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Publication Open Access The epidemiology of subclinical malaria infections in South‑East Asia: findings from cross‑sectional surveys in Thailand– Myanmar border areas, Cambodia, and Vietnam(2015) Mallika Imwong; Nguyen, Thuy Nhien; Rupam Tripura; Peto, Tom J.; Lee, Sue J.; Lwin, Khin Maung; Preyanan Suangkanarat; Atthanee Jeeyapant; Benchawan Vihokhern; Klanarong Wongsaen; Hue, Dao Van; Dong, Le Thanh; Nguyen, Tam‑Uyen; Yoel Lubell; Seidlein, Lorenz von; Mehul Dhorda; Cholrawee Promnarate; Georges Snounou; Benoit Malleret; Laurent Rénia; Lilly Keereecharoen; Pratap Singhasivanon; Pasathorn Sirithiranont; Jem Chalk; Chea Nguon; Hien, Tran Tinh; Nicholas Day; White, Nicholas J.; Arjen Dondorp; Francois Nosten; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unitmultivariate regression model stratified by site. Conclusion: Light microscopy and RDTs identified only a quarter of all parasitaemic participants. The asymptomatic Plasmodium reservoir is considerable, even in low transmission settings. Novel strategiesPublication Open Access Persistent Plasmodium falciparum and Plasmodium vivax infections in a western Cambodian population: implications for prevention, treatment and elimination strategies(2016) Rupam Tripura; Peto, Thomas J.; Jeremy Chalk; Lee, Sue J.; Pasathorn Sirithiranont; Chea Nguon; Mehul Dhorda; Seidlein, Lorenz von; Maude, Richard J.; Day, Nicholas P. J.; Mallika Imwong; White, Nicholas J.; Dondorp, Arjen M.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research UnitBackground: Subclinical Plasmodium parasitaemia is an important reservoir for the transmission and persistence of malaria, particularly in low transmission areas. Methods: Using ultrasensitive quantitative PCR (uPCR) for the detection of parasitaemia, the entire population of three Cambodian villages in Pailin province were followed for 1 year at three-monthly intervals. A cohort of adult participants found initially to have asymptomatic malaria parasitaemia was followed monthly over the same period. Results: The initial cross sectional survey in June 2013 (M0) of 1447 asymptomatic residents found that 32 (2.2 %) had Plasmodium falciparum, 48 (3.3 %) had P. vivax, 4 (0.3 %) had mixed infections and in 142/1447 (9.8 %) malaria was detected but there was insufficient DNA to identify the species (Plasmodium. species). Polymorphisms in the ‘K13-propeller’ associated with reduced susceptibility to artemisinin derivatives (C580Y) were found in 17/32 (51 %) P. falciparum strains. Monthly follow-up without treatment of 24 adult participants with asymptomatic mono or mixed P. falciparum infections found that 3/24 (13 %) remained parasitaemic for 2–4 months, whereas the remaining 21/24 (87 %) participants had cleared their parasitaemia after 1 month. In contrast, 12/34 (35 %) adult participants with P. vivax mono-infection at M0 had malaria parasites (P. vivax or P. sp.) during four or more of the following 11 monthly surveys. Conclusions: This longitudinal survey in a low transmission setting shows limited duration of P. falciparum carriage, but prolonged carriage of P. vivax infections. Radical treatment of P. vivax infections by 8-aminoquinoline regimens may be required to eliminate all malaria from Cambodia. Trial registration ClinicalTrials.gov NCT01872702Publication Open Access Comparative genome‑wide analysis and evolutionary history of haemoglobin‑processing and haem detoxification enzymes in malarial parasites(2016) Patrath Ponsuwanna; Theerarat Kochakarn; Duangkamon Bunditvorapoom; Krittikorn Kümpornsin; Otto, Thomas D.; Chase Ridenour; Kesinee Chotivanich; Prapon Wilairat; White, Nicholas J.; Olivo Miotto; Thanat Chookajorn; Mahidol University. Faculty of Tropical Medicine. Genomic and Evolutionary Medicine Unit, Centre of Excellence in MalariaBackground: Malaria parasites have evolved a series of intricate mechanisms to survive and propagate within host red blood cells. Intra-erythrocytic parasitism requires these organisms to digest haemoglobin and detoxify ironbound haem. These tasks are executed by haemoglobin-specific proteases and haem biocrystallization factors that are components of a large multi-subunit complex. Since haemoglobin processing machineries are functionally and genetically linked to the modes of action and resistance mechanisms