Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients-both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged and normalized the visual2 and somatomotor network connections, and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p = 2e-10, Hedges' g = 1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, anxiety, or demographics. It had moderate test-retest reliability (ICC = 0.62) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC = 0.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

A non-parametric Bayesian approach for adjusting partial compliance in sequential decision making.

Existing methods for estimating the mean outcome under a given sequential treatment rule often rely on intention-to-treat analyses, which estimate the effect of following a certain treatment rule regardless of compliance behavior of patients. There are two major concerns with intention-to-treat analyses: (1) the estimated effects are often biased toward the null effect; (2) the results are not generalizable and reproducible due to the potentially differential compliance behavior. These are particularly problematic in settings with a high level of non-compliance, such as substance use disorder studies. Our work is motivated by the Adaptive Treatment for Alcohol and Cocaine Dependence study (ENGAGE), which is a multi-stage trial that aimed to construct optimal treatment strategies to engage patients in therapy. Due to the relatively low level of compliance in this trial, intention-to-treat analyses essentially estimate the effect of being randomized to a certain treatment, instead of the actual effect of the treatment. We obviate this challenge by defining the target parameter as the mean outcome under a dynamic treatment regime conditional on a potential compliance stratum. We propose a flexible non-parametric Bayesian approach based on principal stratification, which consists of a Gaussian copula model for the joint distribution of the potential compliances, and a Dirichlet process mixture model for the treatment sequence specific outcomes. We conduct extensive simulation studies which highlight the utility of our approach in the context of multi-stage randomized trials. We show robustness of our estimator to non-linear and non-Gaussian settings as well.

Design and characteristics of the prophylactic intra-operative ventricular arrhythmia ablation in high-risk LVAD candidates (PIVATAL) trial.

BACKGROUND: The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra-operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant. METHODS: We designed a prospective, multicenter, open-label, randomized-controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra-operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life. CONCLUSION: The primary aim of this first-ever randomized trial is to assess the efficacy of intra-operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA.

Comparing effectiveness of first-line antiretroviral therapy between peri-urban and rural clinics in KwaZulu-Natal, South Africa.

OBJECTIVES: Viral suppression (VS) is the hallmark of successful antiretroviral therapy (ART) programmes. We sought to compare clinic retention, virological outcomes, drug resistance and mortality between peri-urban and rural settings in South Africa after first-line ART. METHODS: Beginning in July 2014, 1000 (500 peri-urban and 500 rural) ART-naïve patients with HIV were enrolled and managed according to local standard of care. Clinic retention, virological suppression, virological failure (VF), genotypic drug resistance and mortality were assessed. The definition of VS was a viral load ≤1000 copies/ml. Time to event analyses were stratified by site, median age and gender. Kaplan-Meier curves were calculated and graphed with log-rank modelling to compare curves. RESULTS: Based on 2741 patient-years of follow-up, retention and mortality did not differ between sites. Among all 1000 participants, 47%, 84% and 91% had achieved VS by 6, 12 and 24 months, respectively, which was observed earlier in the peri-urban site. At both sites, men aged < 32 years had the highest proportion of VF (15.5%), while women aged > 32 years had the lowest, at 7.1% (p = 0.018). Among 55 genotypes, 42 (76.4%) had at one or more resistance mutations, which did not differ by site. K103N (59%) and M184V (52%) were the most common mutations, followed by V106M and K65R (31% each). Overall, death was infrequent (< 4%). CONCLUSIONS: No significant differences in treatment outcomes between peri-urban and rural clinics were observed. In both settings, young men were especially susceptible to clinic attrition and VF. More effective adherence support for this important demographic group is needed to achieve UNAIDS targets.

Who's slipping through the cracks? A comprehensive individual, clinical and health system characterization of people with virological failure on first-line HIV treatment in Uganda and South Africa.

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.

Estimating mean potential outcome under adaptive treatment length strategies in continuous time.

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.

Bayesian set of best dynamic treatment regimes: Construction and sample size calculation for SMARTs with binary outcomes.

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/.

Efficacy of a Telehealth Delivered Couples' HIV Counseling and Testing (CHTC) Intervention to Improve Formation and Adherence to Safer Sexual Agreements Among Male Couples in the US: Results from a Randomized Control Trial.

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.

Longitudinal trends in produce purchasing behavior: a descriptive study of transaction level data from loyalty card households.

