Outcomes of a remote, decentralized health center-based HIV/AIDS antiretroviral program in Zambia, 2003 to 2007

A cross-sectional study of patients living with HIV/ AIDS treated during 2003 to 2007 in decentralized, rural health centers in Zambia was performed to measure virological outcomes after 12 months of antiretroviral therapy and identify factors associated with virological failure. Data from 228 patients who started antiretroviral therapy >12 months prior were analyzed. In all, 93% received stavudine + lamivudine + nevirapine regimens, and median antiretroviral therapy duration was 23.5 months (interquartile range 20-28). Of the 205 patients tested for viral load, 177 (86%) had viral load <1000 copies/mL. Probability of developing virological failure (viral load >1000 copies/mL) was 8.9% at 24 months and 19.6% at 32 months. Predictors for virological failure were <100% adherence, body mass index <18.5 kg/m(2), and women <40 years old. Of those with virological failure who underwent 3 to 6 months of intensive adherence counseling, 45% obtained virological success. In a remote, resource-limited setting in decentralized health centers, virological and immunological assessments of patients on antiretroviral therapy >12 months showed that positive health outcomes are achievable

Bayesian refinement of protein functional site matching

<p>Abstract</p> <p>Background</p> <p>Matching functional sites is a key problem for the understanding of protein function and evolution. The commonly used graph theoretic approach, and other related approaches, require adjustment of a matching distance threshold <it>a priori </it>according to the noise in atomic positions. This is difficult to pre-determine when matching sites related by varying evolutionary distances and crystallographic precision. Furthermore, sometimes the graph method is unable to identify alternative but important solutions in the neighbourhood of the distance based solution because of strict distance constraints. We consider the Bayesian approach to improve graph based solutions. In principle this approach applies to other methods with strict distance matching constraints. The Bayesian method can flexibly incorporate all types of prior information on specific binding sites (e.g. amino acid types) in contrast to combinatorial formulations.</p> <p>Results</p> <p>We present a new meta-algorithm for matching protein functional sites (active sites and ligand binding sites) based on an initial graph matching followed by refinement using a Markov chain Monte Carlo (MCMC) procedure. This procedure is an innovative extension to our recent work. The method accounts for the 3-dimensional structure of the site as well as the physico-chemical properties of the constituent amino acids. The MCMC procedure can lead to a significant increase in the number of significant matches compared to the graph method as measured independently by rigorously derived p-values.</p> <p>Conclusion</p> <p>MCMC refinement step is able to significantly improve graph based matches. We apply the method to matching NAD(P)(H) binding sites within single Rossmann fold families, between different families in the same superfamily, and in different folds. Within families sites are often well conserved, but there are examples where significant shape based matches do not retain similar amino acid chemistry, indicating that even within families the same ligand may be bound using substantially different physico-chemistry. We also show that the procedure finds significant matches between binding sites for the same co-factor in different families and different folds.</p

Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data [version 1; peer review: 1 approved, 1 approved with reservations]

Background: The -α3.7I-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (HBA) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations

Soil fertility studies with compost and igneous phosphate rock amendments in Malawi

(African Crop Science Journal 1999 7(4): 415-422

Markov chain Monte Carlo implementation of rock fracture modelling

This paper deals with the problem of estimating fracture planes, given only the data at borehole intersections with fractures. We formulate an appropriate model for the problem and give a solution to fitting the planes using a Markov chain Monte Carlo (MCMC) implementation. The basics of MCMC are presented, with particular emphasis given to reversible jump, which is required for changing dimensions. We also give a detailed worked example of the MCMC implementation with reversible jump since our implementation relies heavily on this new methodology. The methods are tested on both simulated and real data. The latter is a unique data set in the form of a granite block, which was sectioned into slices. All joints were located and recorded, and the joint planes obtained by stacking strike lines. This work is important in the risk assessment for the underground storage of hazardous waste. Problems and extensions are discussed.K. V. Mardia , V. B. Nyirongo, A. N. Walder, C. Xu, P. A. Dowd, R. J. Fowell and J. T. Ken

Sulfadoxine-pyrimethamine–based combinations for malaria : a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi

Background: In Malawi, there has been a return of Plasmodium falciparum sensitivity to chloroquine (CQ) since sulfadoxinepyrimethamine (SP) replaced CQ as first line treatment for uncomplicated malaria. When used for prophylaxis, Amodiaquine (AQ) was associated with agranulocytosis but is considered safe for treatment and is increasingly being used in Africa. Here we compare the efficacy, safety and selection of resistance using SP or CQ+SP or artesunate (ART)+SP or AQ+SP for the treatment of uncomplicated falciparum malaria. Methodology and Findings: 455 children aged 1–5 years were recruited into a double-blinded randomised trial comparing SP to the three combination therapies. Using intention to treat analysis with missing outcomes treated as successes, and without adjustment to distinguish recrudescence from new infections, the day 28 adequate clinical and parasitological response (ACPR) rate for SP was 25%, inferior to each of the three combination therapies (p,0.001). AQ+SP had an ACPR rate of 97%, higher than CQ+SP (81%) and ART+SP (70%), p,0.001. Nineteen children developed a neutropenia of #0.56103 cells/ml by day 14, more commonly after AQ+SP (p = 0.03). The mutation pfcrt 76T, associated with CQ resistance, was detected in none of the pre-treatment or post-treatment parasites. The prevalence of the pfmdr1 86Y mutation was higher after treatment with AQ+SP than after SP, p = 0.002. Conclusions: The combination AQ+SP was highly efficacious, despite the low efficacy of SP alone; however, we found evidence that AQ may exert selective pressure for resistance associated mutations many weeks after treatment. This study confirms the return of CQ sensitivity in Malawi and importantly, shows no evidence of the re-emergence of pfcrt 76T after treatment with CQ or AQ. Given the safety record of AQ when used as a prophylaxis, our observations of marked falls in neutrophil counts in the AQ+SP group requires further scrutiny

Histograms and traces of parameters when matching 17 – hydroxysteroid dehydrogenase and carbonyl reductase (1cyd 1)

<p><b>Copyright information:</b></p><p>Taken from "Bayesian refinement of protein functional site matching"</p><p>http://www.biomedcentral.com/1471-2105/8/257</p><p>BMC Bioinformatics 2007;8():257-257.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1940029.</p><p></p