Implementation Fidelity of the National Malaria Control Program in Burkina Faso

Background

Every year 40,000 people die of malaria in Burkina Faso. In 2010, the Burkinabè authorities implemented a national malaria control program that provides for the distribution of mosquito nets and the home-based treatment of children with fever by community health workers. The objective of this study was to measure the implementation fidelity of this program.

Methods

We conducted a case study in two comparable districts (Kaya and Zorgho). Data were collected one year after the program’s implementation through field observations (10 weeks), documentary analysis, and individual interviews with stakeholders (n = 48) working at different levels of the program. The analysis framework looked at the fidelity of (i) the intervention’s content, (ii) its coverage, and (iii) its schedule.

Results

The program’s implementation was relatively faithful to what was originally planned and was comparable in the two districts. It encountered certain obstacles in terms of the provision of supplies. Coverage fidelity was better in Kaya than in Zorgho, where many community health workers (CHW) experienced problems with the restocking of artemisinin-based combination therapy and with remuneration for periods of training. In both districts, the community was rarely involved in the process of selecting CHWs. The components affected by scheduling all experienced successive implementation delays that pushed nets distribution and the initial provision of artemisinin-based combination therapies to the CHWs past the 2010 malaria season.

Conclusions

The activities intended by the program were mostly implemented with good fidelity. However, the implementation was plagued by delays that probably postponed the expected beneficial effects.     

Efficacy,Safety, and Dose of Pafuramidine,a New Oral Drug for Treatment of First Stage Sleeping Sickness,in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies

Background

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.

Methods

The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.

Findings/Conclusion

Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.     

Deformability Assessment of Waterborne Protozoa Using a Microfluidic-Enabled Force Microscopy Probe

Many modern filtration technologies are incapable of the complete removal of Cryptosporidium oocysts from drinking-water. Consequently, Cryptosporidium-contaminated drinking-water supplies can severely implicate both water utilities and consumers. Existing methods for the detection of Cryptosporidium in drinking-water do not discern between non-pathogenic and pathogenic species, nor between viable and non-viable oocysts. Using FluidFM, a novel force spectroscopy method employing microchannelled cantilevers for single-cell level manipulation, we assessed the size and deformability properties of two species of Cryptosporidium that pose varying levels of risk to human health. A comparison of such characteristics demonstrated the ability of FluidFM to discern between Cryptosporidium muris and Cryptosporidium parvum with 86% efficiency, whilst using a measurement throughput which exceeded 50 discrete oocysts per hour. In addition, we measured the deformability properties for untreated and temperature-inactivated oocysts of the highly infective, human pathogenic C. parvum to assess whether deformability may be a marker of viability. Our results indicate that untreated and temperature-inactivated C. parvum oocysts had overlapping but significantly different deformability distributions.     

Identification of human skin bacteria attractive to the Asian Tiger mosquito

Aedes albopictus is a vector of arboviruses and filarial nematodes. Originating from Asia, this mosquito has rapidly expanded its geographical distribution and colonized areas across both temperate and tropical regions. Due to the increase in insecticide resistance, the use of environmentally friendly vector control methods is encouraged worldwide. Using methods based on semiochemicals in baited traps are promising for management of mosquito populations. Interestingly, human skin microbiota was shown to generate volatile compounds that attract the mosquito species Anopheles gambiae and Aedes aegypti. Here, we investigated the composition of skin bacteria from different volunteers and the attractive potential of individual isolates to nulliparous Ae. albopictus females. We showed that three out of 16 tested isolates were more attractive and two were more repulsive. We identified dodecenol as being preferentially produced by attractive isolates and 2-methyl-1-butanol (and to a lesser extent 3-methyl-1-butanol) as being overproduced by these isolates compared with the other ones. Those bacterial volatile organic compounds represent promising candidates but further studies are needed to evaluate their potential application for baited traps improvement.     