BACKGROUND: Household food purchases (HFP) are in the pathway between the community food environment and the foods available in households for consumption. As such, HFP data have emerged as alternatives to monitor population dietary trends over-time. In this paper, we investigate the use of loyalty card datasets as unexplored sources of continuously collected HFP data to describe temporal trends in household produce purchases. METHODS: We partnered with a grocery store chain to obtain a loyalty card database with grocery transactions by household from January 2016-October 2018. We included households in an urban county with complete observations for head of household age group, household income group, and family size. Data were summarized as weighted averages (95% CI) of percent produce purchased out of all foods purchased by household per month. We modeled seasonal and linear trends in the proportion of produce purchases by age group and income while accounting for repeated observations per household using generalized estimating equations. RESULTS: There are 290,098 households in the database (88% of all county households). At baseline, the smallest and largest percent produce purchases are observed among the youngest and lowest income (12.2%, CI 11.1; 13.3) and the oldest and highest income households (19.3, CI 18.9; 19.6); respectively. The seasonal variations are consistent in all age and income groups with an April-June peak gradually descending until December. However, the average linear change in percent produce purchased per household per year varies by age and income being the steepest among the youngest households at each income level (from 1.42%, CI 0.98;1.8 to 0.69%, CI 0.42;0.95) while the oldest households experience almost no annual change. CONCLUSIONS: We explored the potential of a collaboration with a food retailer to use continuously collected loyalty card data for public health nutrition purposes. Our findings suggest a trend towards a healthier pattern in long-term food purchases and household food availability among the youngest households that may lessen the population chronic disease burden if sustained. Understanding the foods available for consumption within households allows public health advocates to develop and evaluate policies and programs promoting foods and nutrients along the life course.

Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial.

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.

Criteria-Based Assessment of a Teleophthalmology Diabetic Retinopathy Evaluation Program in a Primary Care Setting.

Background:Studies have shown that teleophthalmology programs using a nonmydriatic camera in primary care settings can improve rates of diabetic retinopathy (DR) screening. However, such programs are not yet widespread due to common challenges in sustainability.Purpose:To comprehensively evaluate clinical and operational measures of an urban primary care clinic's 1-year pilot teleophthalmology DR evaluation program.Materials and Methods:This retrospective analysis used five metrics to evaluate the program: clinical diabetic retinal exam (DRE) rate, visual acuity and pathology, camera utilization, billing and insurance reimbursements, and outcomes of follow-up referrals.Results:Two hundred eleven patients were screened over 14 months. The DRE rate had more than doubled (34-75%). Of the patients, 55.9% had vision better than 20/50 in each eye and 21% with at least 1 eye worse than or equal to 20/70. DR was noted in 11% of patients. The program's first few months saw greatest camera use. Government and Medicare Advantage insurers were significantly (p < 0.001) less likely to reimburse than commercial insurers. Twenty-seven percent of patients screened had documented follow-up with an eye care provider within 16 months of their screening. Patients diagnosed with DR or recommended follow-up within 1 month were significantly (p < 0.001) more likely to schedule an appointment.Discussion:Challenges to program sustainability include efficient utilization, reimbursement from governmental insurers, and adherence to follow-up recommendations.Conclusions:Assessing teleophthalmology programs with the aforementioned five metrics allows for a comprehensive evaluation of impact and sustainability. This may be utilized to standardize the implementation and evaluation of such programs across diverse settings.

Screening for chronic diseases: optimizing lead time through balancing prescribed frequency and individual adherence.

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.

Traumatic Wounds of the Foot and Ankle: The Landstuhl Regional Medical Center Experience and Historical Perspectives.

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.

Modeling the rate of HIV testing from repeated binary data amidst potential never-testers.

