The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Ethnic identity has been identified as a factor contributing to resilience and coping in African Americans. Ethnic identity includes positive feelings of ethnic affirmation and belonging, appreciation for one’s ethnic identity, and increased ethnic behaviors. This study examines the role of ethnic identity in symptoms of anxiety and depression. Participants were an adult student and community sample (N=572), administered the Beck Anxiety Inventory (BAI), Center for Epidemiologic Studies of Depression Scale (CES-D), State Trait Anxiety Inventory – state portion (STAI-S), and Multigroup Ethnic Identity Measure (MEIM). Compared to European Americans, African Americans reported significantly greater depression and more negative state anxiety, as well as higher levels of ethnic identity. For African Americans, higher ethnic identity was correlated to reduced anxiety and depression, whereas this was not true for European Americans. Findings support the proposition that a strong, positive ethnic identity may serve a protective role among African Americans by moderating the relationship between discriminatory experiences and psychological well-being. An Afrocentric perspective may also contribute to reduced anxiety due to a greater emphasis on a present versus future-oriented worldview. Clinical implications and directions for future research are discussed.

SummaryF plasmid-mediated bacterial conjugation requires interactions between a relaxosome component, TraM, and the coupling protein TraD, a hexameric ring ATPase that forms the cytoplasmic face of the conjugative pore. Here we present the crystal structure of the C-terminal tail of TraD bound to the TraM tetramerization domain, the first structural evidence of relaxosome-coupling protein interactions. The structure reveals the TraD C-terminal peptide bound to each of four symmetry-related grooves on the surface of the TraM tetramer. Extensive protein-protein interactions were observed between the two proteins. Mutational analysis indicates that these interactions are specific and required for efficient F conjugation in vivo. Our results suggest that specific interactions between the C-terminal tail of TraD and the TraM tetramerization domain might lead to more generalized interactions that stabilize the relaxosome-coupling protein complex in preparation for conjugative DNA transfer.

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n=272, mean duration 17.9 months) or LPV/r (n=173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p<0.001), were less likely to have AIDS (p<0.001) or hepatitis C virus (HCV) coinfection (p<0.05), had higher CD4+ T cell nadirs (p<0.001), had lower peak (p<0.001) and current (p<0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p<0.001). Overall, EFV users had worse speed of information processing (p=0.04), verbal fluency (p=0.03), and working memory (p=0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n=329), EFV users performed poorly, whereas among HCV seropositives (n=116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n=269), EFV users had worse speed of information processing (p=0.02) and executive functioning (p=0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.

Summary:Purpose: To determine (a) whether children and teens with epilepsy participate in less physical activity and have higher body mass index (BMI) percentiles for age than do their siblings without epilepsy; and (b) what epilepsy-specific factors limit their participation.Methods: Patients 5-17 years, with a ≥3 month history of epilepsy, a development quotient ≥80, no major motor or sensory impairments, and at least one sibling without epilepsy in a similar age range, were identified from the Neurology Clinic database or at the time of clinic visit. Parents completed a questionnaire regarding sedentary activities and group, individual, and total sports activities. Children aged 11-15 years also completed the physical activity portion of the Health Behavior in School Aged Children questionnaire. Clinic charts were reviewed for seizure type, etiology, frequency, duration of epilepsy, and number of antiepileptic drugs (AEDs) ever taken.Results: Teens with epilepsy participated in fewer group and total sports activities than did controls and were more likely to be potentially overweight or overweight. Receiving three or more AEDs in the past showed a significant negative correlation with sports participation. Although a trend was noted for those with higher seizure frequency to be less active, no other epilepsyspecific factors or prior seizures or seizure-related injury during a sports event correlated with participation in physical activity.Conclusions: Programs that promote exercise in adolescents with epilepsy should be encouraged to improve their physical, psychological, and social well-being.

Individualized selection of patients with early stage hormone receptor positive (HR+) breast cancer for extended endocrine therapy (EET) are required to balance modest gains in outcome with toxicities of prolonged use. This study examined the Breast Cancer Index (BCI) [HOXB13/IL17BR ratio (H/I)] as a predictive biomarker of EET benefit in patients from the Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial. Experimental Design: BCI was tested in primary tumor specimens from 908 patients randomized to receive 2.5 vs 5 years of extended letrozole. The primary endpoint was recurrence-free interval (RFI). Cox models and likelihood ratios tested the interaction between EET and BCI (H/I). Results: BCI (H/I)-High significantly predicted benefit from extended letrozole in the Overall cohort (HR 0.42, 95% CI 0.21-0.84; P=0.011) and Any AI subset (HR 0.34, 0.16-0.73; P=0.004), whereas BCI (H/I)-Low patients did not derive significant benefit (HR 0.95, 0.58-1.56; P=0.84, HR 0.90, 0.53-1.55; P=0.71, respectively); treatment to biomarker interaction was significant (P=0.045, P=0.025, respectively). BCI identified ~50% of patients with clinically high-risk disease that did not benefit, and with clinically low-risk disease that derived significant benefit, from an additional 2.5 years of EET. Conclusions: BCI (H/I) predicted preferential benefit from 5 vs 2.5 years of EET and identified patients with improved outcomes from completing 10 years of adjuvant endocrine therapy. Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early stage HR+ breast cancer. Research.

Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.

Hendra virus (HeV) is one of the two prototypical members of the Henipavirus genus of paramyxoviruses, which are designated biosafety level 4 (BSL-4) organisms due to the high mortality rate of Nipah virus (NiV) and HeV in humans. Paramyxovirus cell entry is mediated by the fusion protein, F, in response to binding of a host receptor by the attachment protein. During posttranslational processing, the fusion peptide of F is released and, upon receptor-induced triggering, inserts into the host cell membrane. As F undergoes a dramatic refolding from its prefusion to postfusion conformation, the fusion peptide brings the host and viral membranes together, allowing entry of the viral RNA. Here, we present the crystal structure of the prefusion form of the HeV F ectodomain. The structure shows very high similarity to the structure of prefusion parainfluenza virus 5 (PIV5) F, with the main structural differences in the membrane distal apical loops and the fusion peptide cleavage loop. Functional assays of mutants show that the apical loop can tolerate perturbation in length and surface residues without loss of function, except for residues involved in the stability and conservation of the F protein fold. Structure-based disulfide mutants were designed to anchor the fusion peptide to conformationally invariant residues of the F head. Two mutants were identified that inhibit F-mediated fusion by stabilizing F in its prefusion conformation.