Population-Level Benefits from Providing Effective HIV Prevention Means to Pregnant Women in High Prevalence Settings

Background:HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention.Methods and Findings:A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RRHIV/preg = 1). It may also prevent 8-15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RRMTCT/preg). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RRHIV/preg = 1) to 25% (RRHIV/preg = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RRHIV/preg = 1, RRMTCT/preg = 1) and 25% (RRHIV/preg = 2, RRMTCT/preg = 4) to the reduction in the residual MTCT.Conclusion:Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated. © 2013 Dimitrov et al

Evaluation of geospatial methods to generate subnational HIV prevalence estimates for local level planning

Objective: There is evidence of substantial subnational variation in the HIV epidemic. However, robust spatial HIV data are often only available at high levels of geographic aggregation and not at the finer resolution needed for decision making. Therefore, spatial analysis methods that leverage available data to provide local estimates of HIV prevalence may be useful. Such methods exist but have not been formally compared when applied to HIV. Design/methods: Six candidate methods – including those used by the Joint United Nations Programme on HIV/AIDS to generate maps and a Bayesian geostatistical approach applied to other diseases – were used to generate maps and subnational estimates of HIV prevalence across three countries using cluster level data from household surveys. Two approaches were used to assess the accuracy of predictions: internal validation, whereby a proportion of input data is held back (test dataset) to challenge predictions; and comparison with location-specific data from household surveys in earlier years. Results: Each of the methods can generate usefully accurate predictions of prevalence at unsampled locations, with the magnitude of the error in predictions similar across approaches. However, the Bayesian geostatistical approach consistently gave marginally the strongest statistical performance across countries and validation procedures. Conclusions: Available methods may be able to furnish estimates of HIV prevalence at finer spatial scales than the data currently allow. The subnational variation revealed can be integrated into planning to ensure responsiveness to the spatial features of the epidemic. The Bayesian geostatistical approach is a promising strategy for integrating HIV data to generate robust local estimates

Causes of Abnormal Ca2+ Transients in Guinea Pig Pathophysiological Ventricular Muscle Revealed by Ca2+ and Action Potential Imaging at Cellular Level

BACKGROUND: Abnormal Ca(2+) transients are often observed in heart muscles under a variety of pathophysiological conditions including ventricular tachycardia. To clarify whether these abnormal Ca(2+) transients can be attributed to abnormal action potential generation or abnormal Ca(2+) handling/excitation-contraction (EC) coupling, we developed a procedure to determine Ca(2+) and action potential signals at the cellular level in isolated heart tissues. METHODOLOGY/PRINCIPAL FINDINGS: After loading ventricular papillary muscle with rhod-2 and di-4-ANEPPS, mono-wavelength fluorescence images from rhod-2 and ratiometric images of two wavelengths of emission from di-4-ANEPPS were sequentially obtained. To mimic the ventricular tachycardia, the ventricular muscles were field-stimulated in non-flowing Krebs solution which elicited abnormal Ca(2+) transients. For the failed and alternating Ca(2+) transient generation, there were two types of causes, i.e., failed or abnormal action potential generation and abnormal EC coupling. In cells showing delayed initiation of Ca(2+) transients with field stimulation, action potential onset was delayed and the rate of rise was slower than in healthy cells. Similar delayed onset was also observed in the presence of heptanol, an inhibitor of gap junction channels but having a non-specific channel blocking effect. A Na(+) channel blocker, on the other hand, reduced the rate of rise of the action potentials but did not result in desynchronization of the action potentials. The delayed onset of action potentials can be explained primarily by impaired gap junctions and partly by Na(+) channel inactivation. CONCLUSIONS/SIGNIFICANCE: Our results indicate that there are multiple patterns for the causes of abnormal Ca(2+) signals and that our methods are useful for investigating the physiology and pathophysiology of heart muscle

A Glial Variant of the Vesicular Monoamine Transporter Is Required To Store Histamine in the Drosophila Visual System

Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems

Trends in HIV & syphilis prevalence and correlates of HIV infection: results from cross-sectional surveys among women attending ante-natal clinics in Northern Tanzania.

BACKGROUND: Sentinel surveillance for HIV in ante-natal clinics (ANC) remains the primary method for collecting timely trend data on HIV prevalence in most of sub-Saharan Africa. We describe prevalence of HIV and syphilis infection and trends over time in HIV prevalence among women attending ante-natal clinics (ANC) in Magu district and Mwanza city, part of Mwanza region in Northern Tanzania. HIV prevalence from ANC surveys in 2000 and 2002 was 10.5% and 10.8% respectively. In previous rounds urban residence, residential mobility, the length of time sexually active before marriage, time since marriage and age of the partner were associated with HIV infection. METHODS: A third round of HIV sentinel surveillance was conducted at ante-natal clinics in Mwanza region, Tanzania during 2006. We interviewed women attending 27 ante-natal clinics. In 15 clinics we also anonymously tested women for syphilis and HIV infection and linked these results to the questionnaire data. RESULTS: HIV prevalence was 7.6% overall in 2006 and 7.4% at the 11 clinics used in previous rounds. Geographical variations in HIV prevalence, apparent in previous rounds, have largely disappeared but syphilis prevalence is still higher in rural clinics. HIV prevalence has declined in urban clinics and is stable in rural clinics. The correlates of HIV infection have changed over time. In this round older age, lower gravidity, remarriage, duration of marriage, sexual activity before marriage, long interval between last birth and pregnancy and child death were all associated with infection. CONCLUSIONS: HIV prevalence trends concur with results from a community-based cohort in the region. Correlates of HIV infection have also changed and more proximate, individual level factors are now more important, in line with the changing epidemiology of infection in this population

Pathways-driven sparse regression identifies pathways and genes associated with high-density lipoprotein cholesterol in two Asian cohorts.

Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune function

Evaluation of geospatial methods to generate subnational HIV prevalence estimates for local level planning

Objective: There is evidence of substantial subnational variation in the HIV epidemic. However, robust spatial HIV data are often only available at high levels of geographic aggregation and not at the finer resolution needed for decision making. Therefore, spatial analysis methods that leverage available data to provide local estimates of HIV prevalence may be useful. Such methods exist but have not been formally compared when applied to HIV. Design/methods: Six candidate methods – including those used by the Joint United Nations Programme on HIV/AIDS to generate maps and a Bayesian geostatistical approach applied to other diseases – were used to generate maps and subnational estimates of HIV prevalence across three countries using cluster level data from household surveys. Two approaches were used to assess the accuracy of predictions: internal validation, whereby a proportion of input data is held back (test dataset) to challenge predictions; and comparison with location-specific data from household surveys in earlier years. Results: Each of the methods can generate usefully accurate predictions of prevalence at unsampled locations, with the magnitude of the error in predictions similar across approaches. However, the Bayesian geostatistical approach consistently gave marginally the strongest statistical performance across countries and validation procedures. Conclusions: Available methods may be able to furnish estimates of HIV prevalence at finer spatial scales than the data currently allow. The subnational variation revealed can be integrated into planning to ensure responsiveness to the spatial features of the epidemic. The Bayesian geostatistical approach is a promising strategy for integrating HIV data to generate robust local estimates.</p