Incidence of WHO stage 3 and 4 conditions following initiation of Anti-Retroviral Therapy in resource limited settings

To determine the incidence of WHO clinical stage 3 and 4 conditions during early anti-retroviral therapy (ART) in resource limited settings (RLS)

Early biting and insecticide resistance in the malaria vector Anopheles might compromise the effectiveness of vector control intervention in Southwestern Uganda.

BACKGROUND: Southwestern Uganda has high malaria heterogeneity despite moderate vector control and other interventions. Moreover, the early biting transmission and increased resistance to insecticides might compromise strategies relying on vector control. Consequently, monitoring of vector behaviour and insecticide efficacy is needed to assess the effectiveness of strategies aiming at malaria control. This eventually led to an entomological survey in two villages with high malaria prevalence in this region. METHODS: During rainy, 2011 and dry season 2012, mosquitoes were collected in Engari and Kigorogoro, Kazo subcounty, using human landing collection, morning indoor resting collection, pyrethrum spray collection and larval collection. Circumsporozoite protein of Plasmodium falciparum sporozoites in female Anopheles mosquitoes was detected using ELISA assay. Bioassays to monitor Anopheles resistance to insecticides were performed. RESULTS: Of the 1,021 female Anopheles species captured, 62% (632) were Anopheles funestus and 36% (371) were Anopheles gambiae s.l. The most common species were Anopheles gambiae s.l. in Engari (75%) and A. funestus in Kigorogoro (83%). Overall, P. falciparum prevalence was 2.9% by ELISA. The daily entomological inoculation rates were estimated at 0.17 and 0.58 infected bites/person/night during rainy and dry season respectively in Engari, and 0.81 infected bites/person/night in Kigorogoro during dry season. In both areas and seasons, an unusually early evening biting peak was observed between 6 - 8 p.m. In Engari, insecticide bioassays showed 85%, 34% and 12% resistance to DDT during the rainy season, dry season and to deltamethrin during the dry season, respectively. In Kigorogoro, 13% resistance to DDT and to deltamethrin was recorded. There was no resistance observed to bendiocarb and pirimiphos methyl. CONCLUSIONS: The heterogeneity of mosquito distribution, entomological indicators and resistance to insecticides in villages with high malaria prevalence highlight the need for a long-term vector control programme and monitoring of insecticide resistance in Uganda. The early evening biting habits of Anopheles combined with resistance to DDT and deltamethrin observed in this study suggest that use of impregnated bed nets alone is insufficient as a malaria control strategy, urging the need for additional interventions in this area of high transmission

Tuberculosis Incidence Rates during 8 Years of Follow-Up of an Antiretroviral Treatment Cohort in South Africa: Comparison with Rates in the Community

BACKGROUND: Although antiretroviral therapy (ART) is known to be associated with time-dependent reductions in tuberculosis (TB) incidence, the long-term impact of ART on incidence remains imprecisely defined due to limited duration of follow-up and incomplete CD4 cell count recovery in existing studies. We determined TB incidence in a South African ART cohort with up to 8 years of follow-up and stratified rates according to CD4 cell count recovery. We compared these rates with those of HIV-uninfected individuals living in the same community. METHODOLOGY/PRINCIPAL FINDINGS: Prospectively collected clinical data on patients receiving ART in a community-based cohort in Cape Town were analysed. 1544 patients with a median follow-up of 5.0 years (IQR 2.4-5.8) were included in the analysis. 484 episodes of incident TB (73.6% culture-confirmed) were diagnosed in 424 patients during 6506 person-years (PYs) of follow-up. The TB incidence rate during the first year of ART was 12.4 (95% CI 10.8-14.4) cases/100PYs and decreased to 4.92 (95% CI 3.64-8.62) cases/100PYs between 5 and 8 years of ART. During person-time accrued within CD4 cell strata 0-100, 101-200, 201-300, 301-400, 401-500, 501-700 and ≥700 cells/µL, TB incidence rates (95% CI) were 25.5 (21.6-30.3), 11.2 (9.4-13.5), 7.9 (6.4-9.7), 5.0 (3.9-6.6), 5.1 (3.8-6.8), 4.1 (3.1-5.4) and 2.7 (1.7-4.5) cases/100PYs, respectively. Overall, 75% (95% CI 70.9-78.8) of TB episodes were recurrent cases. Updated CD4 cell count and viral load measurements were independently associated with long-term TB risk. TB rates during person-time accrued in the highest CD4 cell count stratum (>700 cells/µL) were 4.4-fold higher that the rate in HIV uninfected individuals living in the same community (2.7 versus 0.62 cases/100PYs; 95%CI 0.58-0.65). CONCLUSIONS/SIGNIFICANCE: TB rates during long-term ART remained substantially greater than rates in the local HIV uninfected populations regardless of duration of ART or attainment of CD4 cell counts exceeding 700 cells/µL

Verbal Autopsy: Reliability and Validity Estimates for Causes of Death in the Golestan Cohort Study in Iran

BACKGROUND: Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medical records. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran. METHOD: A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists ("reviewers") independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard. RESULTS: VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa>0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95%CI: 0.78-0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95%CI: 0.85-0.99). CONCLUSIONS: VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country

