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IntroductionIdentifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models.MethodsIn-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes.ResultsIndividuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure.ConclusionsDiverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

BackgroundPersons with HIV (PWH) with high mobility face obstacles to HIV care engagement and viral suppression. We sought to understand whether a patient-centered intervention for mobile PWH would improve viral suppression and retention in care, and if so, which subgroups would benefit most.MethodsIn a randomized trial, we evaluated the effect of an intervention designed to address barriers to care among mobile (≥2 weeks out of community in previous year) PWH with viral nonsuppression or recent missed visits in Kenya and Uganda (NCT04810650). The intervention included dynamic choice of a "travel pack" (emergency antiretroviral therapy [ART] supply, discrete ART packaging, and travel checklist), multimonth and offsite refills, facilitated transfer to out-of-community clinics, and hotline access to a mobility coordinator. The primary outcome was viral suppression (

IntroductionOptimizing HIV prevention may require structured approaches for providing client-centred choices as well as community-based entry points and delivery. We evaluated the effect of a dynamic choice model for HIV prevention, delivered by community health workers (CHWs) with clinician support, on the use of biomedical prevention among persons at risk of HIV in rural East Africa.MethodsWe conducted a cluster randomized trial among persons (≥15 years) with current or anticipated HIV risk in 16 villages in Uganda and Kenya (SEARCH; NCT04810650). The intervention was a client-centred HIV prevention model, including (1) structured client choice of product (pre-exposure prophylaxis [PrEP] or post-exposure prophylaxis [PEP]), service location (clinic or out-of-clinic) and HIV testing modality (self-test or rapid test), with the ability to switch over time; (2) a structured assessment of patient barriers and development of a personalized support plan; and (3) phone access to a clinician 24/7. The intervention was delivered by CHWs and supported by clinicians who oversaw PrEP and PEP initiation and monitoring. Participants in control villages were referred to local health facilities for HIV prevention services, delivered by Ministry of Health staff. The primary outcome was biomedical prevention coverage: a proportion of 48-week follow-up with self-reported PrEP or PEP use.ResultsFrom May to July 2021, we enrolled 429 people (212 intervention; 217 control): 57% women and 35% aged 15-24 years. Among intervention participants, 58% chose PrEP and 58% chose PEP at least once over follow-up; self-testing increased from 52% (baseline) to 71% (week 48); ≥98% chose out-of-facility service delivery. Among 413 (96%) participants with the primary outcome ascertained, average biomedical prevention coverage was 28.0% in the intervention versus 0.5% in the control: a difference of 27.5% (95% CI: 23.0-31.9%, p

IntroductionUnhealthy alcohol use significantly contributes to viral non-suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy alcohol use in sub-Saharan Africa (SSA).MethodsAs part of the SEARCH study (NCT04810650), we conducted an individually randomized trial in Kenya and Uganda of a brief, skills-based alcohol intervention among PWH with self-reported unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C], prior 3 months, ≥3/female; ≥4/male) and at risk of viral non-suppression, defined as either recent HIV viral non-suppression (≥400 copies/ml), missed visits, out of care or new diagnosis. The intervention included baseline and 3-month in-person counselling sessions with interim booster phone calls every 3 weeks. The primary outcome was HIV viral suppression (200 ng/ml (RR 0.97, 95% CI: 0.92-1.02).ConclusionsIn a randomized trial of 401 PWH with unhealthy alcohol use and risk for viral non-suppression, a brief alcohol intervention reduced unhealthy alcohol use but did not affect viral suppression at 24 weeks. Brief alcohol interventions have the potential to improve the health of PWH in SSA by reducing alcohol use, a significant driver of HIV-associated co-morbidities.

Across research disciplines, cluster randomized trials (CRTs) are commonly implemented to evaluate interventions delivered to groups of participants, such as communities and clinics. Despite advances in the design and analysis of CRTs, several challenges remain. First, there are many possible ways to specify the causal effect of interest (eg, at the individual-level or at the cluster-level). Second, the theoretical and practical performance of common methods for CRT analysis remain poorly understood. Here, we present a general framework to formally define an array of causal effects in terms of summary measures of counterfactual outcomes. Next, we provide a comprehensive overview of CRT estimators, including the t-test, generalized estimating equations (GEE), augmented-GEE, and targeted maximum likelihood estimation (TMLE). Using finite sample simulations, we illustrate the practical performance of these estimators for different causal effects and when, as commonly occurs, there are limited numbers of clusters of different sizes. Finally, our application to data from the Preterm Birth Initiative (PTBi) study demonstrates the real-world impact of varying cluster sizes and targeting effects at the cluster-level or at the individual-level. Specifically, the relative effect of the PTBi intervention was 0.81 at the cluster-level, corresponding to a 19% reduction in outcome incidence, and was 0.66 at the individual-level, corresponding to a 34% reduction in outcome risk. Given its flexibility to estimate a variety of user-specified effects and ability to adaptively adjust for covariates for precision gains while maintaining Type-I error control, we conclude TMLE is a promising tool for CRT analysis.

