BACKGROUND Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing in fections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the “propeller” region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)

Influence of the dry period on mammary growth was studied using multiparous Holstein cows. Sixty days before expected parturition, 13 cows were dried off, and another 13 cows were milked throughout the prepartum period. Lactating cows and dry cows were slaughtered at 53, 35, 20, and 7 d prepartum. Total mammary parenchymal DNA increased twofold from 53 to 7 d prepartum without influence of lactation status. However, overall rate of [3H]thymidine incorporation by mammary tissue was 80% greater in dry cows than in lactating cows, indicating that replacement of mammary cells was greater in dry cows. Of the mammary cells labeled with [3H]thymidine, the percentage of epithelial cells in dry cows was greater than that in lactating cows (96% vs. 86%). By 7 d prepartum, epithelial calls accounted for a greater percentage of total mammary cells in dry cows than in lactating cows (83% vs. 74%). Tissue area occupied by alveolar or ductular lumina decreased by 25 d into the dry period (35 d prepartum) and then increased to a maximum by 7 d prepartum. None of the mammary epithelial cells in dry cows were classified as secretory at 35 d prepartum, but 98% of the epithelial cells of dry cows were classified as secretory at 7 d prepartum. Results indicated that mammary involution did not occur during a typical dry period of dairy cows. Data suggest that a dry period is important for replacing senescent mammary epithelial cells and increasing the epithelial component of the gland prior to the next lactation.

Penicillium chrysogenum strain P1 was grown on complex media in 10 and 100 L agitated fermenters at various aeration rates and stirrer speeds. Samples were removed at intervals for measurements of the culture morphology. At high stirrer speeds (1000 and 1200 rpm) in 10-L fermentations the rate of decrease in the mean effective hyphal length was faster and the rate of penicillin production was lower than fermentations done at 800 rpm. At similar power inputs per unit volume in 100-L fermentations, the change in mean effective hyphal length was less and higher penicillin production rates were observed. This work comparing the results at two scales has shown that neither of the concepts of impeller tip speed or the dissipation rate of turbulence have general validity as a measure of hyphal damage. Our results are reasonaby well correlated by groups similar to circulation rate (ND(i) (3)/V) with lower circulation rates being beneficial. An adaptation of the van Suijdam and Metz relationship, expressed as P/D(i) (3)t(c), was most successful. Our data are insufficient to demonstrate the generality of the relationship but do support the concept of a dispersion zone around the impellers in which mycelia may be damaged. The greater the frequency of circulation of mycelia through the zone the greater the damage and the lower the rate of penicillin synthesis by the culture.