of several anti-malarial drugs, an understanding of their evolutionary history is important for drug development and drug resistance prevention. Methods: Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within Plasmodium species, and with the representatives of Apicomplexan species with various host tropisms, were created. Genetic variants were mapped onto existing three-dimensional structures. Genome-wide single nucleotide polymorphism data were used to analyse the selective pressure and the effect of these mutations at the structural level. Results: Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites especially in the Plasmodium falciparum and P. reichenowi lineage. Expansion of haemoglobin-specific plasmepsins occurred after the separation event of Plasmodium species, but the other members of the plasmepsin family were evolutionarily conserved with one copy for each sub-group in every Apicomplexan species. Haemoglobin-specific falcipains are separated from invasion-related falcipain, and their expansions within one specific locus arose independently in both P. falciparum and P. vivax lineages. Gene conversion between P. falciparum falcipain 2A and 2B was observed in artemisinin-resistant strains. Comparison between the numbers of non-synonymous and synonymous mutations suggests a strong selective pressure at falcipain and plasmepsin genes. The locations of amino acid changes from non-synonymous mutations mapped onto protein structures revealed clusters of amino acid residues in close proximity or near the active sites of proteases. Conclusion: A high degree of polymorphism at the haemoglobin processing genes implicates an imposition of selective pressure. The identification in recent years of functional redundancy of haemoglobin-specific proteases makes them less appealing as potential drug targets, but their expansions, especially in the human malaria parasite lineages, unequivocally point toward their functional significance during the independent and repetitive adaptation events in malaria parasite evolutionary history.Publication Open Access Spatio-temporal patterns of malaria infection in Bhutan: a country embarking on malaria elimination(2011-04-16) Wangdi, Kinley; Jaranit Kaewkungwal; จรณิต แก้วกังวาล; Pratap Singhasivanon; ประตาป สิงหศิวานนท์; Tassanee Silawan; Saranath Lawpoolsri; สารนาถ ล้อพูลศรี; White, Nicholas J.; Wangdi, Kinley; Mahidol University. Faculty of Tropical Medicine. Department of Tropical Hygiene.BACKGROUND: At the verge of elimination of malaria in Bhutan, this study was carried out to analyse the trend of malaria in the endemic districts of Bhutan and to identify malaria clusters at the sub-districts. The findings would aid in implementing the control activities. Poisson regression was performed to study the trend of malaria incidences at district level from 1994 to 2008. Spatial Empirical Bayesian smoothing was deployed to identify clusters of malaria at the sub-district level from 2004 to 2008. RESULTS: Trend of the overall districts and most of the endemic districts have decreased except Pemagatshel, which has an increase in the trend. Spatial cluster-outlier analysis showed that malaria clusters were mostly concentrated in the central and eastern Bhutan in three districts of Dagana, Samdrup Jongkhar and Sarpang. The disease clusters were reported throughout the year. Clusters extended to the non-transmission areas in the eastern Bhutan. CONCLUSIONS: There is significant decrease in the trend of malaria with the elimination at the sight. The decrease in the trend can be attributed to the success of the control and preventive measures. In order to realize the target of elimination of malaria, the control measure needs to be prioritized in these high-risk clusters of malaria.Publication Open Access Protein-based signatures of functional evolution in Plasmodium falciparum(2011-09-14) Gardner, Kate B.; Sinha, Ipsita; Bustamante, Leyla Y.; Day, Nicholas P.J.; White, Nicholas J.; Woodrow, Charles J.; Woodrow, Charles J.; Mahidol University. Faculty of Tropical Medicine. Wellcome Trust Mahidol University-Oxford Tropical Medicine Research Unit (MORU).possessed high levels of hydrophilicity, a marker of non-globularity. The propensity for such regions to act as potent sources of non-synonymous genetic drift within extant P. falciparum isolates