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2. Liposomal Amphotericin B and Flucytosine Antifungal Strategy for Talaromycosis (LAmB-FAST) (LAmB-FAST)

Author

National Institute of Allergy and Infectious Diseases (NIAID), Pham Ngoc Thach University of Medicine, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, National Hospital for Tropical Diseases, Hanoi, Vietnam, Bach Mai Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand., Maharat Nakhon Ratchasima Hospital, Chiang Mai University, Guangzhou 8th People's Hospital, Shenzhen Third People's Hospital, Gilead Sciences, and Viatris Inc.

Published
2024

4. ChulaCov19 Vaccine in Healthy Adults

Author

Chula Vaccine Research Center (ChulaVRC), Bangkok, Thailand, Center of Excellence in Vaccine Research and Development, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, Chula Clinical Research Center (Chula CRC), King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, King Chulalongkorn Memorial Hospital (KCMH), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, Center of Excellence for Vaccine Trial (Vaccine Trial Centre), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and National Vaccine Institute, Thailand

Published
2023

5. Stress Echo 2030: the Novel ABCDE-(FGLPR) Protocol to Define the Future of Imaging (SE2030)

Author

National Research Council, Institute of Clinical Physiology, Italy, Mayo Clinic, Hospital Sao Vicente de Paulo e Hospital de Cidade, Passo Fundo, Brasil, Cardarelli Hospital, Naples, Italy, Ospedale per gli Infermi, Faenza, Ravenna, Italy, Institute of Family Medicine, University of Szeged, Hungary, Montepulciano Hospital, Siena, University of Pisa, University Hospital, Pleven, Bulgaria, Tomsk National Research Medical Centre of the Russian, University Hospital, Szeged, Hungary, Elisabeth Hospital, Hódmezővásárhely, Hungary, DASA, San Paolo, Brasil, University of Banja Luka University Clinical Centre of the Republic of Srpska, University of A Coruna, La Coruna, Spain, Antwerp University Hospital, Edegem, Belgium, Università Luigi Vanvitelli della Campania, Dolo Hospital, Venice, Italy, Institute for Cardiovascular Diseases Dedinje, School of Medicine, Belgrade, Serbia, Investigaciones Medicas, Bieganski Hospital, Medical University, Lodz, Poland, Medical University of Silesia, Katowice, Poland, Federal University of Paranà, Curitiba, Brasil, Siriraj Hospital, Mahidol University, Bangkok, Thailand., Careggi Hospital, Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico, Saint Petersburg State University Hospital, Russian Federation, Clinical Hospital Zvezdara, Medical School, University of Belgrade, Serbia, University Center Serbia, Medical School, University of Belgrade, Serbia, University Hospital, Padua, Italy, Sant'Anna School of Advanced Study, Pisa, University Hospital, Siena, Italy, Vilnius University, Lithuania, University of Parma, Universita di Verona, Malpighi Hospital, Bologna, Italy, University of Modena and Reggio Emilia, Presidio Ospedale San Paolo. Milano, IRCCS reggio emilia, Association for Public Health 'Salute Pubblica', Brindisi, Italy, University Hospital, Catania, Ospedale San Camillo, Rome, Italy, University of Salerno, University of Algarve, Portugal., Heart Center, Hospital da Cruz Vermelha, Lisbon, University of Bari, Hospital Motta di Livenza, Treviso, Centro Cardiologico Monzino, Italian Society of Echocardiography and Cardiovascular Imaging, San Luca Hospital, Lucca, and Hospital Sao José, Criciuma, Brasil

Published
2021

6. Resource Sparing Curative Radiotherapy for Locally Advanced Squamous Cell Cancer of the Head and Neck: The HYPNO Trial (HYPNO)

Author

Centro de Lucha contra el Cáncer, Montevideo, Uruguay, Institute Rotary Cancer Hospital, New Delhi, India, Tata Memorial Centre, Bahawalpur Institute of Nuclear Medicine and Oncology, Bahawalpur, Pakistan, GKNM Hospital, Tamil Nadu, India, Fundacion Escuela de Medicina Nuclear, Mendoza, Argentina, Instituto de Oncología y Radiobiología, Havana, Cuba, University of Indonesia, Jakarta, Indonesia, St Luke's Medical Centre, Quezon City, Manilla, Phillippines, University of Pretoria, Pretoria, South Africa, Mahidol University, Bangkok, Thailand, University of Maryland, College Park, and Barretos Cancer Hospital, Barretos, Brazil

Published
2019

7. Non-communicable disease outcomes among adults living with HIV in Asia

Author

Law, Matthew, Kirby Institute, Faculty of Medicine, UNSW, Jiamsakul, Awachana, Kirby Institute, Faculty of Medicine, UNSW, Kumaraswamy, Nagalingeswaran, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), VHS-Infectious Diseases Medical Centre, VHS, Chennai, India, Kiertiburanakul, Sasisopin, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Bijker, Rimke, Kirby Institute, Faculty of Medicine, UNSW, Law, Matthew, Kirby Institute, Faculty of Medicine, UNSW, Jiamsakul, Awachana, Kirby Institute, Faculty of Medicine, UNSW, Kumaraswamy, Nagalingeswaran, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), VHS-Infectious Diseases Medical Centre, VHS, Chennai, India, Kiertiburanakul, Sasisopin, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and Bijker, Rimke, Kirby Institute, Faculty of Medicine, UNSW

Abstract

The introduction of effective antiretroviral therapy (ART) has dramatically increased life expectancy of people living with HIV (PLHIV). However, due to lifestyle factors, side effects of ART, ongoing inflammation and immune activation, and ageing, non-communicable diseases (NCDs) are becoming more apparent in this population. This will prove challenging in some countries in the Asian region, where health systems are already strained by a high HIV burden and limited resources are available to provide optimal care for all PLHIV. The aim of this thesis was to investigate NCDs – primarily cardiovascular disease (CVD), diabetes and kidney disease – and related outcomes in PLHIV in the Asian region. All analyses were based on routinely collected data from the TREAT Asia cohorts, two large adult observational cohorts of PLHIV in 12 countries across the Asia-Pacific region. Similar to what is happening at the global level, ART uptake across this region has increased over time. Among those on ART in the TREAT Asia cohorts, there was a considerable burden of comorbid CVD, diabetes and kidney disease. Risk factors for CVD were primarily of modifiable nature, such as hypertension, unfavourable lipid levels and overweight. It was estimated that the CVD incidence might double in the next decade, although this could be largely addressed by implementing interventions that target CVD risk factors. Diabetes and prediabetes were strongly associated with mortality. When assessing risk factors of mortality after long-term exposure to ART, the findings showed that diabetes, kidney disease, and hepatitis were associated with increased mortality, while treatment continuity remained important to improve survival. Overall, the findings indicate that there was suboptimal monitoring for NCDs in the TREAT Asia cohorts.With the growing population of PLHIV who are on life-long ART, there is an urgent need for integrated NCD and HIV care. Timely interventions are key to reducing the unnecessary m

Published
2020

8. Artemia salina Lethality and Histopathological Studies of Siam Weed, Chromolaena odorata

Author

Sirinthipaporn, Anushika; Mahidol University International College, Mahidol University, Salaya Campus, Nakhon Pathom 73170, Jiraungkoorskul, Kanitta; Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Jiraungkoorskul, Wannee; Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Sirinthipaporn, Anushika; Mahidol University International College, Mahidol University, Salaya Campus, Nakhon Pathom 73170, Jiraungkoorskul, Kanitta; Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, and Jiraungkoorskul, Wannee; Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400

Abstract

Siam weed, Chromolaena odorata, leaves, stem, and root were extracted with aqueous and ethanol solvents within 1, 3, 5 and 24 hours. The extractions were determined amount of total phenolic compound using Folin-Ciocalteu reagent. The extract that showed the highest amount of total phenolic compound was used for evaluating the cytotoxicity test against Artemia salina at varying concentrations as 0, 50, 500, 5,000 and 50,000 ppm. The cytotoxicity data were determined the median and 90% lethal concentration, LC50 and LC90, respectively, within 24 hours. The result revealed that the highest amount of total phenolic compound was 198.02+3.96 mg of gallic acid equivalent per gram of aqueous leaf extraction in 24 h. Therefore, the 24-hour aqueous extract of C. odorata leaf expressed the 24-h LC50 and LC90 values in A. salina were 43, 551 and 78,391 ppm, respectively. The lesions were observed in intestinal parts such as edema, deformation or elongation of the enterocytes, blebbing cells, and pyknotic cells.

Published
2017

9. HIV Drug Resistance and Adherence to Antiretroviral Therapy in Asia

Author

Law, Matthew, Kirby Institute, Faculty of Medicine, UNSW, Kerr, Stephen, HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand, Sungkanuparp, Somnuek, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Jiamsakul, Awachana, Kirby Institute, Faculty of Medicine, UNSW, Law, Matthew, Kirby Institute, Faculty of Medicine, UNSW, Kerr, Stephen, HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand, Sungkanuparp, Somnuek, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and Jiamsakul, Awachana, Kirby Institute, Faculty of Medicine, UNSW

Abstract

The expansion of combination antiretroviral therapy (cART) in resource-limited settings has led to improved survival but also the emergence of HIV drug resistance associated mutations (RAMs). As treatment strategies lean towards earlier cART initiation, it is expected that an increasing number of HIV-infected individuals will be exposed to cART for longer, potentially leading to higher prevalence of RAMs in both treatment naive, through transmitted RAMs, and treatment experienced individuals. This thesis aims to evaluate RAMs in recently infected individuals and those who have failed first-line cART in Asia. Additionally, adherence to cART, an important predictor of RAMs, was also investigated.Analysis datasets were obtained from the TREAT Asia HIV databases. Firstly, the applications of different types of resistance interpretation systems on HIV-1 CRF01_AE were compared. Proportions of RAMs in recently-infected and treatment experienced individuals were then analysed, and the corresponding second-line virological outcome adjusting for adherence and genotypic susceptibility score were determined. Levels of suboptimal adherence utilising the self-reported questionnaire were evaluated. Additionally, the effects of unplanned treatment interruptions on treatment outcomes after cART resumption were investigated. Although developed from subtype B, genotypic and virtual phenotypic resistance interpretation systems proved to be reliable in their predicted resistance calls for non-B subtypes, particularly CRF01_AE. RAMs in recently infected individuals were below 15%, however, multi-drug RAMs found in patients failing first-line cART existed in a high proportion but were not associated with second-line virological suppression. Adherence was the only factor showing a significant association, conferring the importance of high-level adherence beyond first-line therapy. Sites that assessed adherence more frequently, and longer time on cART, were associated with better adherence.