The Hazard Ratio (HR) is a well-established treatment effect measure in randomized trials involving right-censored time-to-events, and the Cardiovascular Outcome Trials (CVOTs) conducted since the FDA’s 2008 guidance have indeed largely evaluated excess risk by estimating a Cox HR. On the other hand, the limitations of the Cox model and of the HR as a causal estimand are well known, and the FDA’s updated 2020 CVOT guidance invites us to reassess this default approach to survival analyses. We highlight the shortcomings of Cox HR-based analyses and present an alternative following the causal roadmap—moving in a principled way from a counterfactual causal question to identifying a statistical estimand, and finally to targeted estimation in a large statistical model. We show in simulations the robustness of Targeted Maximum Likelihood Estimation (TMLE) to informative censoring and model misspecification and demonstrate a targeted learning analogue of the original Cox HR-based analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. We discuss the potential reliability, interpretability, and efficiency gains to be had by updating our survival methods to incorporate the recent decades of advancements in formal causal frameworks and efficient nonparametricestimation.

IntroductionPerson-centred HIV prevention delivery models that offer structured choices in product, testing and visit location may increase coverage. However, data are lacking on the actual uptake of choices among persons at risk of HIV in southern Africa. In an ongoing randomized study (SEARCH; NCT04810650) in rural East Africa, we evaluated the uptake of choices made when offered in a person-centred, dynamic choice model for HIV prevention.MethodsUsing the PRECEDE framework, we developed a persont-centred, Dynamic Choice HIV Prevention (DCP) intervention for persons at risk of HIV in three settings in rural Kenya and Uganda: antenatal clinic (ANC), outpatient department (OPD) and in the community. Components include: provider training on product choice (predisposing); flexibility and responsiveness to client desires and choices (pre-exposure prophylaxis [PrEP]/post-exposure prophylaxis [PEP], clinic vs. off-site visits and self- or clinician-based HIV testing) (enabling); and client and staff feedback (reinforcing). All clients received a structured assessment of barriers with personalized plans to address them, mobile phone access to clinicians (24 hours/7 days/week) and integrated reproductive health services. In this interim analysis, we describe the uptake of choices of product, location and testing during the first 24 weeks of follow-up (April 2021-March 2022).ResultsA total of 612 (203 ANC, 197 OPD and 212 community) participants were randomized to the person-centred DCP intervention. We delivered the DCP intervention in all three settings with diverse populations: ANC: 39% pregnant; median age: 24 years; OPD: 39% male, median age 27 years; and community: 42% male, median age: 29 years. Baseline choice of PrEP was highest in ANC (98%) vs. OPD (84%) and community (40%); whereas the proportion of adults selecting PEP was higher in the community (46%) vs. OPD (8%) and ANC (1%). Personal preference for off-site visits increased over time (65% at week 24 vs. 35% at baseline). Interest in alternative HIV testing modalities grew over time (38% baseline self-testing vs. 58% at week 24).ConclusionsA person-centred model incorporating structured choice in biomedical prevention and care delivery options in settings with demographically diverse groups, in rural Kenya and Uganda, was responsive to varying personal preferences over time in HIV prevention programmes.