was confirmed at chromosomal regions containing genes knownPublication 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 Geographic distribution of amino acid mutations in DHFR and DHPS in Plasmodium vivax isolates from Lao PDR, India and Colombia(2016) Naowarat Saralamba; Supatchara Nakeesathit; Mayfong Mayxay; Newton, Paul N.; Lyda Osorio; Kim, Jung‑Ryong; White, Nicholas J.; Day, Nicholas P. J.; Dondorp, Arjen M.; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and GeneticsBackground: Non-synonymous mutations in dhfr and dhps genes in Plasmodium vivax are associated with sulfadoxine– pyrimethamine (SP) resistance. The present study aimed to assess the prevalence of point mutations in P. vivax dhfr (pvdhfr) and P. vivax dhps (pvdhps) genes in three countries: Lao PDR, India and Colombia. Methods: Samples from 203 microscopically diagnosed vivax malaria were collected from the three countries. Five codons at positions 13, 57, 58, 61, and 117 of pvdhfr and two codons at positions 383 and 553 of pvdhps were examined by polymerase chain reaction-restriction fragment length polymorphism methodology. Results: The largest number of 58R/117 N double mutations in pvdhfr was observed in Colombia (94.3 %), while the corresponding wild-type amino acids were found at high frequencies in Lao PDR during 2001–2004 (57.8 %). Size polymorphism analysis of the tandem repeats within pvdhfr revealed that 74.3 % of all the isolates carried the type B variant. Eighty-nine per cent of all the isolates examined carried wild-type pvdhps A383 and A553. Conclusions: Although SP is not generally used to treat P. vivax infections, mutations in dhfr and dhps that confer antifolate resistance in P. vivax are common. The data strongly suggest that, when used primarily to treat falciparum malaria, SP can exert a substantial selective pressure on P. vivax populations, and this can lead to point mutations in dhfr and dhps. Accurate data on the global geographic distribution of dhfr and dhps genotypes should help to inform anti-malarial drug-use policies.Publication Open Access Modelling malaria elimination on the internet(2011-07-14) Maude, Richard J.; Sompob Saralamba; สมภพ ศรลัมพ์; Lewis, Adrian; Sherwood, Dean; White, Nicholas J.; Day, Nicholas P.J.; Dondorp, Arjen M.; White, Lisa J.; Maude, Richard J.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research UnitBACKGROUND: Unprecedented efforts are underway to eliminate malaria. Mathematical modelling can help to determine the optimal strategies for malaria elimination in different epidemiological settings. This is necessary as there is limited scope for expensive and time-consuming field studies and failure of planned elimination strategies is likely to discourage ongoing investment by funders. However, there has been very little modelling of malaria elimination and little direct involvement of policymakers in its development. There is thus an urgent need for user-friendly and accessible models purpose-designed in collaboration with policymakers to answer pertinent questions arising from the field. RESULTS: An internet site is presented with a simple mathematical modelling platform for population level models of malaria elimination. It is freely accessible to all and designed to be flexible so both the platform and models can be developed through interaction with users. The site is an accessible introduction to modelling for a non-mathematical audience, and lessons learned from the project will help inform future development of mathematical models and improve communication of modelling results. Currently it hosts a simple model of strategies for malaria elimination and this will be developed, and more models added, over time. The iterative process of feedback and development will result in an educational and planning tool for non-modellers to assist with malaria elimination efforts worldwide. CONCLUSIONS: By collaboration with end users, iterative development of mathematical models of malaria elimination through this internet platform will maximize its potential as an educational and public health policy planning tool. It will also assist with preliminary optimisation of local malaria elimination strategies before commitment of valuable resources.Publication Open Access A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan(2014-02-21) Natsuda