Many longitudinal studies with a binary outcome measure involve a fraction of subjects with a homogeneous response profile. In our motivating data set, a study on the rate of human immunodeficiency virus (HIV) self-testing in a population of men who have sex with men (MSM), a substantial proportion of the subjects did not self-test during the follow-up study. The observed data in this context consist of a binary sequence for each subject indicating whether or not that subject experienced any events between consecutive observation time points, so subjects who never self-tested were observed to have a response vector consisting entirely of zeros. Conventional longitudinal analysis is not equipped to handle questions regarding the rate of events (as opposed to the odds, as in the classical logistic regression model). With the exception of discrete mixture models, such methods are also not equipped to handle settings in which there may exist a group of subjects for whom no events will ever occur, i.e. a so-called "never-responder" group. In this article, we model the observed data assuming that events occur according to some unobserved continuous-time stochastic process. In particular, we consider the underlying subject-specific processes to be Poisson conditional on some unobserved frailty, leading to a natural focus on modeling event rates. Specifically, we propose to use the power variance function (PVF) family of frailty distributions, which contains both the gamma and inverse Gaussian distributions as special cases and allows for the existence of a class of subjects having zero frailty. We generalize a computational algorithm developed for a log-gamma random intercept model (Conaway, 1990. A random effects model for binary data. Biometrics46, 317-328) to compute the exact marginal likelihood, which is then maximized to obtain estimates of model parameters. We conduct simulation studies, exploring the performance of the proposed method in comparison with competitors. Applying the PVF as well as a Gaussian random intercept model and a corresponding discrete mixture model to our motivating data set, we conclude that the group assigned to receive follow-up messages via SMS was self-testing at a significantly lower rate than the control group, but that there is no evidence to support the existence of a group of never-testers.

Evaluating the impact of antiretroviral and antiseizure medication interactions on treatment effectiveness among outpatient clinic attendees with HIV in Zambia.

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 human immunodeficiency virus (HIV) among people living with HIV in Zambia. METHODS: Eligible participants were ≥18 years of age and concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data were obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVLs), 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 taking carbamazepine (37 on monotherapy), and all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a tenofovir/lamivudine backbone. The majority (94%) were on a stable ARV regimen for >6 months. Median CD4 nadir was 205 cells/mm3 (interquartile range [IQR] 88-389), and 60% of participants had commenced ARV treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm3 (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm3 . Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm3 . None had documented adherence concerns by providers; however, two had events concerning for clinical failure. HIV genotype testing showed mutations in three participants. Carbamazepine was not found to correlate with elevated pVL (P = .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 Impacts of Residential Location on the Risk of HIV Virologic Failure Among ART Users in Durban, South Africa.

Using a case-control study of patients receiving antiretroviral treatment (ART) in 2010-2012 at McCord Hospital in Durban, South Africa, we sought to understand how residential locations impact patients' risk of virologic failure (VF). Using generalized estimating equations to fit logistic regression models, we estimated the associations of VF with socioeconomic status (SES) and geographic access to care. We then determined whether neighborhood-level poverty modifies the association between individual-level SES and VF. Automobile ownership for men and having non-spouse family members pay medical care for women remained independently associated with increased odds of VF for patients dwelling in moderately and severely poor neighborhoods. Closer geographic proximity to medical care was positively associated with VF among men, while higher neighborhood-level poverty was positively associated with VF among women. The programmatic implications of our findings include developing ART adherence interventions that address the role of gender in both the socioeconomic and geographical contexts.

Improved Survival and Cure Rates With Concurrent Treatment for Multidrug-Resistant Tuberculosis-Human Immunodeficiency Virus Coinfection in South Africa.

Background: Mortality in multidrug-resistant (MDR) tuberculosis-human immunodeficiency virus (HIV) coinfection has historically been high, but most studies predated the availability of antiretroviral therapy (ART). We prospectively compared survival and treatment outcomes in MDR tuberculosis-HIV-coinfected patients on ART to those in patients with MDR tuberculosis alone. Methods: This observational study enrolled culture-confirmed MDR tuberculosis patients with and without HIV in South Africa between 2011 and 2013. Participants received standardized MDR tuberculosis and HIV regimens and were followed monthly for treatment response, adverse events, and adherence. The primary outcome was survival. Results: Among 206 participants, 150 were HIV infected, 131 (64%) were female, and the median age was 33 years (interquartile range [IQR], 26-41). Of the 191 participants with a final MDR tuberculosis outcome, 130 (73%) were cured or completed treatment, which did not differ by HIV status (P = .50). After 2 years, CD4 count increased a median of 140 cells/mm3 (P = .005), and 64% had an undetectable HIV viral load. HIV-infected and HIV-uninfected participants had high rates of survival (86% and 94%, respectively; P = .34). The strongest risk factor for mortality was having a CD4 count ≤100 cells/mm3 (adjusted hazards ratio, 15.6; 95% confidence interval, 4.4-55.6). Conclusions: Survival and treatment outcomes among MDR tuberculosis-HIV individuals receiving concurrent ART approached those of HIV-uninfected patients. The greatest risk of death was among HIV-infected individuals with CD4 counts ≤100 cells/mm3. These findings provide critical evidence to support concurrent treatment of MDR tuberculosis and HIV.