Published
2015

10. Development of Acyclovir-loaded Bovine Serum Albumin Nanoparticles for Ocular Drug Delivery

Author

Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative., Noomwong, Pawinee; Silom Medical Co.Ltd. Bangkok, Thailand, Ratanasak, Wantanee; Faculty of Veterinary Sciences, Mahidol University, Salaya, Nakhon Pathom, Thailand., Polnok, Assadang; Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000, Thailand., Sarisuta, Narong; Department of Manufacturing Pharmacy Faculty of Pharmacy Mahidol University Bangkok 10400 THAILAND, Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative., Noomwong, Pawinee; Silom Medical Co.Ltd. Bangkok, Thailand, Ratanasak, Wantanee; Faculty of Veterinary Sciences, Mahidol University, Salaya, Nakhon Pathom, Thailand., Polnok, Assadang; Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000, Thailand., and Sarisuta, Narong; Department of Manufacturing Pharmacy Faculty of Pharmacy Mahidol University Bangkok 10400 THAILAND

Abstract

The aim of the present study was to develop acyclovir (ACV) ocular drug delivery systems of bovine serum albumin (BSA) nanoparticles as well as to assess their in vivo transcorneal permeability. The ACV-loaded nanoparticles with 4 % and 8 % drug loading were prepared by desolvation method. Morphology of the nanoparticles under scanning electron microscopy was spherical in shape and uniform in size. The mean sizes and entrapment efficiencies of ACV-loaded BSA nanoparticles were in the range of 125 - 132 nm and 15 - 25 %, respectively. Increasing the amount of ACV added into the formulation led to significant reduction of entrapment efficiency of nanoparticles. The results from in vivo transcorneal permeation studies revealed that ACV-loaded BSA nanoparticles could readily permeate through the rabbits’ cornea and bring about maximum ACV concentrations within 30 min and prolonged till 120 min.

Published
2012

13. pWCP is a widely distributed and highly conserved Wolbachia plasmid in Culex pipiens and Culex quinquefasciatus mosquitoes worldwide

Author

Amani Ghousein, Jordan Tutagata, Hans Schrieke, Manuel Etienne, Victor Chaumeau, Sebastien Boyer, Nonito Pages, David Roiz, A. Murat Eren, Guillaume Cambray, Julie Reveillaud, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Démoustication, Conseil Général de Martinique, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB), Carl Von Ossietzky Universität Oldenburg = Carl von Ossietzky University of Oldenburg (OFFIS), Marine Biological Laboratory, Woods Hole, Massachusetts, USA, Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Diversité, Génomes & Interactions Microorganismes - Insectes [Montpellier] (DGIMI), and Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Montpellier (UM)

Subjects
[SDV]Life Sciences [q-bio], General Medicine
Abstract

Mosquitoes represent the most important pathogen vectors and are responsible for the spread of a wide variety of poorly treatable diseases. Wolbachia are obligate intracellular bacteria that are widely distributed among arthropods and collectively represents one of the most promising solutions for vector control. In particular, Wolbachia has been shown to limit the transmission of pathogens, and to dramatically affect the reproductive behavior of their host through its phage WO. While much research has focused on deciphering and exploring the biocontrol applications of these WO-related phenotypes, the extent and potential impact of the Wolbachia mobilome remain poorly appreciated. Notably, several Wolbachia plasmids, carrying WO-like genes and Insertion Sequences (IS), thus possibly interrelated to other genetic units of the endosymbiont, have been recently discovered. Here we investigated the diversity and biogeography of the first described plasmid of Wolbachia in Culex pipiens (pWCP) in several islands and continental countries around the world—including Cambodia, Guadeloupe, Martinique, Thailand, and Mexico—together with mosquito strains from colonies that evolved for 2 to 30 years in the laboratory. We used PCR and qPCR to determine the presence and copy number of pWCP in individual mosquitoes, and highly accurate Sanger sequencing to evaluate potential variations. Together with earlier observation, our results show that pWCP is omnipresent and strikingly conserved among Wolbachia populations within mosquitoes from distant geographies and environmental conditions. These data suggest a critical role for the plasmid in Wolbachia ecology and evolution, and the potential of a great tool for further genetic dissection and possible manipulation of this endosymbiont.

Published
2023

14. Malaria temporal dynamic clustering for surveillance and intervention planning

Author

Legendre, E., Lehot, L., Dieng, S., Rebaudet, S., Thu, A. M., Rae, J. D., Delmas, G., Girond, F., Herbreteau, Vincent, Nosten, F., Landier, Jordi, Gaudart, J., Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), Hôpital Européen [Fondation Ambroise Paré - Marseille], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford-Mahidol University [Bangkok], Mahidol University [Bangkok], University of Oxford, UMR Espace-Dev Guyane, Institut de Recherche pour le Développement (IRD)-Université de Perpignan Via Domitia (UPVD)-Avignon Université (AU)-Université de La Réunion (UR)-Université de Guyane (UG)-Université des Antilles (UA)-Université de Montpellier (UM), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Hôpital de la Timone [CHU - APHM] (TIMONE), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Seasonal malaria, Infectious Diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Epidemiology, Virology, [SDE]Environmental Sciences, Public Health, Environmental and Occupational Health, Temporal dynamics, Parasitology, Microbiology, Clustering
Abstract

BackgroundTargeting interventions where most needed and effective is crucial for public health. Malaria control and elimination strategies increasingly rely on stratification to guide surveillance, to allocate vector control campaigns, and to prioritize access to community-based early diagnosis and treatment (EDT). We developed an original approach of dynamic clustering to improve local discrimination between heterogeneous malaria transmission settings.MethodsWe analysed weekly malaria incidence records obtained from community-based EDT (malaria posts) in Karen/Kayin state, Myanmar. We smoothed longitudinal incidence series over multiple seasons using functional transformation. We regrouped village incidence series into clusters using a dynamic time warping clustering and compared them to the standard, 5-category annual incidence standard stratification.ResultsWe included 1,115 villages from 2016 to 2020. We identified elevenP. falciparumandP. vivaxincidence clusters which differed by amplitude, trends and seasonality. Specifically the 124 villages classified as “high transmission area” in the standardP. falciparumstratification belonged to the 11 distinct groups when accounting to inter-annual trends and intra-annual variations. Likewise forP. vivax, 399 “high transmission” villages actually corresponded to the 11 distinct dynamics.ConclusionOur temporal dynamic clustering methodology is easy to implement and extracts more information than standard malaria stratification. Our method exploits longitudinal surveillance data to distinguish local dynamics, such as increasing inter-annual trends or seasonal differences, providing key information for decision-making. It is relevant to malaria strategies in other settings and to other diseases, especially when many countries deploy health information systems and collect increasing amounts of health outcome data.FundingThe Bill & Melinda Gates Foundation, The Global Fund against AIDS, Tuberculosis and Malaria (the Regional Artemisinin Initiative) and the Wellcome Trust funded the METF program.

Published
2023

15. Association between the proportion of Plasmodium falciparum and Plasmodium vivax infections detected by passive surveillance and the magnitude of the asymptomatic reservoir in the community: a pooled analysis of paired health facility and community data

Author

Chris Drakeley, Julia Mwesigwa, Umberto D'Alessandro, Antonio M. Quispe, Kimberly M. Fornace, Joanna Gallay, Michelle A. Chang, Jacklin F. Mosha, Siv Sovannaroth, Jordi Landier, Fitsum G. Tadesse, Nuno Sepúlveda, André Siqueira, Gilles Delmas, François Nosten, Ewan Cameron, Teun Bousema, Fe Espino, Daniel J. Bridges, Jennifer C. Stevenson, Koukeo Phommasone, Emilie Pothin, John M. Miller, Karen E. S. Hamre, Alyssa J. Young, Mayfong Mayxay, Marcus V. G. Lacerda, Shunmay Yeung, Lynn Grignard, Arjen M. Dondorp, Thomas P. Eisele, Peter W. Gething, Gillian Stresman, Pauline Joy Lorenzo, Daniel M. Parker, Katherine E. Battle, Jean Frantz Lemoine, Maria Lourdes M. Macalinao, Lorenz von Seidlein, Jane Achan, London School of Hygiene and Tropical Medicine (LSHTM), Universidade de Lisboa (ULISBOA), London School of Hygiene & Tropical Medicine [Fajara, The Gambia], PATH Malaria Control and Elimination Partnership in Africa [Chainama Grounds Lusaka, Zambia] (MACEPA), National Malaria Elimination Centre [Chainama Grounds Lusaka, Zambia] (Ministry of Health), Tulane University School of Public Health and Tropical Medicine [New Orleans, LA, USA], Mwanza Medical Research Centre [Mwanza, Tanzania], Research Institute for Tropical Medicine [Manila, Philippines], Radboud University Medical Center [Nijmegen], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Universidad Continental [Huancayo, Peru], Fundação de Medicina Tropical Dr Heitor Vieira Dourado [Manaus, Brazil], Universidade do Estado do Amazonas (UEA), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), Instituto Elimina [Manaus, Brazil], National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Swiss Tropical and Public Health Institute [Basel], Clinton health Access Initiative Boston (CHAI), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Clinton Health Access Initiative [Port-au-Prince, Haiti], Programme National de Contrôle de la Malaria, Ministère de la Santé Publique et de la Population [Port-au-Prince, Haiti] (MSPP), Mahosot Hospital [Vientiane, Laos], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford], University of Health Sciences [Vientiane, Laos] (UHS), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [Irvine] (UCI), University of California, Mahidol University [Bangkok], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Perth Children's Hospital [Nedlands, WA, Australia], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Institute for Disease Modelling [Seattle, WA, USA], Graduate School, AII - Infectious diseases, APH - Global Health, APH - Methodology, Intensive Care Medicine, Universidade de Lisboa = University of Lisbon (ULISBOA), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), University of Oxford, University of California [Irvine] (UC Irvine), University of California (UC), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, and Dupuis, Christine

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Plasmodium vivax, Vivax, law.invention, 0302 clinical medicine, law, 80 and over, Prevalence, 2.2 Factors relating to the physical environment, Cluster Analysis, Medicine, Public Health Surveillance, Longitudinal Studies, Aetiology, Malaria, Falciparum, Child, Asymptomatic Infections, Aged, 80 and over, screening and diagnosis, education.field_of_study, biology, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Detection, Infectious Diseases, Transmission (mechanics), Medical Microbiology, Child, Preschool, Public Health and Health Services, Female, 4.4 Population screening, Seasons, medicine.symptom, Infection, Falciparum, Adult, medicine.medical_specialty, Asia, Adolescent, Clinical Sciences, 030231 tropical medicine, Population, Plasmodium falciparum, Microbiology, Asymptomatic, Article, Young Adult, 03 medical and health sciences, Rare Diseases, All institutes and research themes of the Radboud University Medical Center, Clinical Research, parasitic diseases, Malaria, Vivax, Humans, Preschool, education, Aged, Disease Reservoirs, business.industry, Public health, Infant, Bayes Theorem, Odds ratio, biology.organism_classification, medicine.disease, Malaria, Vector-Borne Diseases, Good Health and Well Being, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Cross-Sectional Studies, 030104 developmental biology, Africa, Human medicine, Health Facilities, Americas, business, Demography
Abstract

Background: \ud Passively collected malaria case data are the foundation for public health decision making. However, because of population-level immunity, infections might not always be sufficiently symptomatic to prompt individuals to seek care. Understanding the proportion of all Plasmodium spp infections expected to be detected by the health system becomes particularly paramount in elimination settings. The aim of this study was to determine the association between the proportion of infections detected and transmission intensity for Plasmodium falciparum and Plasmodium vivax in several global endemic settings.\ud \ud Methods: \ud The proportion of infections detected in routine malaria data, P(Detect), was derived from paired household cross-sectional survey and routinely collected malaria data within health facilities. P(Detect) was estimated using a Bayesian model in 431 clusters spanning the Americas, Africa, and Asia. The association between P(Detect) and malaria prevalence was assessed using log-linear regression models. Changes in P(Detect) over time were evaluated using data from 13 timepoints over 2 years from The Gambia.\ud \ud Findings: \ud The median estimated P(Detect) across all clusters was 12·5% (IQR 5·3–25·0) for P falciparum and 10·1% (5·0–18·3) for P vivax and decreased as the estimated log-PCR community prevalence increased (adjusted odds ratio [OR] for P falciparum 0·63, 95% CI 0·57–0·69; adjusted OR for P vivax 0·52, 0·47–0·57). Factors associated with increasing P(Detect) included smaller catchment population size, high transmission season, improved care-seeking behaviour by infected individuals, and recent increases (within the previous year) in transmission intensity.\ud \ud Interpretation: \ud The proportion of all infections detected within health systems increases once transmission intensity is sufficiently low. The likely explanation for P falciparum is that reduced exposure to infection leads to lower levels of protective immunity in the population, increasing the likelihood that infected individuals will become symptomatic and seek care. These factors might also be true for P vivax but a better understanding of the transmission biology is needed to attribute likely reasons for the observed trend. In low transmission and pre-elimination settings, enhancing access to care and improvements in care-seeking behaviour of infected individuals will lead to an increased proportion of infections detected in the community and might contribute to accelerating the interruption of transmission.\ud \ud Funding: \ud Wellcome Trust.