IntroductionSwitch to dolutegravir (DTG) in treatment-experienced people living with HIV (PLH) is associated with excess weight gain in some settings; data are limited from rural low-income settings with low obesity prevalence.MethodsIn rural Kenya, we conducted a retrospective cohort study at 8 HIV clinics and a single-site prospective cohort study including adults switching to DTG during countrywide transition to DTG/tenofovir DF(TDF)/emtricitabine as first-line HIV treatment. In the retrospective analysis, we used preswitch data to model postswitch weight trajectory had each participant not switched to DTG and contrasted observed vs. predicted postswitch weight. In the prospective analysis, we measured weight post-DTG switch and evaluated predictors of 6-month weight change.ResultsOur retrospective cohort included 4445 PLH who switched to DTG between 2018 and 2020. Mean 12-month weight change was 0.6 kg preswitch and 0.8 kg postswitch. Among those on TDF throughout (n = 3374; 83% on efavirenz preswitch), 12-month postswitch weight was 0.7 kg more than predicted for women (95% CI: 0.4, 1.0) and similar among men (0.04 kg; 95% CI -0.3, 0.4). In our prospective cohort (n = 135, 100% female), mean 6-month weight change was +0.4 kg (IQR -1.1, 2.0 kg). Predicted gain varied by baseline food insecurity: +1.1 kg (95% CI: 0.34, 1.87) among food secure, -0.09 kg (95% CI -0.71, 0.54) among moderate insecure, and +0.27 kg (95% CI -0.82, 1.36) among severe insecurity.ConclusionIn contrast to some reports of large weight gain following switch to DTG, we observed small weight increases in women and no weight change in men following DTG switch when on TDF throughout. Weight gain may be attenuated by food insecurity, though was modest even among food secure.

Given an (optimal) dynamic treatment rule, it may be of interest to evaluate that rule - that is, to ask the causal question: what is the expected outcome had every subject received treatment according to that rule? In this paper, we study the performance of estimators that approximate the true value of: (1) an a priori known dynamic treatment rule (2) the true, unknown optimal dynamic treatment rule (ODTR); (3) an estimated ODTR, a so-called "data-adaptive parameter," whose true value depends on the sample. Using simulations of point-treatment data, we specifically investigate: (1) the impact of increasingly data-adaptive estimation of nuisance parameters and/or of the ODTR on performance; (2) the potential for improved efficiency and bias reduction through the use of semiparametric efficient estimators; and, (3) the importance of sample splitting based on the cross-validated targeted maximum likelihood estimator (CV-TMLE) for accurate inference. In the simulations considered, there was very little cost and many benefits to using CV-TMLE to estimate the value of the true and estimated ODTR; importantly, and in contrast to non cross-validated estimators, the performance of CV-TMLE was maintained even when highly data-adaptive algorithms were used to estimate both nuisance parameters and the ODTR. In addition, we apply these estimators for the value of the rule to the "Interventions" study, an ongoing randomized controlled trial, to identify whether assigning cognitive behavioral therapy (CBT) to criminal justice-involved adults with mental illness using an ODTR significantly reduces the probability of recidivism, compared to assigning CBT in a non-individualized way.

The optimal dynamic treatment rule (ODTR) framework offers an approach for understanding which kinds of patients respond best to specific treatments - in other words, treatment effect heterogeneity. Recently, there has been a proliferation of methods for estimating the ODTR. One such method is an extension of the SuperLearner algorithm - an ensemble method to optimally combine candidate algorithms extensively used in prediction problems - to ODTRs. Following the ``causal roadmap," we causally and statistically define the ODTR and provide an introduction to estimating it using the ODTR SuperLearner. Additionally, we highlight practical choices when implementing the algorithm, including choice of candidate algorithms, metalearners to combine the candidates, and risk functions to select the best combination of algorithms. Using simulations, we illustrate how estimating the ODTR using this SuperLearner approach can uncover treatment effect heterogeneity more effectively than traditional approaches based on fitting a parametric regression of the outcome on the treatment, covariates and treatment-covariate interactions. We investigate the implications of choices in implementing an ODTR SuperLearner at various sample sizes. Our results show the advantages of: (1) including a combination of both flexible machine learning algorithms and simple parametric estimators in the library of candidate algorithms; (2) using an ensemble metalearner to combine candidates rather than selecting only the best-performing candidate; (3) using the mean outcome under the rule as a risk function. Finally, we apply the ODTR SuperLearner to the ``Interventions" study, an ongoing randomized controlled trial, to identify which justice-involved adults with mental illness benefit most from cognitive behavioral therapy to reduce criminal re-offending.

Cluster randomized trials (CRTs) randomly assign an intervention to groups of individuals (e.g., clinics or communities) and measure outcomes on individuals in those groups. While offering many advantages, this experimental design introduces challenges that are only partially addressed by existing analytic approaches. First, outcomes are often missing for some individuals within clusters. Failing to appropriately adjust for differential outcome measurement can result in biased estimates and inference. Second, CRTs often randomize limited numbers of clusters, resulting in chance imbalances on baseline outcome predictors between arms. Failing to adaptively adjust for these imbalances and other predictive covariates can result in efficiency losses. To address these methodological gaps, we propose and evaluate a novel two-stage targeted minimum loss-based estimator to adjust for baseline covariates in a manner that optimizes precision, after controlling for baseline and postbaseline causes of missing outcomes. Finite sample simulations illustrate that our approach can nearly eliminate bias due to differential outcome measurement, while existing CRT estimators yield misleading results and inferences. Application to real data from the SEARCH community randomized trial demonstrates the gains in efficiency afforded through adaptive adjustment for baseline covariates, after controlling for missingness on individual-level outcomes.

