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Publication Open Access Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia.(2013-01-02) Takala-Harrisona, Shannon; Clark, Taane G.; Cummings, Michael P.; Miotto,Olivo; Dondorp, Arjen M.; Fukudaf, Mark M.; Nosten, Francois; Noedl, Harald; Mallika Imwong; มัลลิกา อิ่มวงศ์; Bethell, Delia; Se, Youry; Lon, Chanthap; Tyner, Stuart D.; Saunders, David L.; Socheat, Duong; Ariey, Frederic; Phyo, Aung Pyae; Starzengruber, Peter; Fuehrer, Hans-Peter; Swoboda, Paul; Stepniewska, Kasia; Flegg, Jennifer; Arze, Cesar; Cerqueira, Gustavo C.; Silva, Joana C.; Ricklefs, Stacy M.; Porcella, Stephen F.; Stephens, Robert M.; Adams, Matthew; Kenefic, Leo J.; Campino, Susana; Auburn, Sarah; MacInnis, Bronwyn; Kwiatkowski, Dominic P.; Su, Xin-zhuan; White, Nicholas J.; Ringwald, Pascal; Plowe, Christopher V.; Plowe, Christopher V.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Research Unit.; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics.; Mahidol University. Faculty of Tropical Medicine. Shoklo Malaria Research Unit.The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.Publication Open Access Plasmodium falciparum Kelch 13 mutations and treatment response in patients in Hpa-Pun District, Northern Kayin State, Myanmar.(2017) Bonnington, Craig A.; Aung Pyae Phyo; Ashley, Elizabeth A.; Mallika Imwong; Kanlaya Sriprawat; Parker, Daniel M.; Proux, Stephane; White, Nicholas J.; Nosten, Francois; Mahidol University. Faculty of Tropical Medicine. Shoklo Malaria Research Unit; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unit; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and GeneticsBackground: Artemisinin resistance, linked to polymorphisms in the Kelch gene on chromosome 13 of Plasmodium falciparum (k13), has outpaced containment eforts in South East Asia. For national malaria control programmes in the region, it is important to establish a surveillance system which includes monitoring for k13 polymorphisms associated with the clinical phenotype. Methods: Between February and December 2013, parasite clearance was assessed in 35 patients with uncomplicated P. falciparum treated with artesunate monotherapy followed by 3-day ACT in an isolated area on the Myanmar– Thai border with relatively low artemisinin drug pressure. Molecular testing for k13 mutations was performed on dry blood spots collected on admission. Results: The proportion of k13 mutations in these patients was 41.7%, and only 5 alleles were detected: C580Y, I205T, M476I, R561H, and F446I. Of these, F446I was the most common, and was associated with a longer parasite clearance half-life (median) 4.1 (min–max 2.3–6.7) hours compared to 2.5 (min–max 1.6–8.7) in wildtype (p = 0·01). The prevalence of k13 mutant parasites was much lower than the proportion of k13 mutants detected 200 km south in a much less remote setting where the prevalence of k13 mutants was 84% with 15 distinct alleles in 2013 of which C580Y predominated. Conclusions: This study provides evidence of artemisinin resistance in a remote part of eastern Myanmar. The prevalence of k13 mutations as well as allele diversity varies considerably across short distances, presumably because of historical patterns of artemisinin use and population movements.Publication Open Access Population genetic analysis of Plasmodium falciparum parasites using a customized Illumina GoldenGate genotyping assay.(2011) Campino, Susana; Auburn, Sarah; Kivinen, Katja; Zongo, Issaka; Ouedraogo, Jean-Bosco; Mangano, Valentina; Djimde, Abdoulaye; Doumbo, Ogobara K.; Kiara, Steven M.; Nzila, Alexis; Borrmann, Steffen; Marsh, Kevin; Michon, Pascal; Mueller, Ivo; Siba, Peter; Jiang, Hongying; Su, Xin-Zhuan; Chanaki Amaratunga; Socheat, Duong; Fairhurst, Rick M.; Mallika Imwong; มัลลิกา อิ่มวงศ์; Anderson, Timothy; Nosten, Francois; White, Nicholas J.; Gwilliam, Rhian; Deloukas, Panos; MacInnis, Bronwyn; Newbold, Christopher I.; Rockett, Kirk; Clark, Taane G.; Kwiatkowski, Dominic P.; Campino, Susana; Fitzgerald, J. Ross; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford University Research Unit.; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine.; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics.The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum.Publication Open Access Improved pregnancy outcome in refugees and migrants despite low literacy on the Thai-Burmese border: results of three cross-sectional surveys(2011-06-17) Carrara, Verena I.; Hogan, Celia; De Pree, Cecilia; Nosten, Francois; McGready, Rose; Carrara, Verena I.; Mahidol University. Faculty of Tropical MedicineBACKGROUND: Maternal and infant