Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 – 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36–17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

No abstract

Summaryobjectives In December 2005 and March 2006, Niger conducted nationwide integrated campaigns to distribute polio vaccine and long lasting insecticide-treated nets (LLINs) to children <5 years of age. We evaluated the campaign effectiveness, net retention, insecticide-treated net (ITN) ownership, and usage.methods Two nationwide cross-sectional surveys in January 2006 (dry season) and September 2006 (rainy season), using a stratified two-stage cluster sampling design. We mapped selected communities, selected households by simple random sampling, and administered questionnaires by interviewers using personal digital assistants.results The first survey showed that ITN ownership in all households was 6.3% prior to the campaign, increasing to 65.1% after the campaign in the second survey. The second survey also showed that 73.4% of households with children <5 received an LLIN and that 97.7% of households that received ‡ one LLIN retained it. The wealth equity ratio for ITN ownership in households with children <5 increased from 0.17 prior to the campaign to 0.79 afterward. During the dry season, 15.4% of all children <5 and 11.3% of pregnant women slept under an ITN, while during rainy season, 55.5% of children <5 and 48.2% of pregnant women slept under an ITN.conclusions Free distribution during the integrated campaign rapidly increased ITN ownership and decreased inequities between those in the highest and lowest wealth quintiles. Retention of ITNs was very high, and usage was high during malaria transmission season. However, ITN ownership and usage by vulnerable groups continues to fall short of RBM targets, and additional strategies are needed to increase ownership and usage.

Dyspnea in patients could arise from both an urge to breathe and increased effort of breathing. Two qualitatively different sensations, "air hunger" and "respiratory work and effort," arising from different afferent sources are hypothesized. In the laboratory, breathing below the spontaneous level may produce an uncomfortable sensation of air hunger, and breathing above it a sensation of work or effort. Measurement of a single sensory dimension cannot distinguish these as separate sensations; we therefore measured two sensory dimensions and attempted to vary them independently. In five normal subjects we obtained simultaneous ratings of air hunger and of work and effort while independently varying PCO(2) or the level of targeted voluntary breathing. We found a difference in response to the two stimulus dimensions: air hunger ratings changed more steeply when PCO(2) was altered and ventilation was constant; work or effort ratings changed more steeply when ventilation was altered and PCO(2) was constant. We conclude that "air hunger" is qualitatively different from "work and effort" and arises from different afferent sources.