Monte Carlo methods for nonparametric regression with heteroscedastic measurement error.

Nonparametric regression is a fundamental problem in statistics but challenging when the independent variable is measured with error. Among the first approaches was an extension of deconvoluting kernel density estimators for homescedastic measurement error. The main contribution of this article is to propose a new simulation-based nonparametric regression estimator for the heteroscedastic measurement error case. Similar to some earlier proposals, our estimator is built on principles underlying deconvoluting kernel density estimators. However, the proposed estimation procedure uses Monte Carlo methods for estimating nonlinear functions of a normal mean, which is different than any previous estimator. We show that the estimator has desirable operating characteristics in both large and small samples and apply the method to a study of benzene exposure in Chinese factory workers.

Regularity of a renewal process estimated from binary data.

Assessment of the regularity of a sequence of events over time is important for clinical decision-making as well as informing public health policy. Our motivating example involves determining the effect of an intervention on the regularity of HIV self-testing behavior among high-risk individuals when exact self-testing times are not recorded. Assuming that these unobserved testing times follow a renewal process, the goals of this work are to develop suitable methods for estimating its distributional parameters when only the presence or absence of at least one event per subject in each of several observation windows is recorded. We propose two approaches to estimation and inference: a likelihood-based discrete survival model using only time to first event; and a potentially more efficient quasi-likelihood approach based on the forward recurrence time distribution using all available data. Regularity is quantified and estimated by the coefficient of variation (CV) of the interevent time distribution. Focusing on the gamma renewal process, where the shape parameter of the corresponding interevent time distribution has a monotone relationship with its CV, we conduct simulation studies to evaluate the performance of the proposed methods. We then apply them to our motivating example, concluding that the use of text message reminders significantly improves the regularity of self-testing, but not its frequency. A discussion on interesting directions for further research is provided.

Mortality & recurrent seizure risk after new-onset seizure in HIV-positive Zambian adults.

BACKGROUND: Recurrent seizure risks in HIV-positive people with new-onset seizure are largely unknown, making it challenging to offer optimal recommendations regarding antiepileptic drug (AED) initiation. Existing outcomes data is limited, and risk factor identification requires a diagnostic assessment, which is often unavailable in regions heavily effected by HIV, like sub-Saharan Africa. METHODS: HIV-positive Zambian adults with new-onset seizure were enrolled in a prospective cohort study to determine seizure recurrence and risk factors for recurrence. Seizure etiology was evaluated, and recurrent seizures and medication usage were assessed during clinic visits. Due to unexpectedly high mortality rates, predictors of death were evaluated using proportional hazards with Gray's test to compare cumulative incidence functions for recurrent seizure across groups adjusting for the competing outcome of death. RESULTS: 95 patients were enrolled (mean age 37 years, 43% female, 83% with Karnofsky > 50) and followed for a mean of 293 days (median 241 (IQR: 29-532)). At presentation, 50 (53%) were in status epilepticus. The majority (91, 85%) had advanced HIV disease and 65 (68%) were not on combined antiretroviral therapy (cART). After extensive workup, seizure etiology remained unknown in 16 (17%). Average time to cART initiation after enrollment was 61 days. During follow up, 37 (39%) died and 23 (24%) had recurrent seizure. Most deaths (25/37, 68%) occurred in the first 60 days post-index seizure. Individuals with advanced HIV were more likely to die (HR: 19.1 [95% CI: 1.1-333.4]) as were those whose seizure etiology remained unknown (HR: 2.2 [95% CI: 1.1-4.4]). Among participants that survived from enrolment to the end of data collection on 10 May 2013 (n = 58), 20 (34%) experienced recurrent seizures. CONCLUSIONS: New-onset seizure among HIV-positive Zambian adults is associated with high mortality despite good functional status prior to presentation. Advanced HIV infection and failure to identify an underlying seizure etiology are associated with greater mortality. Recurrent seizures occur in over a third of survivors within only 2 years of follow-up. This provides evidence to support AED initiation after first seizure in HIV-positive individuals with advanced HIV disease at the time of presentation though the risks of AED-cART interactions remain a concern and warrant further study.