ObjectivesTo identify incident SARS-CoV-2 infections and inform effective mitigation strategies in university settings, we piloted an integrated symptom and exposure monitoring and testing system among a cohort of university students and employees.DesignProspective cohort study.SettingA public university in California from June to August 2020.Participants2180 university students and 738 university employees.Primary outcome measuresAt baseline and endline, we tested participants for active SARS-CoV-2 infection via quantitative PCR (qPCR) test and collected blood samples for antibody testing. Participants received notifications to complete additional qPCR tests throughout the study if they reported symptoms or exposures in daily surveys or were selected for surveillance testing. Viral whole genome sequencing was performed on positive qPCR samples, and phylogenetic trees were constructed with these genomes and external genomes.ResultsOver the study period, 57 students (2.6%) and 3 employees (0.4%) were diagnosed with SARS-CoV-2 infection via qPCR test. Phylogenetic analyses revealed that a super-spreader event among undergraduates in congregate housing accounted for at least 48% of cases among study participants but did not spread beyond campus. Test positivity was higher among participants who self-reported symptoms (incidence rate ratio (IRR) 12.7; 95% CI 7.4 to 21.8) or had household exposures (IRR 10.3; 95% CI 4.8 to 22.0) that triggered notifications to test. Most (91%) participants with newly identified antibodies at endline had been diagnosed with incident infection via qPCR test during the study.ConclusionsOur findings suggest that integrated monitoring systems can successfully identify and link at-risk students to SARS-CoV-2 testing. As the study took place before the evolution of highly transmissible variants and widespread availability of vaccines and rapid antigen tests, further research is necessary to adapt and evaluate similar systems in the present context.

BackgroundGenetic tests for variants in MYOT (P2; rs1138656462), FLNC (P3a; rs1139799323 or P3b; rs1142918816) and MYOZ3 (P4; rs1142544043) genes are offered commercially to diagnose myofibrillar myopathy (MFM) and type 2 polysaccharide storage myopathy (PSSM2) in Quarter Horses (QH).ObjectivesTo determine if PSSM2-QH has histopathological features of MFM. To compare genotype and allele frequencies of variants P2, P3, P4 between control-QH and PSSM2-QH diagnosed by histopathology.Study designRetrospective cross-sectional.MethodsThe study includes a total of 229 healthy control-QH, 163 PSSM2-QH GYS1 mutation negative. Desmin stains of gluteal/semimembranosus muscle were evaluated. Purported disease alleles P2, P3a, P3b, P4 were genotyped by pyrosequencing. Genotype, allele frequency and total number of variant alleles or loci were compared between phenotypes using additive/genotypic and dominant models and quantitative effects evaluated by multivariable logistic regression.ResultsHistopathological features of MFM were absent in all QH. A P variant allele at any locus was not associated (P > .05) with a histopathological diagnosis of PSSM2 and one or more P variants were common in control-QH (57%) and PSSM2-QH (61%). Allele frequencies (control/PSSM2) were: 0.24/0.21 (P2), 0.07/0.12 (P3a), 0.07/0.11 (P3b) and 0.06/0.08 (P4). P3a and P3b loci were not independent (r2  = 0.894); and not associated with PSSM2 histopathology comparing the haplotype of both P3a and P3b variants to other haplotypes. A receiver operator curve did not accurately predict the PSSM2 phenotype (AUC = 0.67, 95% CI 0.62-0.72), and there was no difference in the total number of variant loci or total variant allele count between control-QH and PSSM2-QH.Main limitationsP3a and P3b were not in complete linkage disequilibrium.ConclusionsThe P2, P3 and P4 variants in genes associated with human MFM were not associated with PSSM2 in 392 QH. Their use would improperly diagnose PSSM2/MFM in 57% of healthy QH and fail to diagnose PSSM2 in 40% of QH with histopathological evidence of PSSM2.

BackgroundSocial network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies.MethodsWe assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette-Guérin [BCG] vaccination) with targeted maximum likelihood estimation.ResultsAmong 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.1]) and the most (top 10%) male contacts (1.5 [1.3-1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2-2.9]).ConclusionsSocial networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted.

