We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10 −7 to P = 4 × 10 −14 , with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.The malaria parasite Plasmodium falciparum kills on the order of a million African children each year 1 , and this is a small fraction of the number of infected individuals in the population [1][2][3] . In communities where everyone is repeatedly infected with P. falciparum, host genetic factors account for ~25% of the risk of severe malaria, that is, life-threatening forms of the disease 3 . The strongest known determinant of risk, hemoglobin S (HbS), accounts for 2% of the total variation, implying that only a small fraction of genetic resistance factors have so far been discovered 3 . Identifying the genetic basis of protective immunity against severe malaria may provide important insights for vaccine development.Here we examine the possibility of approaching this problem by genome-wide association (GWA) analysis. There are many unsolved methodological questions about how to conduct an effective GWA study in Africa 4 . High levels of ethnic diversity may result in false-positive associations owing to population structure. Variations in haplotype structure between different ethnic groups may reduce power to detect GWA signals, particularly when data are amalgamated across multiple study sites. Low LD implies the need for denser genotyping arrays than are currently available: a crude estimate is that an African GWA study with 1.5 million SNPs would have approximately the same statistical power as a European study with Jallow et al.Page 2Nat Genet. Author manuscript; available in PMC 2010 September 21. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 0.6 million SNPs5, but this is based on HapMap data from a single ethnic group and a larger number of SNPs may be needed to achieve adequate power across different ethnic groups.We carried out an initial GWA study in Gambian children that explores these methodological questions. Genotyping of ~500,000 SNPs was conducted on 1,060 cases of severe malaria and 1...

School-age children have attracted relatively little attention as a group in need of special measures to protect them against malaria. However, increasing success in lowering the level of malaria transmission in many previously highly endemic areas will result in children acquiring immunity to malaria later in life than has been the case in the past. Thus, it can be anticipated that in the coming years there will be an increase in the incidence of both uncomplicated and severe malaria in school-age children in many previously highly endemic areas. In this review, which focuses primarily on Africa, recent data on the prevalence of malaria parasitaemia and on the incidence of clinical malaria in African school-age children are presented and evidence that malaria adversely effects school performance is reviewed. Long-lasting insecticide treated bednets (LLIN) are an effective method of malaria control but several studies have shown that school-age children use LLINs less frequently than other population groups. Antimalarial drugs are being used in different ways to control malaria in school-age children including screening and treatment and intermittent preventive treatment. Some studies of chemoprevention in school-age children have shown reductions in anaemia and improved school performance but this has not been the case in all trials and more research is needed to identify the situations in which chemoprevention is likely to be most effective and, in these situations, which type of intervention should be used. In the longer term, malaria vaccines may have an important role in protecting this important section of the community from malaria. Regardless of the control approach selected, it is important this is incorporated into the overall programme of measures being undertaken to enhance the health of African school-age children.

No abstract

Primaquine was officially licensed as an anti-malarial drug by the FDA in 1952. It has remained the only FDA licensed drug capable of clearing the intra-hepatic schizonts and hypnozoites of Plasmodium vivax. This update and review focuses on five major aspects of primaquine use in treatment of vivax malaria, namely: a) evidence of efficacy of primaquine for its current indications; b) potential hazards of its widespread use, c) critical analysis of reported resistance against primaquine containing regimens; d) evidence for combining primaquine with artemisinins in areas of chloroquine resistance; and e) the potential for replacement of primaquine with newer drugs.

Tetanus is becoming rarer in both industrialized and developing nations due to an effective vaccination program. In 2010, the World Health Organization estimated there was a 93% reduction in newborns dying from tetanus worldwide, compared to the situation in the late 1980s. Due to its rarity, many diagnostic delays occur as physicians may not consider the diagnosis until the manifestations become overt. Without timely diagnosis and proper treatment, severe tetanus is fatal (mortality is also influenced by the comorbidities of the patient). The principles of treating tetanus are: reducing muscle spasms, rigidity and autonomic instability (with ventilatory support when necessary); neutralization of tetanus toxin with human antitetanus immunoglobulin or equine antitetanus sera; wound debridement; and administration of antibiotics to eradicate locally proliferating bacteria at the wound site. It is difficult to conduct trials on different treatment modalities in tetanus due to both logistical and ethical reasons. However, it is imperative that physicians are aware of the best evidence-based treatment strategies currently available to improve the outcome of patients. This review concentrates on analyzing the current evidence on the pharmacological management of tetanus.

Large-scale studies of genomic variation could assist efforts to eliminate malaria.

Scrub typhus is a zoonosis caused by the pathogen Orientia tsutsugamushi (O. tsutsugamushi). The disease has significant prevalence in eastern and Southeast Asia. Usually presenting as an acute febrile illness, the diagnosis is often missed because of similarities with other tropical febrile infections. Many unusual manifestations are present, and these are described in this review, together with an outline of current knowledge of pathophysiology. Awareness of these unusual clinical manifestations will help the clinician to arrive at an early diagnosis, resulting in early administration of appropriate antibiotics. Prognostic indicators for severe disease have not yet been clearly established.

A double-blind, placebo-controlled trial of nine months duration was carried out to investigate the impact of malaria and its prevention on the educational attainment of school children in a malaria-endemic area in southern Sri Lanka where both Plasmodium falciparum and P. vivax infections are prevalent. A total of 587 children attending grades 1-5 in four schools and resident in the area were randomly allocated to chloroquine (n = 295) and placebo (n = 292) arms. Language and mathematics scores of end-of-term school examinations for 1998 and 1999 and number of days absent and reasons for absenteeism during seven months pre-intervention and nine months of the intervention were recorded. The results indicate that there were no differences in language (95% confidence interval [CI] = 48.44-53.78 in chloroquine group and 50.43-55.81 in placebo group) and mathematics (95% CI = 49.24-54.38 in chloroquine group and 51.12-56.38 in placebo group) scores between the two groups prior to the intervention. During the intervention, the malaria incidence rate decreased by 55% (95% CI = 49-61%) and school absenteeism due to malaria was reduced by 62.5% (95% CI = 57-68%) in children who received chloroquine compared with the placebo group. Post-intervention, children who received chloroquine scored approximately 26% higher in both language (95% CI = 21-31%) and mathematics (95% CI = 23-33%) than children who received placebo. In a multivariate model, educational attainment was significantly associated with taking chloroquine prophylaxis and absenteeism due to malaria (P < 0.001 for both) but not due to health causes other than malaria or non-health causes. Language scores were associated with number of malaria attacks (P < 0.022). Educational attainment was significantly better among children whose compliance to chloroquine prophylaxis was higher (P < 0.001). The data suggest that malarial attacks have an adverse impact on the educational attainment of the school child and prevention of these attacks significantly improves educational attainment of children living in malaria-endemic areas.