Published
2020

16. Orientia tsutsugamushi dynamics in vectors and hosts: ecology and risk factors for foci of scrub typhus transmission in northern Thailand

Author

Serge Morand, Neeranuch Thangnimitchok, Paul N. Newton, Tri Wangrangsimakul, Nicholas P. J. Day, Kittipong Chaisiri, Daniel H. Paris, Piangnet Jaiboon, Ivo Elliott, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Department of Clinical Tropical Medicine [Bangkok, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok], Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Basel (Unibas), Swiss Tropical and Public Health Institute [Basel], Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Kasetsart University - KU (THAILAND), Kasetsart University (KU), This research was funded in whole, or in part, by the Wellcome Trust (105731/Z/14/Z). SM was supported by the French ANR FutureHealthSEA ANR17-CE35-0003-01., and ANR-17-CE35-0003,FutureHealthSEA,Scénarios de la santé en Asie du Sud-Est: changements d'utilisation des terres, changement climatique et maladies infectieuses(2017)

Subjects
Mite Infestations, Orientia tsutsugamushi, [SDV]Life Sciences [q-bio], 030231 tropical medicine, Ecological and Environmental Phenomena, Rodentia, Infectious and parasitic diseases, RC109-216, Trombiculidae, Scrub typhus, Disease Vectors, 03 medical and health sciences, Diversity index, 0302 clinical medicine, Risk Factors, Zoonoses, Leptotrombidium deliense, medicine, Animals, Humans, 030304 developmental biology, Mammals, 0303 health sciences, Ecology, biology, Research, Bandicota indica, Species diversity, Chigger, 15. Life on land, bacterial infections and mycoses, Thailand, biology.organism_classification, medicine.disease, Rats, 3. Good health, Infectious Diseases, Scrub Typhus, Vector (epidemiology), Parasitology, Species richness
Abstract

Background Scrub typhus is an important neglected vector-borne zoonotic disease across the Asia–Pacific region, with an expanding known distribution. The disease ecology is poorly understood, despite the large global burden of disease. The key determinants of high-risk areas of transmission to humans are unknown. Methods Small mammals and chiggers were collected over an 18-month period at three sites of differing ecological profiles with high scrub typhus transmission in Chiang Rai Province, northern Thailand. Field samples were identified and tested for Orientia tsutsugamushi by real-time PCR. The rates and dynamics of infection were recorded, and positive and negative individuals were mapped over time at the scale of single villages. Ecological analyses were performed to describe the species richness, community structure and interactions between infected and uninfected species and habitats. Generalised linear modelling (GLM) was applied to examine these interactions. Results The site with the highest rates of human infection was associated with the highest number of infected chigger pools (41%), individual chiggers (16%), proportion of the known vector species Leptotrombidium deliense (71%) and chigger index (151). Chigger species diversity was lowest (Shannon diversity index H′: 1.77) and rodent density appeared to be high. There were no consistent discrete foci of infection identified at any of the study sites. The small mammals Rattus tanezumi and Bandicota indica and the chiggers L. deliense and Walchia kritochaeta emerged as central nodes in the network analysis. In the GLM, the end of the dry season, and to a lesser extent the end of the wet season, was associated with O. tsutsugamushi-infected small mammals and chiggers. A clear positive association was seen between O. tsutsugamushi-positive chigger pools and the combination of O. tsutsugamushi-positive chigger pools and O. tsutsugamushi-positive small mammals with lowland habitats. Conclusions These findings begin to reveal some of the factors that may determine high-risk foci of scrub typhus at a fine local scale. Understanding these factors may allow practical public health interventions to reduce disease risk. Further studies are needed in areas with diverse ecology. Graphical abstract

Published
2022

17. Probing the distinct chemosensitivity of Plasmodium vivax liver stage parasites and demonstration of 8-aminoquinoline radical cure activity in vitro

Author

Adeline C. Y. Chua, Saorin Kim, Bruce Russell, Eakpor Piv, Sivkeng Ouk, Rays H. Y. Jiang, Zaira Rizopoulos, Dennis E. Kyle, Sivchheng Phal, Pablo Bifani, Bros Doeurk, Amélie Vantaux, Julie Péneau, Nana Akua Awuku, Sangrawee Suriyakan, Brice Campo, Benoit Witkowski, Chansophea Chhin, Mélanie Rouillier, Sreyvouch Phen, Chantrea Vong, Praphan Kittiphanakun, Steven P. Maher, François Nosten, Chiara Andolina, Amy J. Conway, Caitlin A. Cooper, Baura Tat, Victor Chaumeau, Center for Tropical and Emerging Global Diseases, University of Georgia [USA], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Agency for science, technology and research [Singapore] (A*STAR), University of Otago [Dunedin, Nouvelle-Zélande], Health and Biosecurity [Canberra, ACT, Australia] (CSIRO), Medicines for Malaria Venture (MMV), Université de Genève (UNIGE), University of South Florida [Tampa] (USF), Yong Loo Lin School of Medicine [Singapore], London School of Hygiene and Tropical Medicine (LSHTM), Funding support was provided by the NUHS (WBS R-571-000-040-133 to P.B.), the Bill & Melinda Gates Foundation (OPP1023601 to D.E.K.), and Medicines for Malaria Venture (RD/2017/0042 to B.W. and A.V., RD/16/1082 and RD/15/0022 to S.P.M. and D.E.K.) For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accept Manuscript version arising from this submission., and We thank the malaria patients of northwestern Thailand and northeastern Cambodia for participation in this study. We thank Celgene for providing analogs of MMV676121. We thank Irene Hallyburton and Mark Anderson of the Dundee Drug Discovery Unit at Dundee University for providing PfABS data. The Pathogen Box biological activity data produced for Medicines for Malaria Venture27 (https://www.mmv.org/sites/default/files/uploads/docs/mmv_open/Pathogen_Box_Activity_Biological_Data_Smiles.xlsx) is provided, with MMV's permission, as supplemental material in the online version of this report. We thank Dr. Erika Flannery at Novartis Institute for Tropical Diseases and Dr. Jeremy Burrows of Medicines for Malaria Venture for critical review of the manuscript. HCI data from drug studies was produced in part by the Biomedical Microscopy Core at the University of Georgia, supported by the Georgia Research Alliance. The Shoklo Malaria Research Unit is part of the Mahidol Oxford Research Unit, supported by the Wellcome Trust of Great Britain [220211].

Subjects
Time Factors, Primaquine, Tafenoquine, Plasmodium vivax, Diseases, 030204 cardiovascular system & hematology, Pharmacology, chemistry.chemical_compound, 0302 clinical medicine, Parasitic Sensitivity Tests, Chloroquine, Medicine, 030212 general & internal medicine, 0303 health sciences, Multidisciplinary, Molecular Structure, biology, Drug discovery, Biological techniques, Drug Synergism, 3. Good health, Liver, Drug development, Aminoquinolines, medicine.drug, 8-Aminoquinoline, Science, Article, Antimalarials, 03 medical and health sciences, parasitic diseases, Malaria, Vivax, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030304 developmental biology, Liver stage, Life Cycle Stages, Dose-Response Relationship, Drug, 030306 microbiology, business.industry, biology.organism_classification, In vitro, ROC Curve, chemistry, business
Abstract

Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.

Published
2021

18. Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria

Author

Jordi Landier, Thomas J. Peto, Frank Smithuis, Mavuto Mukaka, Mark Debackere, Walter R. J. Taylor, Lorenz von Seidlein, Arnaud Tarantola, Tran Tinh Hien, Arjen M. Dondorp, Rupam Tripura, Arantxa Roca-Feltrer, Koukeo Phommasone, Pimnara Peerawaranun, Sim Kheng, François Nosten, Nicholas J. White, Philippe Buchy, Joel Tarning, Sinoun Muth, Lek Dysoley, Soy Ty Kheang, Thuy Nguyen, Didier Menard, Ngak Song, Chy Say, Leang Rithea, Mayfong Mayxay, Kak Neeraj, Rick M. Fairhurst, Richard M. Hoglund, Intensive Care Medicine, Graduate School, Radiology and Nuclear Medicine, Mahidol University [Bangkok], University of Oxford, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), VU University Medical Center [Amsterdam], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Mahosot Hospital [Vientiane, Laos], Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], University of Health Sciences [Vientiane, Laos] (UHS), National Institute of Public Health [Phnom Penh, Cambodge], AQUITY Global Inc [Potomac, MD, USA], University Research Co. [Washington, MD, USA] (URC), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Malaria Consortium [London, UK] (MCL), MSF Belgium Cambodia Malaria Program [Phnom Penh, Cambodia], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Keng Kang III Khan Chamkamon [Phnom Penh, Cambodia], GSK Vaccines [Singapore, Singapore], Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was partly supported by a Wellcome Innovator award (WT-iTP-2018/001), but the Wellcome Trust was not involved in any aspect of this study., Malbec, Odile, University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Primaquine, [SDV]Life Sciences [q-bio], RC955-962, Plasmodium vivax, Infectious and parasitic diseases, RC109-216, 0302 clinical medicine, Arctic medicine. Tropical medicine, 030212 general & internal medicine, Allometric scaling, Child, Aged, 80 and over, biology, Dosing regimen, Age Factors, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Child, Preschool, Female, medicine.drug, Adult, Adolescent, 030231 tropical medicine, Drug Administration Schedule, 03 medical and health sciences, Antimalarials, Young Adult, Animal science, Pharmacokinetics, Age-based dosing, medicine, Malaria, Vivax, Humans, Dosing, Aged, business.industry, Research, Weight-based dosing, Body Weight, Infant, biology.organism_classification, Target dose, Regimen, Vivax malaria, Parasitology, business
Abstract

Background In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. Methods The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. Results The proposed weight-based regimen has 5 dosing bands: (i) 5–7 kg, 5 mg, resulting in 0.71–1.0 mg/kg/day; (ii) 8–16 kg, 7.5 mg, 0.47–0.94 mg/kg/day; (iii) 17–40 kg, 15 mg, 0.38–0.88 mg/kg/day; (iv) 41–80 kg, 30 mg, 0.37–0.73 mg/kg/day; and (v) 81–100 kg, 45 mg, 0.45–0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6–11 months, 5 mg, 0.43–1.0 mg/kg/day; (ii) 1–5 years, 7.5 mg, 0.35–1.25 mg/kg/day; (iii) 6–14 years, 15 mg, 0.30–1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35–1.07 mg/kg/day. Conclusion The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Published
2021