Youth living with HIV in sub-Saharan Africa have poor HIV care outcomes. We determined the association of recent significant life-events with HIV antiretroviral treatment (ART) initiation and HIV viral suppression in youth aged 15-24 years living with HIV in rural Kenya and Uganda. This was a cross-sectional analysis of 995 youth enrolled in the SEARCH Youth study. At baseline, providers assessed recent (within 6 months) life-events, defined as changes in schooling/employment, residence, partnerships, sickness, incarceration status, family strife or death, and birth/pregnancy, self-reported alcohol use, being a parent, and HIV-status disclosure. We examined the frequencies of events and their association with ART status and HIV viral suppression (2 significant life-events (aOR = 0.61, 95% CI:0.45-0.85) and consuming alcohol (aOR = 0.61, 95% CI:0.43-0.87) were associated with a lower odds of HIV viral suppression, while disclosure of HIV-status to partner (aOR = 2.39, 95% CI:1.6-3.5) or to family (aOR = 1.86, 95% CI:1.3-2.7), being a parent (aOR = 1.8, 95% CI:1.2-2.5), and being single (aOR = 1.6, 95% CI:1.3-2.1) had a higher odds. This suggest that two or more recent life-events and alcohol use are key barriers to ART initiation and achievement of viral suppression among youth living with HIV in rural East Africa.Trial registration: ClinicalTrials.gov identifier: NCT03848728..

BackgroundAntiretroviral therapy (ART) assures major gains in health outcomes among people living with HIV, however, this benefit may not be realized by all due to care interruptions. Mobile populations comprise a subgroup that is likely to have sub-optimal care engagement, resulting in discontinuation of ART. We sought to evaluate the barriers to care engagement among highly mobile individuals living with HIV and explore options aimed at improving engagement in care for this group.MethodsQualitative in-depth interviews were conducted in 2020 among a purposive sample of twelve persons living with HIV and eight health care providers in western Kenya, within a mixed methods study of mobility in communities participating in the SEARCH trial (NCT01864603). We explored the barriers to care engagement among mobile individuals living with HIV and explored different options aimed at enhancing care engagement. These included options such as a coded card containing treatment details, alternative drug packaging to conceal drug identity, longer refills to cover travel period, wrist bands with data storage capability to enable data transfer and "warm handoff" by providers to new clinics upon transfer. Data were inductively analyzed to understand the barriers and acceptability of potential interventions to address them.ResultsStigma and lack of disclosure, rigid work schedules, and unpredictability of travel were major barriers to care engagement for highly mobile individuals living with HIV. Additionally, lack of flexibility in clinic schedules and poor provider attitude were identified as health-system-associated barriers to care engagement. Options that enhance flexibility, convenience and access to care were viewed as the most effective means of addressing the barriers to care by both patients and providers. The most preferred option was a coded card with treatment details followed by alternative drug packaging to conceal drug identity due to stigma and longer refills to cover travel periods.ConclusionHighly mobile individuals living with HIV desire responsive, flexible, convenient and patient-centered care delivery models to enhance care engagement. They embraced simple health delivery improvements such as coded cards, alternative drug packaging and longer refills to address challenges of mobility.

The genomic sequence of the horse has been available since 2009, providing critical resources for discovering important genomic variants regarding both animal health and population structures. However, to fully understand the functional implications of these variants, detailed annotation of the horse genome is required. Due to the limited availability of functional data for the equine genome, as well as the technical limitations of short-read RNA-seq, existing annotation of the equine genome contains limited information about important aspects of gene regulation, such as alternate isoforms and regulatory elements, which are either not transcribed or transcribed at a very low level. To solve above problems, the Functional Annotation of the Animal Genomes (FAANG) project proposed a systemic approach to tissue collection, phenotyping, and data generation, adopting the blueprint laid out by the Encyclopedia of DNA Elements (ENCODE) project. Here we detail the first comprehensive overview of gene expression and regulation in the horse, presenting 39,625 novel transcripts, 84,613 candidate cis-regulatory elements (CRE) and their target genes, 332,115 open chromatin regions genome wide across a diverse set of tissues. We showed substantial concordance between chromatin accessibility, chromatin states in different genic features and gene expression. This comprehensive and expanded set of genomics resources will provide the equine research community ample opportunities for studies of complex traits in the horse.

