Age-related vascular disease accounted for the failure to lower the neurologic complication rate of cerebral angiography despite technical advances.

Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance.

SUMMARY Background Haemoglobinopathies variously reduce the risk of developing malaria syndromes. Quantifying these relationships may strengthen the foundation for translational studies of malaria pathogenesis and immunity. Methods The databases of MEDLINE and Embase (1950 – September 9, 2011) were searched to identify studies that estimated the risk of malaria in patients with and without haemoglobinopathies. Additional studies were identified from reference lists. Included outcomes were Plasmodium falciparum-related outcomes of severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and P. vivax malaria. Two independent reviewers identified studies, assessed their quality, and extracted data; data were meta-analyzed when outcomes were reported in more than one study. Findings Of 62 identified studies, 44 reported on HbAS, 19 on HbAC and HbCC, and 18 on α-thalassaemia. Case-control studies showed a decreased risk of severe malaria for HbAS (summary Odds Ratio [OR] 0.09; 95% confidence interval [CI] 0.06 – 0.12), HbCC (summary OR 0.27; 95% CI 0.11 – 0.63), homozygous α-thalassaemia (summary OR 0.63; 95% CI 0.48 – 0.83), HbAC (summary OR 0.83; 95% CI 0.74 – 0.92), and heterozygous α-thalassaemia (summary OR 0.83; 95% CI 0.74 – 0.92). Only HbAS was consistently associated with protection from uncomplicated malaria (summary Incidence Rate Ratio 0.69; 95% CI 0.61 – 0.79); none demonstrated protection from asymptomatic parasitaemia. There was a paucity of clinical studies investigating β-thalassaemia, HbE, P. vivax malaria, and pregnancy-associated malaria. Interpretation Protection from severe malaria syndromes is significant for HbAS, HbCC, HbAC, and homozygous and heterozygous α-thalassaemia, but these haemoglobinopathies differ substantially in the degrees of protection. Protection from uncomplicated malaria and asymptomatic parasitaemia is mild or absent. By attenuating the severity of malaria, haemoglobinopathies serve as a model for investigating the mechanisms of malaria pathogenesis and immunity.