19. Genetic surveillance in the Greater Mekong subregion and South Asia to support malaria control and elimination

Author

Jordi Landier, Abdullah Abu Sayeed, Seila Suon, Kim-Tuyen Nguyen, Kate Rowlands, Frank Smithuis, Chanon Kunasol, Chanaki Amaratunga, Sasithon Pukrittayakamee, Keobouphaphone Chindavongsa, Jacob Almagro Garcia, Richard D. Pearson, Mozam Ali, Xin Hui S Chan, Katie Love, Naomi Park, Pascal Ringwald, Richard J. Maude, Cristina V. Ariani, Mehul Dhorda, Marie A. Onyamboko, Daniel M. Parker, Tin Maung Hlaing, Scott Goodwin, Namfon Kotanan, Thang Ngo Duc, Gilles Delmas, Huy Rekol, Rick M. Fairhurst, Victoria Simpson, Arjen M. Dondorp, Le Thanh Dong, Bouasy Hongvanthong, Tran Tinh Hien, Rapeephan R. Maude, Thomas J. Peto, Shavanthi Rajatileka, Roberto Amato, Thanat Chookajorn, Ben Jeffery, Anna E. Jeffreys, Nicole Zdrojewski, Caterina I. Fanello, Eleanor Drury, Mihir Kekre, Myo Thant, John Sillitoe, Olivo Miotto, Aung Myint Thu, James J Callery, Subrata Baidya, Paul N. Newton, Ranitha Vongpromek, Prativa K Behera, Borimas Hanboonkunupakarn, Rob W. van der Pluijm, Jim Stalker, Anupkumar R. Anvikar, Sonexay Phalivong, Dawn Muddyman, Nguyen Thuy-Nhien, Christina Hubbart, Rithea Leang, Lorenz von Seidlein, Nicholas P. J. Day, Phrutsamon Wongnak, Jonathan Keatley, Hoa Nguyen, Cinzia Malangone, Parthasarathi Satpathi, Abul Faiz, Dysoley Lek, François Nosten, Christopher G Jacob, Rupam Tripura, Sara E. Canavati, Huynh Hong Quang, Kirk A. Rockett, Neena Valecha, Thuy Nguyen, Kimberly J. Johnson, Tran Minh Nhat, Didar Uddin, Caroline O. Buckee, Akhter ul Islam, Podjanee Jittamala, Mayfong Mayxay, Amir Hossain, Viengxay Vanisaveth, Elizabeth A. Ashley, Dominic P. Kwiatkowski, Sanghamitra Satpathi, Aung Pyae Phyo, Amar Tripura, Nguyen Hoang Chau, Sónia Gonçalves, Khin Lin, Cheah Huch, Wellcome Sanger Institute [Hinxton, Royaume-Uni], Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Mahosot Hospital [Vientiane, Laos], Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), University of Oxford [Oxford], Mahidol University [Bangkok], Harvard T.H. Chan School of Public Health, Institute of Malariology, Parasitology, and Entomology [Quy Nhon, Vietnam] (IMPE), Centre of Malariology, Parasitology, and Entomology [Vientiane, Lao People’s Democratic Republic] (CMPE), National Institute of Malariology, Parasitology and Entomology [Hanoi], National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, Chittagong Medical College Hospital [Chittagong, Bangladesh] (CMCH), World Health Organization [Geneva], Institute of Malariology, Parasitology, and Entomology [Ho Chi Minh City, Vietnam] (IMPE), Vysnova Partners Inc [Hanoi, Vietnam] (VPI), University of Kinshasa (UNIKIN), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [Irvine] (UCI), University of California, Royal Society of Thailand [Bangkok, Thailand], Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], The Department of Medical Research (Upper Myanmar), Defence Services Medical Research Centre [Naypyitaw, Myanmar] (DSMRC), Midnapore Medical College [Midnapur, India] (MMC), ispat general hospital [Rourkela, India] (IGH), Agartala Medical College [Agartala, India] (AMC), National Institute of Malaria Research [New Dehli, Inde] (NIMR), Indian Council of Medical Research [New Dehli] (ICMR), Ramu Upazila Health Complex [Cox’s Bazar, Bangladesh] (RUHC), The Wellcome Trust Sanger Institute [Cambridge], WorldWide Antimalarial Resistance Network [Bangkok] (WWARN), WorldWide Antimalarial Resistance Network (WWARN), Université de Washington Seattle-Université de Washington Seattle, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of California [Irvine] (UC Irvine), University of California (UC), University of Washington [Seattle]-University of Washington [Seattle], and Malbec, Odile

Subjects
Plasmodium, History, [SDV]Life Sciences [q-bio], Drug Resistance, global health, Drug resistance, Barcode, law.invention, law, Genotype, Biology (General), Aetiology, Microbiology and Infectious Disease, 0303 health sciences, Bangladesh, General Neuroscience, General Medicine, asia, 3. Good health, [SDV] Life Sciences [q-bio], Geography, Infectious Diseases, Democratic Republic of the Congo, Medicine, epidemiology, Genetic Engineering, Malaria control, Infection, Research Article, medicine.medical_specialty, South asia, Asia, QH301-705.5, Science, infectious disease, Plasmodium falciparum, malaria, Library science, Southeastern, India, General Biochemistry, Genetics and Molecular Biology, Antimalarials, 03 medical and health sciences, Rare Diseases, Simple sample, Clinical Research, Environmental health, medicine, Genetics, Humans, Animals, Disease Eradication, 030304 developmental biology, drug resistance, General Immunology and Microbiology, 030306 microbiology, Public health, microbiology, Genetic data, Genetic Therapy, medicine.disease, genetic surveillance, Compendium, Resistance monitoring, Data sharing, Vector-Borne Diseases, Epidemiology and Global Health, Good Health and Well Being, Communicable Disease Control, Antimicrobial Resistance, Biochemistry and Cell Biology, Malaria, 2.6 Resources and infrastructure (aetiology)
Abstract

Author(s): Jacob, Christopher G; Thuy-Nhien, Nguyen; Mayxay, Mayfong; Maude, Richard J; Quang, Huynh Hong; Hongvanthong, Bouasy; Vanisaveth, Viengxay; Ngo Duc, Thang; Rekol, Huy; van der Pluijm, Rob; von Seidlein, Lorenz; Fairhurst, Rick; Nosten, Francois; Hossain, Md Amir; Park, Naomi; Goodwin, Scott; Ringwald, Pascal; Chindavongsa, Keobouphaphone; Newton, Paul; Ashley, Elizabeth; Phalivong, Sonexay; Maude, Rapeephan; Leang, Rithea; Huch, Cheah; Dong, Le Thanh; Nguyen, Kim-Tuyen; Nhat, Tran Minh; Hien, Tran Tinh; Nguyen, Hoa; Zdrojewski, Nicole; Canavati, Sara; Sayeed, Abdullah Abu; Uddin, Didar; Buckee, Caroline; Fanello, Caterina I; Onyamboko, Marie; Peto, Thomas; Tripura, Rupam; Amaratunga, Chanaki; Myint Thu, Aung; Delmas, Gilles; Landier, Jordi; Parker, Daniel M; Chau, Nguyen Hoang; Lek, Dysoley; Suon, Seila; Callery, James; Jittamala, Podjanee; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Phyo, Aung Pyae; Smithuis, Frank; Lin, Khin; Thant, Myo; Hlaing, Tin Maung; Satpathi, Parthasarathi; Satpathi, Sanghamitra; Behera, Prativa K; Tripura, Amar; Baidya, Subrata; Valecha, Neena; Anvikar, Anupkumar R; Ul Islam, Akhter; Faiz, Abul; Kunasol, Chanon; Drury, Eleanor; Kekre, Mihir; Ali, Mozam; Love, Katie; Rajatileka, Shavanthi; Jeffreys, Anna E; Rowlands, Kate; Hubbart, Christina S; Dhorda, Mehul; Vongpromek, Ranitha; Kotanan, Namfon; Wongnak, Phrutsamon; Almagro Garcia, Jacob; Pearson, Richard D; Ariani, Cristina V; Chookajorn, Thanat; Malangone, Cinzia; Nguyen, T; Stalker, Jim; Jeffery, Ben | Abstract: BackgroundNational Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures.MethodsSamples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs.ResultsGenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs.ConclusionsGenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community.FundingThe GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of samples were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Published
2021

20. A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: is it time to reconsider the current contraindication?

Author

Virgilio E. Failoc-Rojas, Carlos Chaccour, Pascal Del Giudice, Jaime Piquero-Casals, Menno R. Smit, Kevin C. Kobylinski, Georgina S. Humphreys, Kasia Stepniewska, Céline Dard, Sabine Specht, Wuelton Marcelo Monteiro, Franck Boralevi, Jean T. Coulibaly, Philippe J Guerin, Antoni Soriano-Arandes, Belen Pedrique, David Wimmersberger, Lucia Romani, Marimar Sáez-De-ocariz, Kalynn Kennon, Daniel T. Engelman, Virak Khieu, Anne Faisant, Michael Marks, Marie Pierre Brenier-Pinchart, Annabel Maruani, Andrew C Steer, Podjanee Jittamala, Lorenz von Seidlein, Oliver Sokana, Eli Harriss, Nicholas J. White, Jennifer Keiser, Institut Català de la Salut, [Jittamala P] Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [Monteiro W] Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil. Universidade do Estado do Amazonas, Manaus, Brazil. [Smit MR] Amsterdam Centre for Global Child Health, Emma Children's Hospital, Amsterdam, The Netherlands. University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands. Malaria Epidemiology Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom. [Pedrique B, Specht S] Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland. [Chaccour CJ] ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. Ifakara Health Institute, Ifakara, United Republic of Tanzania. Instituto de Medicina Tropical Universidad de Navarra, Pamplona, Spain. [Soriano-Arandes A] Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Centre Hospitalier de Basse-Terre [Guadeloupe], Centre Hospitalier Intercommunal Fréjus - St Raphaël (CHI Fréjus - St Raphaël), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Bordeaux [Bordeaux], General Paediatrics, APH - Global Health, Downs, Jennifer A., and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques

Subjects
Pediatrics, Ectoparasitic Infections, [SDV]Life Sciences [q-bio], RC955-962, Helminthiasis, Administration, Oral, Onchocerciasis, Geographical locations, Antibiòtics macròlids - Ús terapèutic, Scabies, Families, Medical Conditions, 0302 clinical medicine, Ivermectin, Arctic medicine. Tropical medicine, Medicine and Health Sciences, compuestos orgánicos::lactonas::policétidos::macrólidos::ivermectina [COMPUESTOS QUÍMICOS Y DROGAS], 030212 general & internal medicine, Antibiòtics macròlids - Efectes secundaris, Children, Anthelmintics, Pediatria, wa_900, Neglected Diseases, qv_250, Research Assessment, 3. Good health, Europe, Infectious Diseases, Strongyloidiasis, Systematic review, terapéutica::contraindicaciones::contraindicaciones de los medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Research Design, Helminth Infections, Child, Preschool, Meta-analysis, Other subheadings::Other subheadings::/administration & dosage [Other subheadings], France, Public aspects of medicine, RA1-1270, Research Article, Neglected Tropical Diseases, medicine.drug, wc_880, medicine.medical_specialty, wa_950, Systematic Reviews, Clinical Research Design, 030231 tropical medicine, Health Occupations::Medicine::Pediatrics [DISCIPLINES AND OCCUPATIONS], Sexually Transmitted Diseases, MEDLINE, Research and Analysis Methods, wa_110, 03 medical and health sciences, qx_200, Parasitic Diseases, medicine, Humans, European Union, Trichuriasis, Adverse effect, profesiones sanitarias::medicina::pediatría [DISCIPLINAS Y OCUPACIONES], ws_430, Otros calificadores::Otros calificadores::/administración & dosificación [Otros calificadores], business.industry, Body Weight, Public Health, Environmental and Occupational Health, Infant, Therapeutics::Contraindications::Contraindications, Drug [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Tropical Diseases, medicine.disease, Clinical trial, Soil-Transmitted Helminthiases, Age Groups, People and Places, Population Groupings, Adverse Events, business
Abstract

