Social inequality and HIV-testing

The plan to increase HIV testing is a cornerstone of the international health strategy against the HIV/AIDS epidemic, particularly in sub-Saharan Africa. This paper highlights a problematic aspect of that plan: the reliance on clinic- rather than home-based testing. First, drawing on DHS data from across Africa, we demonstrate the substantial differences in socio-demographic and economic profiles between those who report having ever had an HIV test, and those who report never having had one. Then, using data from a random household survey in rural Malawi, we show that substituting home-based for clinic-based testing may eliminate this source of inequality between those tested and those not tested. This result, which is stable across modeling frameworks, has important implications for accurately and equitably addressing the counseling and treatment programs that comprise the international health strategy against AIDS, and that promise to shape the future trajectory of the epidemic in Africa and beyond.AIDS/HIV, home-based testing, inequality, Malawi

Hotspots and Coldspots: Household and village-level variation in orphanhood prevalence in rural Malawi

We explore the spatial distribution of orphans in two areas of Malawi. We first review pertinent themes in qualitative data collected in our research sites. Then, using spatial analysis, we show how positive and negative clusters of orphans—which we term orphanhood "hotspots" and "coldspots"—can be found at the village and sub-village levels. In the third and longest section of the paper, and using multilevel analyses with both simple and complex variance structures, we evaluate the relationship between the presence of orphans and a range of individual, household and village-level characteristics, including households' spatial relationship to each other and to other local sites of significance. This series of analyses shows that the most important covariates of orphan presence are the density of settlement, household size, and religious characteristics, with the latter measured simultaneously at both household and village-level. Other characteristics like education, reported mortality levels and HIV infection, are wholly unrelated to orphan prevalence at all analytic levels. Wealth and various spatial characteristics are only marginally associated with orphan prevalence. We conclude by reviewing some difficulties in explaining causal mechanisms underlying these observed relationships, and discussing conceptual, theoretical and programmatic implications.Africa, AIDS/HIV, Malawi, multilevel model, orphan prevalence, orphans, spatial analysis

Mortality among Married Men in Rural Kenya and Malawi

Using prospective longitudinal data, this article describes recent changes in the levels of adult mortality among married men aged 20–59 in selected rural areas of Malawi and Kenya, and in the age pattern of their mortality. Sampled areas have, respectively, moderate and high HIV prevalence. The observed annual probability of dying for males interviewed in an initial wave of each study and then reported as deceased in follow-up interviews is 0.031 in Nyanza and 0.016 in Malawi. Compared to life table estimates for equivalent age groups generated from Kenya’s 1989 census and Malawi’s 1987 census, these results  represent a 3-fold increase over 1980s census levels. These changes have reduced life expectancy at age 20 by about 14 years in Nyanza and 7 years in Malawi. Observed mortality is consistent with a younger age of HIV infection in Nyanza. Sample characteristics suggest that these levels underestimate the total effect of AIDS on mortality

Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation.

α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of experimental and theoretical approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its soluble state to the aggregated state that is associated with neurodegeneration and to its associated disease states.This work was supported by the UK BBSRC and the Wellcome Trust (CMD, TPJK, MV), the Frances and Augustus Newman Foundation (TPJK), Magdalene College, Cambridge (AKB) , St John’s College, Cambridge (TCTM), the Cambridge Home and EU Scholarship Scheme (GM), Elan Pharmaceuticals (CMD, TPJK, MV, CG) and the Leverhulme Trust (AKB).This is the accepted manuscript. The final version is available from NPG at http://www.nature.com/nchembio/journal/v11/n3/abs/nchembio.1750.htm

Assembly and function of the Photosystem II manganese stabilizing protein: lessons from its natively unfolded behavior

The Photosystem II (PS II) manganese stabilizing protein (MSP) possesses characteristics, including thermostability, ascribed to the natively unfolded class of proteins (Lydakis-Simantiris et al. (1999) Biochemistry 38: 404–414). A site-directed mutant of MSP, C28A, C51A, which lacks the -S–S- bridge, also binds to PS II at wild-type levels and reconstitutes oxygen evolution activity [Betts et al. (1996) Biochim Biophys Acta 1274: 135–142], although the mutant protein is even more disordered in solution. Both WT and C28A, C51A MSP aggregate upon heating, but an examination of the effects of protein concentration and pH on heat-induced aggregation showed that each MSP species exhibited greater resistance to aggregation at a pH near their p I (5.2) than do either bovine serum albumin (BSA) or carbonic anhydrase, which were used as model water soluble proteins. Increases in pH above the p I of the MSPs and BSA enhanced their aggregation resistance, a behavior which can be predicted from their charge (MSP) or a combination of charge and stabilization by -S–S- bonds (BSA). In the case of aggregation resistance by MSP, this is likely to be an important factor in its ability to avoid unproductive self-association reactions in favor of formation of the protein–protein interactions that lead to formation of the functional oxygen evolving complex.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43544/1/11120_2004_Article_7759.pd

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

Funder: All funders per study are acknowledged in the Supplementary FileA new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH