and examined whether viability can be predicted by biological or management-based factors. Under recent management practices and without imports or exports of animals, 64% of populations will decline in size over the next 25 years, and only 18% would retain ≥90% of the founding gene diversity (GD) in 100 years. However, viability would improve if programs can implement management changes (e.g., increasing reproduction, increasing holding space, and importing genetically unique individuals, as appropriate): only 16% of populations would still decline in 25 years, and 49% would retain ≥90% GD in 100 years. Programs with more participating institutions and a "green" Association of Zoos and Aquariums animal program designation were projected to have higher metrics of demographic viability, and those with longer lifespans and lower recent death rates were projected to have higher metrics of genetic viability. Due to the large variation in species life history, management goals, and constraints across programs, our findings suggest there is unlikely to be a single path to long-term viability that would be appropriate for all zoo populations.

Interest in developing periphytic diatom and bacterial indicators of nutrient effects continues to grow in support of the assessment and management of stream ecosystems and their watersheds. However, temporal variability could confound relationships between indicators and nutrients, subsequently affecting assessment outcomes. To document how temporal variability affects measures of diatom and bacterial assemblages obtained from DNA metabarcoding, we conducted weekly periphyton and nutrient sampling from July to October 2016 in 25 streams in a 1293 km

Background: Little is known about the impact of non-cardiovascular disease (CVD) burden on 30- -day readmission in heart failure (HF) patients. The aim of the study was to assess the role of non-CVD burden on 30-day readmission in HF patients. \ Methods: We analyzed the effect of non-CVD burden by frequency of ICD-9 code categories on readmis­sions of patients discharged with a primary diagnosis of HF. We first modeled the probability of readmis­sion within 30 days as a function of demographic and clinical covariates in a randomly selected training dataset of the total cohort. Variable selection was carried out using a bootstrap LASSO procedure with 1000 bootstrap samples, the final model was tested on a validation dataset. Adjusted odds ratios and confidence intervals were reported in the validation dataset. Results: There were a total of 6228 HF hospitalizations, 1523 (24%) with readmission within 30 days of discharge. The strongest predictor for 30-day readmissions was any hospital admission in the prior year (p < 0.001). Cardiovascular risk factors did not enter the final model. However, digestive system diseases increased the risk for readmission by 17% for each diagnosis (p = 0.046), while respiratory diseases and genitourinary diseases showed a trend toward a higher risk of readmission (p = 0.07 and p = 0.09, respectively). Non-CVDs out-competed cardiovascular covariates previously reported to predict readmission. Conclusions: In patients with HF hospitalization, prior admissions predicted 30-day readmission. Diseases of the digestive system also increase 30-day readmission rates. Assessment of non-CVD burden in HF patients could serve as an important risk marker for 30-day readmissions.

Objectives There is conflicting evidence on the impact of pre-existing HIV drug resistance mutations (DRMs) in patients infected with non-B subtype virus. Methods We performed a case–cohort substudy of the AIDS Drug Resistance Surveillance Study, which enrolled South African patients initiating first-line efavirenz/emtricitabine/tenofovir. Pre-ART DRMs were detected by Illumina sequencing of HIV pol and DRMs present at Results The evaluable population included 178 participants from a randomly selected subcohort (16 with VF, 162 without VF) and 83 additional participants with VF. In the subcohort, 16% of participants harboured ≥1 majority DRM. The presence of any majority DRM was associated with a 3-fold greater risk of VF (P = 0.002), which increased to 9.2-fold (P Conclusions In a South African cohort, the presence of majority DRMs increased the risk of VF, especially for participants receiving

Background: Viral suppression (VS) is the hallmark of successful antiretroviral therapy (ART) programs. We sought to compare clinic retention, virologic outcomes, drug resistance, and mortality between peri-urban and rural settings in South Africa after first-line ART. Methods: ADReSS was a prospective study where 1,000 ART-naive people with HIV were enrolled, 500 at each site (one urban and one rural), between July 2014 and September 2016 and observed until July 2018. Participants were managed per local standard of care. Endpoints assessed included clinic retention, virologic suppression (VS), virologic failure (VF), genotypic drug resistance, and mortality. VS was defined as a viral load (VL) £1000 copies/mL. Time to event analyses were stratified (by site, median age, and gender). Kaplan-Meier (KM) curves were calculated and graphed with log-rank modelling to compare curves. Findings: Based on 2,741 patient-years of follow-up, retention and mortality did not differ between sites. Among all 1,000 participants, 73·9%, 83·9%, and 87·7% had achieved VS by six, 12, and 24 months, respectively, which was observed earlier in the peri-urban site. At both sites, men 32 years had the lowest with just 7·1% (p=0·018). Of all participants achieving VS, only 63 (8·7%) subsequently developed VF. This rate did not differ by site but was greater for men

Background: There is a critical gap in HIV prevention science around the development of interventions that help male couples form and adhere to safer sexual agreements. This paper reports the results of a randomized controlled trial (RCT) to assess the efficacy of Nexus , a telehealth delivered intervention that combines Couples’ HIV Counseling and Testing (CHTC) with home-based HIV-testing, examining the impact of the intervention on the couples’ formation and adherence to safer sexual agreements. Methods: Between 2016 and 2018, 424 male couples were recruited online from across the U.S and equally randomized to the intervention arm (a telehealth delivered CHTC session with two home HIV-testing kits) or a control arm (two home HIV-testing kits), with study assessments at baseline, 3 and 6 months. Outcomes included the formation and adherence to safer sexual agreements, dyadic discordance in reporting sexual agreements, breakage of sexual agreements, and perceptions of the benefit of PrEP. Findings: Couples randomized to the intervention arm had significantly greater odds of reporting a safer sexual agreement (3 months OR 1.87, 95%CI 1.21-2.90, p-value 0.005, and 6 months OR 1.84, p-value 0.007), lower odds of reporting discordant sexual agreements at 6 months (OR 0.62, p-value 0.048), and a significantly lower odds of reporting breaking their sexual agreement (3 months OR 0.51, p-value 0.035, and 6 months OR 0.23, p-value 0.000). By 6 months, couples in the intervention arm were less likely to say PrEP was beneficial to one (RRR 0.33, P=0.000) or both of them (RRR 0.29, P=0.000) than being beneficial to neither of the partners. Interpretation: The high levels of acceptability and efficacy of the intervention demonstrate strong potential for the scale-up of this efficacious intervention that leverages existing interventions (CHTC) and delivers them through a low-cost telehealth platform to create significant behavioral change among male couples. Trial Registration: The study was registered on ClinicalTrials.gov (NCT02335138) Funding: The study was supported by National Institutes of Health (Grant No. R01HD078131). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Ethical approval was obtained from the University of Michigan (HUM00102906) Institutional Review Board.