Background Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. Methodology/Principal findings A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. Conclusions/Significance Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance., Author summary Oral ivermectin is a safe and efficacious drug for the treatment of neglected tropical diseases. To date, ivermectin is not indicated in children weighing less than 15 kg because there have been insufficient safety data to support a change of recommendation. A PRISMA-level systematic review was conducted, and 97 potential sources were identified. All lead investigators were contacted to share individual patient data if they could provide the minimum criteria. These were the known weights of the children less than 15 kg in whom there were possible adverse events. A total of 17 investigators replied, sharing individual-level patient data (IPD) from 15 studies, which represent a database of 1,088 children weighing less than 15 kg treated with oral ivermectin. Overall 18 adverse events were reported in 1.4% (15/1,088) of children, all of which were mild and self-limiting. No serious adverse events were recorded. These data suggest that ivermectin is safe for use in children weighing less than 15 kilograms. Further data from well-designed clinical trials are needed to assess the safety of oral ivermectin at escalating doses in children weighing less than 15 kg.

Published
2021

21. Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis

Author

David L. Saunders, Ari W. Satyagraha, Sunil Parikh, Daniel A. Pfeffer, Benedikt Ley, Yongshu He, François Nosten, Asrat Hailu Mekuria, Marcus V. G. Lacerda, Kamala Ley-Thriemer, Ayodhia Pitaloka Pasaribu, Wasif A. Khan, Duangdao Palasuwan, Liwang Cui, Germana Bancone, Sampa Pal, Rosalind E. Howes, Jeanne Rini Poespoprodjo, Mohammad Shafiul Alam, Saorin Kim, Michael E. von Fricken, Chanthap Lon, Muzamil Mahdi Abdel Hamid, Gonzalo J. Domingo, Michelle E. Roh, Nwe Nwe Oo, Patrick Adu, Fe Espino, David J. Price, Lorenz von Seidlein, Ochaka Julie Egesie, Yap Boum, Nimol Khim, Arantxa Roca-Feltrer, Marcelo A M Brito, Pimlak Charoenkwan, Gisela Henriques, Archie C. A. Clements, Inge Sutanto, Michele D. Spring, Pooja Bansil, Zeshuai Deng, Wuelton Marcelo Monteiro, Ric N. Price, Thomas A. Weppelmann, Didier Menard, Menzies School of Health Research [Australia], Charles Darwin University, Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford], University of Cape Coast [Ghana], International Center for Diarrheal Disease Research [Mohakhali, Bangladesh], PATH [Seattle], Mbarara University of Science and Technology [Mbarara] (MUST), Epicentre Ouganda [Mbarara] [Médecins Sans Frontières], Epicentre [Paris] [Médecins Sans Frontières], Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Chiang Mai University (CMU), Curtin University [Perth], Planning and Transport Research Centre (PATREC), Pennsylvania State University (Penn State), Penn State System, Kunming University of Science and Technology (KMUST), University of Jos [Nigeria], Research Institute for Tropical Medicine [Muntinlupa City, Philippines], George Mason University [Fairfax], University of Khartoum, London School of Hygiene and Tropical Medicine (LSHTM), Laboratoire d'épidémiologie moléculaire, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Addis Ababa University (AAU), Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Department of Medical Research (Lower Myanmar) [Yangon], Chulalongkorn University [Bangkok], Yale School of Public Health (YSPH), Universitas Sumatera Utara, Yayasan Pengembangan Kesehatan dan Masyarakat Papua (YPKMP), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, The Peter Doherty Institute for Infection and Immunity [Melbourne], University of Melbourne-The Royal Melbourne Hospital, Malaria Consortium [Phnom Penh, Cambodge], University of California [San Francisco] (UCSF), University of California, Uniformed Services University of the Health Sciences (USUHS), University of Indonesia (UI), Florida International University [Miami] (FIU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Eijkman Institute for Molecular Biology [Jakarta], Nuffield Department of Clinical Medicine [Oxford], This work was funded by the Wellcome Trust (200909 awarded to RNP) and the Bill & Melinda Gates Foundation (OPP1164105). GB and FN are part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme funded by the Wellcome Trust. This work was supported by the Australian Centre for Research Excellence on Malaria Elimination (ACREME), funded by the National Health and Medical Research Council of Australia (APP 1134989)., Charles Darwin University [Australia], University of Oxford, Institut Pasteur [Paris] (IP), University of Oxford-Mahidol University [Bangkok], University of California [San Francisco] (UC San Francisco), University of California (UC), and University of Oxford-Mahidol University [Bangkok]-Wellcome Trust

Subjects
Male, Plasmodium, Glucose-6-phosphate dehydrogenase activity, Primaquine, 030204 cardiovascular system & hematology, Gastroenterology, 0302 clinical medicine, Spectrum Analysis Techniques, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Spectrophotometry, Medicine and Health Sciences, 030212 general & internal medicine, Child, Glucose-6-Phosphate Dehydrogenase Deficiency, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, Chemistry, Drugs, Anemia, Repeatability, Hematology, General Medicine, Middle Aged, Haemolysis, 3. Good health, Meta-analysis, Child, Preschool, Engineering and Technology, Medicine, Female, medicine.drug, Research Article, Quality Control, Adult, medicine.medical_specialty, Adolescent, Coefficient of variation, Population, Glucosephosphate Dehydrogenase, Research and Analysis Methods, 03 medical and health sciences, Antimalarials, Young Adult, Internal medicine, Parasite Groups, Industrial Engineering, Parasitic Diseases, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, education, Aged, Pharmacology, Chromatography, business.industry, Hemolytic Anemia, Infant, Newborn, Biology and Life Sciences, Infant, Correction, medicine.disease, Tropical Diseases, Malaria, Glucosephosphate Dehydrogenase Deficiency, Parasitology, business, Apicomplexa, Glucose-6-phosphate dehydrogenase deficiency
Abstract

Background The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold. Methods and findings Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3–14.0) for the Trinity assay and 8.3 U/g Hb (6.8–15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%–94%) to 100% (95% CI: 96%–100%) and specificity from 96% (95% CI: 89%–99%) to 100% (100%–100%). However, when considering intermediate deficiency (, Daniel Pfeffer and coauthors report on the assessment of glucose-6-phosphate dehydrogenase activity, which is required for safe use of some malaria treatments., Author summary Why was this study done? Complete cure of vivax malaria, the most geographically widespread malaria species, requires the use of 8-aminoquinoline drugs to clear dormant liver stages of the parasite (‘radical cure’); however, these drugs can cause severe haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Ultraviolet (UV) spectrophotometry is used as the reference test to measure G6PD activity, for validating new point-of-care diagnostics, and to determine population-specific definitions of G6PD deficiency. Currently, there is no universal threshold to define G6PD deficiency, and each laboratory must invest time and resources to derive site- and laboratory-specific definitions of G6PD deficiency. What did the researchers do and find? We pooled measurements of G6PD activity from studies conducted across different countries and laboratories worldwide. We assessed the comparability of spectrophotometry results between these laboratories to see whether a universal definition and diagnostic cutoff for G6PD deficiency could be determined. There was substantial variation in the performance and absolute measurements of spectrophotometry conducted in different laboratories, hindering the definition of a universal cutoff for G6PD deficiency. What do these findings mean? These findings highlight the importance of quality-control measures to minimise the influence of laboratory procedures on observed measurements. The data suggest that while a robust universal, assay-specific G6PD activity cutoff value can be established for diagnosis of severe G6PD deficiency (

Published
2020

22. The estimated burden of scrub typhus in Thailand from national surveillance data (2003-2018)

Author

Tri Wangrangsimakul, Supalert Nedsuwan, Ivo Elliott, Nicholas P. J. Day, Soawapak Hinjoy, Serge Morand, Kittipong Chaisiri, Rawadee Kumlert, Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Chiangrai Prachanukroh Hospital, Ministry of Public Health [Thailand], Mahidol University [Bangkok], Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Kasetsart University - KU (THAILAND), Kasetsart University (KU), TW and NPJD are funded by the Wellcome Trust, UK, as part of the MORU Tropical Health Network institutional funding support. IE is funded by the Wellcome Trust, UK, as part of a Clinical Training Fellowship (grant number 105731/Z/14/Z). SM, RK and KC are supported by the French ANR FutureHealthSEA (ANR-17-CE35-0003-02) 'Predictive scenarios of health in Southeast Asia: linking land use and climate changes to infectious diseases'., ANR-17-CE35-0003,FutureHealthSEA,Scénarios de la santé en Asie du Sud-Est: changements d'utilisation des terres, changement climatique et maladies infectieuses(2017), Department of Helminthology, Faculty of Tropical Medicine, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), ANR: ANR17-CE35-0003-01,FutureHealthSEA, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford-University of Oxford, and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE)

Subjects
Bacterial Diseases, 0301 basic medicine, Atmospheric Science, Epidemiology, Rain, [SDV]Life Sciences [q-bio], RC955-962, Scrub typhus, Forests, Geographical Locations, 0302 clinical medicine, Cost of Illness, Risk Factors, Arctic medicine. Tropical medicine, Medicine and Health Sciences, Public and Occupational Health, Child, Aged, 80 and over, Disease surveillance, education.field_of_study, Ecology, Incidence, Population size, Incidence (epidemiology), Middle Aged, Thailand, Terrestrial Environments, 3. Good health, Professions, Infectious Diseases, Geography, Child, Preschool, Epidemiological Monitoring, Agricultural Workers, Topography, Medical, Public aspects of medicine, RA1-1270, Research Article, Adult, medicine.medical_specialty, Asia, Adolescent, 030231 tropical medicine, Population, Disease Surveillance, Ecosystems, Typhus, Young Adult, 03 medical and health sciences, Meteorology, medicine, Humans, education, Disease burden, Aged, Ecology and Environmental Sciences, Public Health, Environmental and Occupational Health, Infant, Biology and Life Sciences, Tropics, medicine.disease, bacterial infections and mycoses, 030104 developmental biology, Scrub Typhus, People and Places, Earth Sciences, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Population Groupings, Demography
Abstract