Within‐generation consequences of postsettlement mortality for trait composition in wild populations: An experimental test

There is a critical need to understand patterns and causes of intraspecific variation in physiological performance in order to predict the distribution and dynamics of wild populations under natural and human‐induced environmental change. However, the usual explanation for trait differences, local adaptation, fails to account for the small‐scale phenotypic and genetic divergence observed in fishes and other species with dispersive early life stages. We tested the hypothesis that local‐scale variation in the strength of selective mortality in early life mediates the trait composition in later life stages. Through in situ experiments, we manipulated exposure to predators in the coral reef damselfish Dascyllus aruanus and examined consequences for subsequent growth performance under common garden conditions. Groups of 20 recently settled D. aruanus were outplanted to experimental coral colonies in Moorea lagoon and either exposed to natural predation mortality (52% mortality in three days) or protected from predators with cages for three days. After postsettlement mortality, predator‐exposed groups were shorter than predator‐protected ones, while groups with lower survival were in better condition, suggesting that predators removed the longer, thinner individuals. Growth of both treatment groups was subsequently compared under common conditions. We did not detect consequences of predator exposure for subsequent growth performance: Growth over the following 37 days was not affected by the prior predator treatment or survival. Genotyping at 10 microsatellite loci did indicate, however, that predator exposure significantly influenced the genetic composition of groups. We conclude that postsettlement mortality did not have carryover effects on the subsequent growth performance of cohorts in this instance, despite evidence for directional selection during the initial mortality phase.     

Explicit-solvent molecular dynamics simulations of the polysaccharide schizophyllan in water

Schizophyllan is a beta(1-->3)-D-glucan polysaccharide with beta(1-->6)-branched lateral glucose residues that presents a very stiff triple-helical structure under most experimental conditions. Despite the remarkable stability of this structure (which persists up to 120 degrees C in aqueous solution), schizophyllan undergoes a major change of state around 7 degrees C in water that has been hypothesized to result from an order-disorder transition in the lateral residues. This hypothesis is only supported by indirect experimental evidence and detailed knowledge (at the atomic level) concerning hydrogen-bonding networks, interactions with the solvent molecules, orientational freedom of the lateral residues, and orientational correlations among them is still lacking. In this study explicit-solvent molecular dynamics simulations of a schizophyllan fragment (complemented by simulations of its tetrasaccharide monomer) are performed at three different temperatures (273 K, 350 K, and 450 K) and with two different types of boundary conditions (finite nonperiodic or infinite periodic fragment) as an attempt to provide detailed structural and dynamical information about the triple-helical conformation in solution and the mechanism of the low-temperature transition. These simulations suggest that three important driving forces for the high stability of the triple helix are i), the limited conformational work involved in its formation; ii), the formation of a dense hydrogen-bonding network at its center; and iii), the formation of interchain hydrogen bonds between main-chain and lateral glucose residues. However, these simulations evidence a moderate and continuous variation of the simulated observables upon increasing the temperature, rather than a sharp transition between the two lowest temperatures (that could be associated with the state transition). Although water-mediated hydrogen-bonded association of neighboring lateral residues is observed, this interaction is not strong enough to promote the formation of an ordered state (correlated motions of the lateral residues), even at the lowest temperature considered.     

Genomewide association analysis in diverse inbred mice: power and population structure

The discovery of quantitative trait loci (QTL) in model organisms has relied heavily on the ability to perform controlled breeding to generate genotypic and phenotypic diversity. Recently, we and others have demonstrated the use of an existing set of diverse inbred mice (referred to here as the mouse diversity panel, MDP) as a QTL mapping population. The use of the MDP population has many advantages relative to traditional F(2) mapping populations, including increased phenotypic diversity, a higher recombination frequency, and the ability to collect genotype and phenotype data in community databases. However, these methods are complicated by population structure inherent in the MDP and the lack of an analytical framework to assess statistical power. To address these issues, we measured gene expression levels in hypothalamus across the MDP. We then mapped these phenotypes as quantitative traits with our association algorithm, resulting in a large set of expression QTL (eQTL). We utilized these eQTL, and specifically cis-eQTL, to develop a novel nonparametric method for association analysis in structured populations like the MDP. These eQTL data confirmed that the MDP is a suitable mapping population for QTL discovery and that eQTL results can serve as a gold standard for relative measures of statistical power.