health has been associated with maternal education level, which is highly associated with literacy. We aimed at estimating literacy rates among reproductive age women attending antenatal clinics in camps for refugees and in migrant clinics in Tak province, north-western Thailand, to determine whether illiteracy had an impact on birth outcomes. METHODS: Three reading assessments were conducted using an identical method each time, in 1995-97, 2003 and 2008. Midwives chose at random one of four pre-set sentences. Each woman was asked to read aloud and scoring was based on a "pass/fail" system. Pregnancy outcomes were compared with maternal literacy rate. RESULTS: Overall, 47% (1149/2424) of women were able to read. A significant improvement was observed among migrant (34% in 2003 vs. 46% in 2008, p = 0.01), but not refugee (47% in 1995-97, 49% in 2003, and 51% in 2008) women. Literate women were significantly more likely to be of non-Karen ethnicity, primigravidae, non-smokers, to remain free from malaria during pregnancy and to deliver in a health clinic. Significant improvements in pregnancy outcome (reductions in premature births, low birth weight newborns and neonatal death) between 1995-97 and 2003 were unrelated to literacy. CONCLUSIONS: Significant reductions in poor pregnancy outcome over time have not been driven by changes in literacy rates, which have remained low. Access to early diagnosis and treatment of malaria in this population, and delivery with skilled birth attendants, despite ongoing low literacy, appears to have played a significant role.Publication Open Access A morphometric and histological study of placental malaria shows significant changes to villous architecture in both Plasmodium falciparum and Plasmodium vivax infection(2014-01-04) Sethawud Chaikitgosiyakul; เสฏฐวุฒิ ชัยกิตโกสิยกุล; Rijken, Marcus J.; Muehlenbachs, Atis; Lee, Sue J.; Urai Chaisri; อุไร ไชยศรี; Parnpen Viriyavejakul; พรรณเพ็ญ วิริยเวชกุล; Turner, Gareth D.; Emsri Pongponratn; เอี่ยมศรี พงศ์พนรัตน์; Nosten, Francois; McGready, Rose; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Research Unit; Mahidol University. Faculty of Tropical Medicine. Department of Tropical PathologyBACKGROUND: Malaria in pregnancy remains a major health problem. Placental malaria infection may cause pathophysiological changes in pregnancy and result in morphological changes to placental villi. Quantitative histomorphological image analysis of placental biopsies was performed to compare placental villous architecture between active or treated placental malaria cases and controls. METHODS: A total of 67 placentas were studied from three clinical groups: control patients who did not have malaria (n = 27), active (n = 14) and treated (n=26) malaria cases, including both Plasmodium falciparum and Plasmodium vivax infections. Image analysis of histological placental sections was performed using ImageJ software to measure the number and size (area) of terminal villi, perimeter measurement per villus and total perimeter per unit area, and number of capillaries per villus (vascularity). Histological features of placental malaria were scored and these results were correlated with malaria status and clinical outcomes. RESULTS: Villous size correlated with vascularity (p <0.0001) but was inversely correlated with observed villi per unit area, (p = 0.0001). Significantly greater villous area and vascularity was observed in UK controls. Indices of histological malaria infection were significantly greater in active versus treated malaria cases. Active placental malaria cases showed significantly smaller villous area (p <0.0084), vascularity (p <0.0139) and perimeter (p <0.0006) than treated malaria cases or controls, but significantly more villi per unit area (p <0.0001). Villous size in treated malaria cases was significantly larger than active placental malaria cases (p <0.001) and similar to controls. There was a significant relationship between villous number and anaemia at the time of infection (p <0.0034), but not placental weight, birth weight or gestational age at delivery. No differences were found between histology or villous morphology comparing infections with P. falciparum or P. vivax. CONCLUSIONS: These results imply that villous size, perimeter and vascularity are acutely decreased during active placental malaria, decreasing the surface area available for gas exchange per villus. However the increased number of villi per unit area offsets this change and persists after treatment. Histopathological and villous architectural changes may be reversed by early detection and appropriate anti-malarial treatment.