Background Scrub typhus is a major cause of acute febrile illness in the tropics and is endemic over large areas of the Asia Pacific region. The national and global burden of scrub typhus remains unclear due to limited data and difficulties surrounding diagnosis. Methodology/Principal findings Scrub typhus reporting data from 2003–2018 were collected from the Thai national disease surveillance system. Additional information including the district, sub-district and village of residence, population, geographical, meteorological and satellite imagery data were also collected for Chiangrai, the province with the highest number of reported cases from 2003–2018. From 2003–2018, 103,345 cases of scrub typhus were reported with the number of reported cases increasing substantially over the observed period. There were more men than women, with agricultural workers the main occupational group affected. The majority of cases occurred in the 15–64 year old age group (72,144/99,543, 72%). Disease burden was greatest in the northern region, accounting for 53% of the total reported cases per year (mean). In the northern region, five provinces–Chiangrai, Chiangmai, Tak, Nan and Mae Hong Son–accounted for 84% (46,927/55,872) of the total cases from the northern region or 45% (46,927/103,345) of cases nationally. The majority of cases occurred from June to November but seasonality was less marked in the southern region. In Chiangrai province, elevation, rainfall, temperature, population size, habitat complexity and diversity of land cover contributed to scrub typhus incidence. Interpretation The burden of scrub typhus in Thailand is high with disease incidence rising significantly over the last two decades. However, disease burden is not uniform with northern provinces particularly affected. Agricultural activity along with geographical, meteorological and land cover factors are likely to contribute to disease incidence. Our report, along with existing epidemiological data, suggests that scrub typhus is the most clinically important rickettsial disease globally., Author summary Scrub typhus, caused by the bacterium Orientia tsutsugamushi, is a major cause of fever in tropical and subtropical Asia. Symptoms can be similar to other common infections such as malaria, dengue, leptospirosis or typhoid, making it difficult to diagnose. Laboratory tests to diagnose scrub typhus are often unavailable, inaccurate, impractical, or too costly. Consequently, the true burden of scrub typhus disease remains unknown. Here, we collected data on the number of reported cases of scrub typhus in Thailand for 2003–2018 from the national surveillance system. There were 103,345 cases reported with incidence rising significantly over the study period. More men than women were affected, agricultural workers were the main occupational group (45%) and most cases (72%) were in adults of working age. The disease was seasonal with the cases mainly occurring during the rainy season from June to November. Five northern provinces were particularly affected with Chiangrai being the province with the highest number of cases. In Chiangrai, agricultural activity, elevation, rainfall, temperature and land cover factors contribute to disease burden. These results improve our understanding of the distribution and burden of scrub typhus in Thailand and help to identify factors that may contribute to disease incidence.

Published
2020

23. Human Plasmodium vivax diversity, population structure and evolutionary origin

Author

Peter G. Kremsner, A. Berry, Ali Ould Mohamed Salem Boukary, Tamirat Gebru Woldearegai, Lise Musset, Eric Legrand, Benjamin Mordmüller, Franck Prugnolle, Carlo Severini, Jean-François Trape, François Renaud, Patrick Durand, Pingchai Harnyuttanakorn, Mohammad Shafiul Alam, Lilia González-Cerón, Khadijetou Mint Lekweiry, Beatriz Acuña Hidalgo, Dionicia Gamboa, François Nosten, Eric Elguero, Gustavo Fontecha, Virginie Rougeron, Oscar Noya, Céline Arnathau, Tepanata Pumpaibool, Sandrine Houzé, Sedigheh Zakeri, Rashidul Haque, Musab M. Ali Albsheer, Muzamil Mahdi Abdel Hamid, Health, Emergence, Adaptation and Transmission (MIVEGEC-HEAT), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Malaria and Vector Research Group (MVRG), Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Dipartimento di Malattie infettive = Department of Infectious Diseases [Rome, Italie] (DMI), Istituto Superiore di Sanità (ISS), Institute for Tropical Medicine = Institut für Tropenmedizin, Reisemedizin, Humanparasitolgie [Tübingen, Allemagne] (ITM), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, German Center for Infectious Research - partner site Tübingen [Tübingen, Allemagne] (DZIF), College of Health and Medical Sciences [Harar, Ethiopie], Haramaya University (HU), Centro Regional de Investigación en Salud Pública = Regional Centre of Research in Public Health [Tapachula, Mexique] (CRISP), National Institute of Public Health = Instituto Nacional de Salud Pública [Cuernavaca, Mexique] (INSP), Microbiology Research Institute = Instituto de Investigaciones en Microbiología [Tegucigalpa, Honduras] (IIM), Universidad Nacional Autónoma de Honduras (UNAH), Instituto de Medicina Tropical 'Alexander von Humboldt' (IMT AvH), Universidad Peruana Cayetano Heredia (UPCH), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), Laboratoire de Parasitologie [Cayenne, Guyane française], Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR - laboratoire associé), Centre Collaborateur OMS pour la surveillance de la résistance aux antipaludiques [Cayenne, Guyane française] (CCOMS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP), Centro para Estudios Sobre Malaria [Venezuela], Instituto de Altos Estudios en Salud Dr. Arnoldo Gabaldón, Instituto de Medicina Tropical [Caracas, Venezuela} (IMT), Universidad Central de Venezuela (UCV), Graduate School [Bangkok, Thailande], Chulalongkorn University [Bangkok], College of Public Health Science [Bangkok, Thailande], Department of Biology, Faculty of Science [Bangkok, Thailande], Faculté des Sciences et Techniques [Nouakchott, Mauritania], University of Khartoum, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Authors thank the ANR Tremplin EVAD 2017, IRD and CNRS-INEE., ANR-17-ERC3-0002,EVAD,Histoire évolutive et adaptation génétique de Plasmodium vivax(2017), Laboratoire MIVEGEC (Université de Montpellier-CNRS-IRD), CREES, Montpellier, France., Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Génétique et évolution des maladies infectieuses (GEMI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto Superiore di Sanita [Rome], Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Legrand, Eric, Histoire évolutive et adaptation génétique de Plasmodium vivax - - EVAD2017 - ANR-17-ERC3-0002 - TERC - VALID, Service de Parasitologie et Mycologie, Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], University of Oxford [Oxford]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and Institut Pasteur [Paris]

Subjects
Evolutionary Genetics, 0301 basic medicine, Plasmodium, MESH: Plasmodium vivax / isolation & purification, Genotyping Techniques, Population genetics, [SDV]Life Sciences [q-bio], RC955-962, Plasmodium vivax, MESH: Global Health, Global Health, Microsatellite Loci, Geographical Locations, MESH: Genotype, 0302 clinical medicine, Arctic medicine. Tropical medicine, Global health, MESH: Genetic Variation, MESH: Plasmodium vivax / genetics, Species diversity, education.field_of_study, Ecology, biology, MESH: Plasmodium vivax / classification, 3. Good health, Infectious Diseases, Parasite evolution, Public aspects of medicine, RA1-1270, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, purl.org/pe-repo/ocde/ford#3.03.06 [https], Research Article, Microsatellite loci, Asia, Genotype, Ecological Metrics, 030231 tropical medicine, Population, MESH: Malaria, Vivax / parasitology, Evolutionary genetics, 03 medical and health sciences, Gene Types, MESH: Genotyping Techniques, Parasite Groups, parasitic diseases, Malaria, Vivax, Genetics, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Parasite Evolution, education, Evolutionary Biology, MESH: Humans, Population Biology, Human evolutionary genetics, Ecology and Environmental Sciences, Public Health, Environmental and Occupational Health, Genetic Variation, Biology and Life Sciences, Species Diversity, Plasmodium falciparum, biology.organism_classification, medicine.disease, 030104 developmental biology, Evolutionary biology, People and Places, Africa, Parasitology, Apicomplexa, Population Genetics, Malaria
Abstract

More than 200 million malaria clinical cases are reported each year due to Plasmodium vivax, the most widespread Plasmodium species in the world. This species has been neglected and understudied for a long time, due to its lower mortality in comparison with Plasmodium falciparum. A renewed interest has emerged in the past decade with the discovery of antimalarial drug resistance and of severe and even fatal human cases. Nonetheless, today there are still significant gaps in our understanding of the population genetics and evolutionary history of P. vivax, particularly because of a lack of genetic data from Africa. To address these gaps, we genotyped 14 microsatellite loci in 834 samples obtained from 28 locations in 20 countries from around the world. We discuss the worldwide population genetic structure and diversity and the evolutionary origin of P. vivax in the world and its introduction into the Americas. This study demonstrates the importance of conducting genome-wide analyses of P. vivax in order to unravel its complex evolutionary history., Author summary Among the five Plasmodium species infecting humans, P. vivax is the most prevalent parasite outside Africa. To date, there has been less research on this species than for Plasmodium falciparum, a more lethal species, principally because of the lack of an in vitro culture system and also because P. vivax is considered relatively benign. Nevertheless, P. vivax is responsible for severe and incapacitating clinical symptoms with significant effects on human health. The emergence of new drug resistance and the discovery of severe and even fatal cases due to P. vivax question the benign status of P. vivax malaria. In recent years, there has been increased interest in characterizing the distribution of genetic variation in P. vivax. However, these studies either generated genetic information from a regional geographic scale or combine genetic datasets generated in different molecular platforms, which is known to generate biased results. In this study, we used a single genotyping platform to genotype 14 microsatellite markers in 834 samples of P. vivax obtained from 28 locations in 20 countries from around the world, including several populations from East and West Africa. We discuss the worldwide population genetic structure and the evolutionary origins of P. vivax, as well as its introduction into the Americas.

Published
2020

24. Mass drug administrations with dihydroartemisinin-piperaquine and single low dose primaquine to eliminate Plasmodium falciparum have only a transient impact on Plasmodium vivax: Findings from randomised controlled trials

Author

Tran Tinh Hien, Mallika Imwong, Mavuto Mukaka, Podjanee Jittmala, Jacher Wiladphaingern, Rupam Tripura, Jordi Landier, Tiengkham Pongvongsa, François Nosten, Chea Nguon, Paul N. Newton, May Myo Thwin, Ladda Kajeechiwa, Daniel M. Parker, Phaik Yeong Cheah, Chan Davoeung, Borimas Hanboonkunupakarn, Bipin Adhikari, Koukeo Phommasone, Huy Rekol, Sasithon Pukrittayakamee, Mayfong Mayxay, Cholrawee Promnarate, Stephane Proux, Thomas J. Peto, Nicholas J. White, Arjen M. Dondorp, Khin Maung Lwin, Mehul Dhorda, Lorenz von Seidlein, Pimnara Peerawaranun, Suphak Nosten, Kesinee Chotivanich, Guy E. Thwaites, Thuy-Nhien Nguyen, Frank Cobelens, Frank van Leth, Nicholas P. J. Day, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, VU University Medical Center [Amsterdam], Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Savannakhet Provincial Health Department [Lao People’s Democratic Republic], Savannakhet Province [Lao People’s Democratic Republic], Department of Clinical Tropical Medicine [Bangkok, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of California [Irvine] (UC Irvine), University of California (UC), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Provincial Health Department [Battambang, Cambodia] (PHD), WWARN Asia Regional Centre [Bangkok, Thailand], Department of Molecular Tropical Medicine and Genetics [Bangkok, Thaïlande], Faculty of Tropical Medicine [Bangkok, Thaïlande], Mahidol University [Bangkok]-Mahidol University [Bangkok], Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), Dupuis, Christine, Graduate School, AII - Infectious diseases, APH - Global Health, APH - Methodology, Global Health, APH - Quality of Care, Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of California [Irvine] (UCI), and University of California