The functional anatomy of semantic retrieval is influenced by gender, menstrual cycle, and sex hormones

This study examines the neurobiology of semantic retrieval and describes the influence of gender, menstrual cycle, and sex hormones on semantic networks. Healthy right-handed subjects (12 men, 12 women) were investigated with 3T-fMRI during synonym generation. Behavioral performance and sex hormone levels were assessed. Women were examined during the early follicular and midluteal cycle phase. The activation pattern in all groups involved left frontal and temporal as well as bilateral medial frontal, cingulate, occipital, basal ganglia, and cerebellar regions. Men showed greater left frontal activation than women in both menstrual cycle phases. Women yielded high correlations of left prefrontal activation with estradiol in the midluteal phase and with progesterone in both phases. Testosterone levels correlated highly with left prefrontal activation in all three groups. In all, we describe a cerebral network involved in semantic processing and demonstrate that it is significantly affected by gender and sex steroid hormones

Reduced Quantitative Ultrasound Bone Mineral Density in HIV-Infected Patients on Antiretroviral Therapy in Senegal

Background: Bone status in HIV-infected patients on antiretroviral treatment (ART) is poorly documented in resource-limited settings. We compared bone mineral density between HIV-infected patients and control subjects from Dakar, Senegal. Methods: A total of 207 (134 women and 73 men) HIV-infected patients from an observational cohort in Dakar (ANRS 1215) and 207 age-and sex-matched controls from the general population were enrolled. Bone mineral density was assessed by quantitative ultrasound (QUS) at the calcaneus, an alternative to the reference method (i.e. dual X-absorptiometry), often not available in resource-limited countries. Results: Mean age was 47.0 (+/- 8.5) years. Patients had received ART for a median duration of 8.8 years; 45% received a protease inhibitor and 27% tenofovir; 84% had undetectable viral load. Patients had lower body mass index (BMI) than controls (23 versus 26 kg/m(2), P<0.001). In unadjusted analysis, QUS bone mineral density was lower in HIV-infected patients than in controls (difference: -0.36 standard deviation, 95% confidence interval (CI): -0.59;-0.12, P = 0.003). Adjusting for BMI, physical activity, smoking and calcium intake attenuated the difference (-0.27, CI: -0.53; -0.002, P = 0.05). Differences in BMI between patients and controls explained a third of the difference in QUS bone mineral density. Among patients, BMI was independently associated with QUS bone mineral density (P<0.001). An association between undetectable viral load and QUS bone density was also suggested (beta = 0.48, CI: 0.02; 0.93; P = 0.04). No association between protease inhibitor or tenofovir use and QUS bone mineral density was found. Conclusion: Senegalese HIV-infected patients had reduced QUS bone mineral density in comparison with control subjects, in part related to their lower BMI. Further investigation is needed to clarify the clinical significance of these observations

Intensive Case Finding and Isoniazid Preventative Therapy in HIV Infected Individuals in Africa: Economic Model and Value of Information Analysis

Background: Tuberculosis (TB) accounts of much of the morbidity and mortality associated with HIV. We evaluate the costeffectiveness of different strategies to actively screen for TB disease in HIV positive individuals, where isoniazid preventative therapy (IPT) is given to those screening negative, and use value of information analysis (VOI) to identify future research priorities. Methodology / Principal Findings: We built an individual sampling model to investigate the costs (2010 US Dollars) and consequences of screening for TB, and providing TB treatment or IPT in adults testing HIV positive in Sub-Saharan Africa. A systematic review and meta-analysis was conducted to assess performance of the nine different TB screening strategies evaluated. Probabilistic sensitivity analysis was conducted to incorporate decision uncertainty, and expected value of perfect information for the entire model and for groups of parameters was calculated. Screening all HIV infected individuals with sputum microscopy was the least costly strategy, with other strategies not cost-effective at WHO recommended thresholds. Screening those with TB symptoms with sputum microscopy and CXR would be cost-effective at a threshold ICER of $7,800 per quality-adjusted life year (QALY), but associated with significant uncertainty. VOI analysis suggests further information would be of value. Conclusions / Significance: Resource-constrained countries in sub-Saharan Africa wishing to scale up TB preventativ

Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa.

Immune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa

Molecular features of the UNC-45 chaperone critical for binding and folding muscle myosin

Myosin is a motor protein that is essential for a variety of processes ranging from intracellular transport to muscle contraction. Folding and assembly of myosin relies on a specific chaperone, UNC-45. To address its substrate-targeting mechanism, we reconstitute the interplay between Caenorhabditis elegans UNC-45 and muscle myosin MHC-B in insect cells. In addition to providing a cellular chaperone assay, the established system enabled us to produce large amounts of functional muscle myosin, as evidenced by a biochemical and structural characterization, and to directly monitor substrate binding to UNC-45. Data from in vitro and cellular chaperone assays, together with crystal structures of binding-deficient UNC-45 mutants, highlight the importance of utilizing a flexible myosin-binding domain. This so-called UCS domain can adopt discrete conformations to efficiently bind and fold substrate. Moreover, our data uncover the molecular basis of temperature-sensitive UNC-45 mutations underlying one of the most prominent motility defects in C. elegans