Jamornthanyawat; นาถสุดา จามรธัญญวาท; Awab, Ghulam R.; Naowarat Tanomsing; เนาวรัตน์ ถนอมสิงห์; Sasithon Pukrittayakamee; ศศิธร ผู้กฤตยาคามี; Yamin, Fazel; Dondorp, Arjen M.; Day, Nicholas P. J.; White, Nicholas J.; Woodrow, Charles J.; Mallika Imwong; มัลลิกา อิ่มวงศ์; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit (MORU); Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and GeneticsGlucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzyme defect and an important problem in areas with Plasmodium vivax infection because of the risk of haemolysis following administration of primaquine to treat the liver forms of the parasite. We undertook a genotypic survey of 713 male individuals across nine provinces of Afghanistan in which malaria is found, four in the north and five in the east. RFLP typing at nucleotide position 563 detected 40 individuals with the Mediterranean mutation 563C>T, an overall prevalence of 5.6%. This varied according to self-reported ethnicity, with prevalence in the Pashtun/Pashai group of 33/369 (8.9%) compared to 7/344 individuals in the rest of the population (2.0%; p<0.001, Chi-squared test). Multivariate analysis of ethnicity and geographical location indicated an adjusted odds ratio of 3.50 (95% CI 1.36-9.02) for the Pashtun/Pashai group, while location showed only a trend towards higher prevalence in eastern provinces (adjusted odds ratio = 1.73, 0.73-4.13). Testing of known polymorphic markers (1311C>T in exon 11, and C93T in intron XI) in a subset of 82 individuals wild-type at C563 revealed a mixture of 3 haplotypes in the background population and was consistent with data from the 1000 Genomes Project and published studies. By comparison individuals with G6PD deficiency showed a highly skewed haplotype distribution, with 95% showing the CT haplotype, a finding consistent with relatively recent appearance and positive selection of the Mediterranean variant in Afghanistan. Overall, the data confirm that the Mediterranean variant of G6PD is common in many ethnic groups in Afghanistan, indicating that screening for G6PD deficiency is required in all individuals before radical treatment of P. vivax with primaquine.Publication Open Access Motivations and perceptions of community advisory boards in the ethics of medical research: the case of the Thai-Myanmar border.(2014-02-17) Maung, Lwin K.; Cheah, Phaik Yeong; Cheah, Phaik Kin; White, Nicholas J.; Day, Nicholas P.; Nosten, Francois; Parker, Michael; Parker, Michael; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unit.BACKGROUND: Community engagement is increasingly promoted as a marker of good, ethical practice in the context of international collaborative research in low-income countries. There is, however, no widely agreed definition of community engagement or of approaches adopted. Justifications given for its use also vary. Community engagement is, for example, variously seen to be of value in: the development of more effective and appropriate consent processes; improved understanding of the aims and forms of research; higher recruitment rates; the identification of important ethical issues; the building of better relationships between the community and researchers; the obtaining of community permission to approach potential research participants; and, the provision of better health care. Despite these diverse and potentially competing claims made for the importance of community engagement, there is very little published evidence on effective models of engagement or their evaluation. METHODS: In this paper, drawing upon interviews with the members of a Community Advisory Board on the Thai-Myanmar border, we describe and critically reflect upon an approach to community engagement which was developed in the context of international collaborative research in the border region. RESULTS AND CONCLUSIONS: Drawing on our analysis, we identify a number of considerations relevant to the development of an approach to evaluating community engagement in this complex research setting. The paper also identifies a range of important ways in which the Community Advisory Board is in practice understood by its members (and perhaps by community members beyond this) to have morally significant roles and responsibilities beyond those usually associated with the successful and appropriate conduct of research.