Subjects
Male, Plasmodium vivax, Primaquine, 0302 clinical medicine, Dihydroartemisinin/piperaquine, MESH: Child, Medicine, Child, MESH: Treatment Outcome, Protozoans, Malarial Parasites, Eukaryota, MESH: Myanmar, MESH: Primaquine, 16. Peace & justice, Artemisinins, 3. Good health, Plasmodium Falciparum, [SDV] Life Sciences [q-bio], Vietnam, MESH: Young Adult, Mass Drug Administration, MESH: Mass Drug Administration, medicine.medical_specialty, Drug Administration, Science, 03 medical and health sciences, Antimalarials, Drug Therapy, MESH: Artemisinins, Humans, Mass drug administration, MESH: Prevalence, Pharmacology, MESH: Adolescent, MESH: Humans, Organisms, Biology and Life Sciences, MESH: Malaria, Vivax, MESH: Adult, medicine.disease, Tropical Diseases, Parasitology, Apicomplexa, MESH: Female, Malaria, Plasmodium, [SDV]Life Sciences [q-bio], Vivax, Myanmar, Geographical Locations, Recurrence, Prevalence, Medicine and Health Sciences, Cumulative incidence, 030212 general & internal medicine, Malaria, Falciparum, 2. Zero hunger, Multidisciplinary, biology, Pharmaceutics, Incidence (epidemiology), MESH: Malaria, Falciparum, Drugs, Treatment Outcome, Quinolines, Female, Cambodia, MESH: Quinolines, medicine.drug, Research Article, Falciparum, Adult, Asia, Adolescent, General Science & Technology, 030231 tropical medicine, Young Adult, Internal medicine, Parasite Groups, parasitic diseases, Malaria, Vivax, Parasitic Diseases, business.industry, MESH: Cambodia, Plasmodium falciparum, biology.organism_classification, MESH: Antimalarials, Parasitic Protozoans, MESH: Male, MESH: Recurrence, People and Places, MESH: Vietnam, business
Abstract

Author(s): Phommasone, Koukeo; van Leth, Frank; Peto, Thomas J; Landier, Jordi; Nguyen, Thuy-Nhien; Tripura, Rupam; Pongvongsa, Tiengkham; Lwin, Khin Maung; Kajeechiwa, Ladda; Thwin, May Myo; Parker, Daniel M; Wiladphaingern, Jacher; Nosten, Suphak; Proux, Stephane; Nguon, Chea; Davoeung, Chan; Rekol, Huy; Adhikari, Bipin; Promnarate, Cholrawee; Chotivanich, Kesinee; Hanboonkunupakarn, Borimas; Jittmala, Podjanee; Cheah, Phaik Yeong; Dhorda, Mehul; Imwong, Mallika; Mukaka, Mavuto; Peerawaranun, Pimnara; Pukrittayakamee, Sasithon; Newton, Paul N; Thwaites, Guy E; Day, Nicholas PJ; Mayxay, Mayfong; Hien, Tran Tinh; Nosten, Francois H; Cobelens, Frank; Dondorp, Arjen M; White, Nicholas J; von Seidlein, Lorenz | Abstract: BackgroundMass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections.MethodsBetween May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression.Results3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42).ConclusionMDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria.

Published
2020

25. Significant efficacy of single low dose primaquine compared to stand alone artemisinin combination therapy in reducing gametocyte carriage in Cambodian patients with uncomplicated multidrug resistant Plasmodium falciparum malaria

Author

Walter R. J. Taylor, Amélie Vantaux, Mavuto Mukaka, Sovannaroth Siv, Nimol Khim, Laura Berne, Dysoley Lek, Saorin Kim, Eakpor Piv, Sophy Chy, Didier Menard, Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), School of Public Health [Phnom Penh, Cambodge], National Institute of Public Health [Phnom Penh, Cambodge], Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], This work was supported by the Institut Pasteur of Cambodia, FEI 5% initiative (grant number 12INI211, ‘Towards malaria elimination: effective strategies against transmission. The new challenges in South East Asia’), Rotary Club (grant number GG1523934, ‘Amélioration des capacités en entomologie des acteurs luttant contre le paludisme et de de la compréhension de la transmission du paludisme’), USAID/PMI/CDC through Malaria Consortium (‘The tolerability and safety of low dose primaquine for transmission blocking in symptomatic falciparum infected Cambodians’) and Dedonder Clayton (grant number EC/MAM/N°325/14). AV was supported by a post-doctoral fellowship from the International Division, Institut Pasteur, Paris, France, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], and This work was supported by the Institut Pasteur of Cambodia, FEI 5% initiative (grant number 12INI211, Towards malaria elimination: effective strategies against transmission. The new challenges in South East Asia), the Rotary Club (grant number GG1523934, Amélioration des capacités en entomologie des acteurs luttant contre le paludisme et de de la compréhension de la transmission du paludisme), USAID/PMI/CDC through the Malaria Consortium (The tolerability and safety of low dose primaquine for transmission blocking in symptomatic falciparum infected Cambodians), and Dedonder Clayton (grant number EC/MAM/N°325/14). A.V. was supported by a postdoctoral fellowship from the International Division, Institut Pasteur, Paris, France.

Subjects
medicine.medical_specialty, Primaquine, Combination therapy, primaquine, 030231 tropical medicine, Plasmodium falciparum, malaria, law.invention, Epidemiology and Surveillance, 03 medical and health sciences, Antimalarials, 0302 clinical medicine, Randomized controlled trial, Asian People, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, parasitic diseases, medicine, Gametocyte, Animals, Humans, Pharmacology (medical), [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030212 general & internal medicine, Artemisinin, Malaria, Falciparum, Pharmacology, biology, business.industry, direct membrane feeding assays, biology.organism_classification, medicine.disease, Artemisinins, direct-membrane feeding assays, Multiple drug resistance, Infectious Diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Drug Therapy, Combination, transmission blocking, business, Cambodia, Malaria, medicine.drug, transmission-blocking
Abstract

Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy., Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.)

Published
2020

26. Towards harmonization of microscopy methods for malaria clinical research studies

Author

Jane Carter, J. Kevin Baird, Ric N. Price, Piero Olliaro, John C. Reeder, Michelle L. Gatton, Peter Obare, Philippe J Guerin, El Hadji Ba, Stephane Proux, Derek Bell, Cheikh Sokhna, Andrew Ramsay, Arjen M. Dondorp, Mehul Dhorda, Ken Lilley, François Nosten, Didier Menard, Kamolrat Silamut, Lenny L Ekawati, Iveth J González, John W. Barnwell, Bernhards Ogutu, Sandra Incardona, WorldWide Antimalarial Resistance Network [Bangkok] (WWARN), WorldWide Antimalarial Resistance Network (WWARN), University of Washington [Seattle]-University of Washington [Seattle], University of Oxford, Mahidol University [Bangkok], Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Eijkman Institute for Molecular Biology [Jakarta], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Amref Health Africa [Kenya], African Medical and Research Foundation (AMREF), Queensland University of Technology [Brisbane] (QUT), Terre des hommes [Lausanne], WorldWide Antimalarial Resistance Network, WWARN, Foundation for Innovative New Diagnostics (FIND), Australian Defence Force Malaria and Infectious Disease Institute [Enoggera] (ADFMIDI), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Kenya Medical Research Institute (KEMRI), Menzies School of Health Research [Australia], Charles Darwin University [Australia], University of Saint Andrews, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), UNICEF Headquarters-World Bank Group-United Nations Development Programme (UNDP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Université de Washington Seattle-Université de Washington Seattle, University of Oxford [Oxford], Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, Charles Darwin University, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-UNICEF Headquarters-World Bank Group-United Nations Development Programme (UNDP), and University of St Andrews. School of Medicine

Subjects
Laboratory Proficiency Testing, MESH: Quality Control, Review, MESH: Laboratory Proficiency Testing, Clinical research, 0302 clinical medicine, RA0421, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RA0421 Public health. Hygiene. Preventive Medicine, Microscopy, 030212 general & internal medicine, Reliability (statistics), Standard, 3. Good health, MESH: Reproducibility of Results, MESH: Staining and Labeling, Infectious Diseases, T-DAS, Quality Control, medicine.medical_specialty, lcsh:Arctic medicine. Tropical medicine, MESH: Microscopy, lcsh:RC955-962, 030231 tropical medicine, MESH: Malaria, Harmonization, Sensitivity and Specificity, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, SDG 3 - Good Health and Well-being, parasitic diseases, medicine, Humans, lcsh:RC109-216, Medical physics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Diagnostic, MESH: Diagnostic Tests, Routine, MESH: Humans, Staining and Labeling, Diagnostic Tests, Routine, business.industry, Reproducibility of Results, medicine.disease, MESH: Sensitivity and Specificity, Malaria, Clinical trial, Quality management system, Parasitology, business, Quality assurance
Abstract

Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.

Published
2020

27. Extreme neonatal hyperbilirubinaemia in refugee and migrant populations

Author

Jordi Landier, Laurence Thielemans, Borimas Hanboonkunupakarn, Claudia Turner, François Nosten, Mue Chae Darakamon, Eva Maria Nadine Wouda, Patrick F. van Rheenen, Aye Aye Nge, Thatsanun Ngerseng, Sanda Khing, Rose McGready, Wah Wah Say, Verena I. Carrara, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University Medical Center Groningen [Groningen] (UMCG), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cambodia-Oxford Medical Research Unit [Siem Reap, Cambodia], Angkor Hospital for Children (AHC), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Swiss Tropical and Public Health Institute [Basel], Dupuis, Christine, University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford [Oxford]-University of Oxford [Oxford], and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Pediatrics, medicine.medical_specialty, Percentile, medicine.medical_treatment, [SDV]Life Sciences [q-bio], low-income and middle-income countries, Exchange transfusion, RJ1-570, Limited access, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, medicine, kernicterus, limited-resource setting, refugee, neurological outcome, neonatal jaundice, 030219 obstetrics & reproductive medicine, Neurodisability, neurodevelopment, business.industry, Gestational age, Retrospective cohort study, Jaundice, medicine.disease, extreme neonatal hyperbilirubinaemia, 3. Good health, Bilirubin encephalopathy, [SDV] Life Sciences [q-bio], migrant, Pediatrics, Perinatology and Child Health, Kernicterus, neonatal hyperbilirubinaemia, medicine.symptom, business
Abstract

ObjectiveTo describe neonatal survival and long-term neurological outcome in neonatal hyperbilirubinaemia (NH) with extreme serum bilirubin (SBR) values.DesignRetrospective chart review, a one-off neurodevelopmental evaluation.SettingSpecial care baby unit in a refugee camp and clinics for migrant populations at the Thailand–Myanmar border with phototherapy facilities but limited access to exchange transfusion (ET).PatientsNeonates ≥28 weeks of gestational age with extreme SBR values and/or acute neurological symptoms, neurodevelopment evaluation conducted at 23–97 months of age.Main outcome measuresNeonatal mortality rate, prevalence of acute bilirubin encephalopathy (ABE) signs, prevalence of delayed development scores based on the Griffiths Mental Development Scale (GMDS).ResultsFrom 2009 to 2014, 1946 neonates were diagnosed with jaundice; 129 (6.6%) had extreme SBR values during NH (extreme NH). In this group, the median peak SBR was 430 (IQR 371–487) µmol/L and the prevalence of ABE was 28.2%. Extreme NH-related mortality was 10.9% (14/129). Median percentile GMDS general score of 37 survivors of extreme NH was poor: 11 (2–42). ‘Performance’, ‘practical reasoning’ and ‘hearing and language’ domains were most affected. Four (10.8%) extreme NH survivors had normal development scores (≥50th centile). Two (5.4%) developed the most severe form of kernicterus spectrum disorders.ConclusionIn this limited-resource setting, poor neonatal survival and neurodevelopmental outcomes, after extreme NH, were high. Early identification and adequate treatment of NH where ET is not readily available are key to minimising the risk of extreme SBR values or neurological symptoms.