Pre-exposure prophylaxis (PrEP) implementation is underway across sub-Saharan Africa. However, little is known about health care providers' experiences with PrEP provision in generalized epidemic settings, particularly outside of selected risk groups. In this study (NCT01864603), universal access to PrEP was offered to adolescents and adults at elevated risk during population-level HIV testing in rural Kenya and Uganda. Providers received training on PrEP prescribing and support from local senior clinicians. We conducted in-depth interviews with providers (n = 19) in four communities in Kenya and Uganda to explore the attitudes and experiences with implementation. Transcripts were coded and analyzed using interpretivist methods. Providers had heterogenous attitudes toward PrEP in its early implementation: some expressed enthusiasm, while others feared being blamed for "failures" (HIV seroconversions) if participants were nonadherent, or that offering PrEP would increase "immorality." Providers supported PrEP usage among HIV-serodifferent couples, whose mutual support for daily pill-taking facilitated harmony and protection from HIV. Providers reported challenges with counseling on "seasons of risk," and safely stopping and restarting PrEP. They felt uptake was hampered for women by difficulties negotiating with partners, and for youth by parental consent requirements. They believed PrEP continuation was hindered by transportation costs, stigma, pill burden, and side effects, and was facilitated by counseling, proactive management of side effects, and home/community-based provision. Providers are critical "implementation actors" in interventions to promote adoption of new technologies such as PrEP. Dedicated training and ongoing support for providers may facilitate successful scale-up.

The role of histone modifications in transcription remains incompletely understood. Here, we examine the relationship between histone modifications and transcription using experimental perturbations combined with sensitive machine-learning tools. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3, consistent with a role for RNA in recruiting PRC2. A subset of DNase-I-hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than an essential regulatory, role in transcription.

BackgroundFewer than 10% of people with hypertension in sub-Saharan Africa are diagnosed, linked to care, and achieve hypertension control. We hypothesized that a one-time financial incentive and phone call reminder for missed appointments would increase linkage to hypertension care following community-based screening in rural Uganda and Kenya.MethodsIn a randomized controlled trial, we conducted community-based hypertension screening and enrolled adults ≥25 years with blood pressure ≥140/90 mmHg on three measures; we excluded participants with known hypertension or hypertensive emergency. The intervention was transportation reimbursement upon linkage (~$5 USD) and up to three reminder phone calls for those not linking within seven days. Control participants received a clinic referral only. Outcomes were linkage to hypertension care within 30 days (primary) and hypertension control

Growing literature has shown heterogenous effects of conditional cash incentives (CCIs) on HIV care retention. The field lacks insights into reasons why incentives impact various patients in different ways-differences that may be due to variations in psychological and social mechanisms of effect. A deeper understanding of patients' perceptions and experiences of CCIs for retention may help to clarify these mechanisms. We conducted a qualitative study embedded in the ADAPT-R trial (NCT#02338739), a sequential multiple assignment randomized trial (SMART) that evaluated economic incentives to support retention in HIV care among persons living with HIV (PLHIV) initiating antiretroviral therapy in Kenya. Participants who attended their scheduled clinic visits received an incentive of approximately $4 each visit. Interviews were conducted between July 2016 and June 2017 with 39 participants to explore attitudes and experiences with economic incentives conditional on care engagement. Analyses revealed that incentives helped PLHIV prioritize care-seeking by alleviating transport barriers and food insecurity: "I decided to forgo [work] and attend clinic […] the voucher relieved me". Patients who borrowed money for care-seeking reported feeling relieved from the burden of indebtedness to others: "I borrow with confidence that I will pay after my appointment." Incentives fostered their autonomy, and enabled them to support others: "I used the money to buy some clothes and Pampers for the children." Participants who were intrinsically motivated to engage in care ("my life depends on the drugs, not the incentive"), and those who mistrusted researchers, reported being less prompted by the incentive itself. For patients not already prioritizing care-seeking, incentives facilitated care engagement through alleviating transport costs, indebtedness and food insecurity, and also supported social role fulfillment. Conditional cash incentives may be an important cue to action to improve progression through the HIV treatment cascade, and contribute to better care retention.

Cytosine methylation patterns have not yet been thoroughly studied in horses. Here, we profile n = 333 samples from 42 horse tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). Using the blood and liver tissues from horses, we develop five epigenetic aging clocks: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. In addition, using blood methylation data from three additional equid species (plains zebra, Grevy's zebras and Somali asses), we develop another clock that applies across all equid species. Castration does not significantly impact the epigenetic aging rate of blood or liver samples from horses. Methylation and RNA data from the same tissues define the relationship between methylation and RNA expression across horse tissues. We expect that the multi-tissue atlas will become a valuable resource.