Published
2020

28. Robust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages

Author

Kevin S. W. Tan, Kate Breyer, Georges Snounou, Clemens H. M. Kocken, Anne Elliot, Bruce Russell, Varakorn Kosaisavee, Bryan K. S. Yeung, Bee Huat Tan, Adeline C. Y. Chua, Rossarin Suwanarusk, Siti Nurdiana Abas, Rou Zhang, Anne-Marie Zeeman, Jee Sun Cho, Benoit Malleret, Laurent Rénia, Roger Le Grand, Dennis E. Kyle, Mary R. Galinski, Christophe Bodenreider, Nathalie Dereuddre-Bosquet, Chester J. Joyner, François Nosten, Dominique Mazier, Szczepan W Baran, Pablo Bifani, Amber Lange, Jessica Jie Ying Ong, Thierry T. Diagana, Steven P. Maher, Caitlin A. Cooper, Andy M. Yip, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Global Health Division, Menzies School of Health Research, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Primate Research Centre [Rijswijk] (BPRC), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Novartis Institute for Tropical Diseases (NITD), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford-Mahidol University [Bangkok], and ANR-17-CE13-0025,IMHyp,Recherches sur l'Hypnozoïte du Paludisme(2017)

Subjects
0301 basic medicine, Erythrocytes, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Science, General Physics and Astronomy, 02 engineering and technology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Malaria transmission, Plasmodium cynomolgi, Anopheles, parasitic diseases, in vitro culture, medicine, Parasite hosting, Model protists, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:Science, Multidisciplinary, Drug discovery, Monkey Diseases, High-throughput screening, Plasmodium falciparum, General Chemistry, 021001 nanoscience & nanotechnology, biology.organism_classification, medicine.disease, Virology, In vitro, 3. Good health, Malaria, 030104 developmental biology, Macaca, lcsh:Q, 0210 nano-technology
Abstract

The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax, the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi, a macaque-infecting species phylogenetically close to P. vivax, was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax. We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti-P. vivax drug discovery efforts., Present understanding of Plasmodium vivax biology is hampered by its inability to grow in vitro. Here, the authors developed an in vitro culture of its simian counterpart, P. cynomolgi, which shares morphological and phenotypic similarities with P. vivax, initiating a new phase in vivax research.

Published
2019

29. Intracluster correlation coefficients in the Greater Mekong Subregion for sample size calculations of cluster randomized malaria trials Malaria Journal

Author

Peerawaranun, Pimnara, Landier, Jordi, Nosten, Francois H., Nguyen, Thuy-Nhien, Hien, Tran Tinh, Tripura, Rupam, Peto, Thomas J., Phommasone, Koukeo, Mayxay, Mayfong, Day, Nicholas P. J., Dondorp, Arjen, White, Nick, von Seidlein, Lorenz, Mukaka, Mavuto, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), VU University Medical Center [Amsterdam], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), NJW is the recipient of the Wellcome Trust Award Number: 101148/Z/13/Z. AMD is the recipient of the Bill and Melinda Gates Foundation Award Number: OPP1081420., HAL AMU, Administrateur, Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and University of Oxford [Oxford]-University of Oxford [Oxford]

Subjects
[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, ICC, Sample size, Incidence, Cluster randomized trial, parasitic diseases, Prevalence, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, P. falciparum, P. vivax Bootstrapping, Malaria
Abstract

International audience; Background: Sample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters. Methods: Data on uPCR-detected Plasmodium falciparum and Plasmodium vivax infections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence of Plasmodium infections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized. Results: The ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 for P. falciparum and P. vivax respectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up. Conclusion: ICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogene-ity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

Published
2019

30. The role of monitoring and evaluation to ensure functional access to community-based early diagnosis and treatment in a malaria elimination programme in Eastern Myanmar

Author

Rae, JD, Nosten, S, Proux, S, Myint Thu, A, Cho, WC, Paw, K, Paw, ES, Shee, PB, Be, SA, Dah, SH, Moo, SKL, Minh, SMC, Shee, PW, Wiladphaingern, J, Tun, SW, Kajeechiwa, L, Thwin, MM, Delmas, G, Nosten, FH, Landier, J, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Bill & Melinda Gates Foundation (OPP1117507), The Global Fund against AIDs, Tuberculosis and Malaria (Regional Artemisinin Initiative & RAI2E), and The Wellcome Trust (041843)., University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford-University of Oxford, and Dupuis, Christine

Subjects
Male, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Pilot Projects, Malaria elimination, Myanmar, Health Services Accessibility, lcsh:Infectious and parasitic diseases, Antimalarials, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Surveys and Questionnaires, parasitic diseases, Disease Transmission, Infectious, Secondary Prevention, Humans, lcsh:RC109-216, Community Health Services, Monitoring and evaluation, Surveillance, Diagnostic Tests, Routine, Research, Malaria post, Malaria, Early Diagnosis, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Health Services Research
Abstract

Background Improving access to early diagnosis and treatment (EDT) has increasingly proven to be a major contributor to decreasing malaria incidence in low-transmission settings. The Malaria Elimination Task Force (METF) has deployed malaria posts set up in Eastern Myanmar, providing free uninterrupted community-based access to EDT in more than 1200 villages. Ensuring high quality services are provided by these malaria posts is essential to reaching elimination targets. The present study aimed to determine the functionality of the malaria posts in the METF programme. Methods This report analysed routinely collected data (weekly reports, individual consultation, diagnostic test quality control) and data collected specifically during monitoring and evaluation visits using descriptive statistics and univariate logistic regression. The presence of major dysfunctions (stock-outs and reported closing; likely to impair the ability of the population to access EDT) or minor dysfunctions (no formal METF training, lack of regular salary, forms and manual not on-site, and low frequency of supervisor visits) and the ability to anticipate dysfunctions through analysis of weekly reports were assessed. Results A total of 65% of malaria posts had no major dysfunction identified during monitoring and evaluation visits, while 86% of malaria posts were fully stocked with tests and medicines used for treatment. Diagnosis was correctly conducted with few false positives and rare mis-speciation of results. Malaria post worker knowledge of malaria treatments showed few gaps, mostly in the treatment of more complex presentations. Malaria posts were well utilized in the population, with 94% of consultations occurring within the first 3 days of fever. In the regression analysis, reported stock-outs and delayed weekly reports were associated with observed major and minor dysfunctions in monitoring and evaluation visits, emphasizing the need to reinforce support to malaria post supervisors, who were responsible for the local logistics of supply and data transmission and day-to-day supervision. Conclusion The malaria posts operating under the METF programme perform to a high standard, with the majority offering uninterrupted access to diagnosis and treatment, and high service uptake in the villages serviced by the programme. However, programme operations can be strengthened by increasing malaria post supervisor visits and re-training malaria post workers. Electronic supplementary material The online version of this article (10.1186/s12936-019-2677-2) contains supplementary material, which is available to authorized users.

Published
2019

31. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study

Author

Chanon Kunasol, Mehul Dhorda, Didier Menard, Frank Smithuis, Mallika Imwong, Rob W. van der Pluijm, Nicholas P. J. Day, Huy Rekol, Kanokon Suwannasin, Olivo Miotto, Arjen M. Dondorp, Kreepol Sutawong, Kyaw Myo Tun, Rupam Tripura, Mayfong Mayxay, Nicholas J. White, Tin Maung Hlaing, Department of Molecular Tropical Medicine and Genetics [Bangkok, Thaïlande], Faculty of Tropical Medicine [Bangkok, Thaïlande], Mahidol University [Bangkok]-Mahidol University [Bangkok], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Buntharik Hospital [Thaïlande], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, University of Health Sciences [Vientiane, Laos] (UHS), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Defence Services Medical Research Centre [Naypyitaw, Myanmar] (DSMRC), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), WWARN Asia Regional Centre [Bangkok, Thailand], Mahidol University [Bangkok], and The Wellcome Trust and the Bill and Melinda Gates Foundation.

Subjects
0301 basic medicine, MESH: Mutation, 030231 tropical medicine, Plasmodium falciparum, Drug Resistance, Drug resistance, Biology, MESH: Genotype, 03 medical and health sciences, Antimalarials, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Piperaquine, Genotype, MESH: Artemisinins, parasitic diseases, medicine, MESH: Molecular Epidemiology, Humans, Artemisinin, Malaria, Falciparum, MESH: Thailand, Genotyping, MESH: Plasmodium falciparum, MESH: Humans, Molecular epidemiology, MESH: Cambodia, MESH: Malaria, Falciparum, Articles, medicine.disease, biology.organism_classification, Virology, MESH: Antimalarials, Artemisinins, 3. Good health, 030104 developmental biology, Infectious Diseases, MESH: Laos, MESH: Drug Resistance, MESH: Microsatellite Repeats, Malaria, MESH: Quinolines, medicine.drug
Abstract

Erratum in : Corrections. [Lancet Infect Dis. 2017]Comment in : Evidence of a hard selective sweep for artemisinin resistant Plasmodium falciparum. [Lancet Infect Dis. 2017]; International audience; BACKGROUND:Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion.METHODS:In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness.FINDINGS:As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014-15, a single long PfKelch13 C580Y haplotype (-50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin.INTERPRETATION:Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective.

Published
2017

32. Mass spectrometry-based proteomic techniques to identify cerebrospinal fluid biomarkers for diagnosing suspected central nervous system infections. A systematic review

Author

Bevin Gangadharan, Xavier de Lamballerie, Paul N. Newton, Abhinav Kumar, Tehmina Bharucha, Markus Winterberg, Nicole Zitzmann, Audrey Dubot-Pérès, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Department of Biochemistry [Oxford, UK] (Institute of Glycobiology ), Institute of Glycobiology [Oxford, UK], Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], The work was supported by the University of Oxford and the Medical Research Council [grant number MR/N013468/1]. It wasalso supported by the Oxford Glycobiology endowment, Total Foundation, Horizon 2020 research and innovation programmeEVAg [grant number 653316], the Institute of Research for Development (IRD), Aix-Marseille University, the Wellcome Trust of Great Britain that supports LOMWRU and PNN., University of Oxford-University of Oxford, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, and BUISINE, Soline

Subjects
0301 basic medicine, Male, Proteomics, Proteome, Cns infections, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), English language, medicine.disease_cause, 0302 clinical medicine, Cerebrospinal fluid, Central Nervous System Infections, Diagnosis, 030212 general & internal medicine, Biomarker discovery, Child, Cerebrospinal Fluid, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Aged, 80 and over, Cross Infection, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Diagnostic Techniques, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Peptide sequencing, Drainage, Biomarker (medicine), Female, Microbiology (medical), Adult, medicine.medical_specialty, Adolescent, Neurological infections, 030106 microbiology, Central nervous system, Article, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Aged, Mass spectrometry, business.industry, Infant, Newborn, Infant, ROC Curve, business, Biomarkers
Abstract

Highlights • We performed a systematic review of MS-based peptide sequencing to identify cerebrospinal fluid biomarkers to diagnose neurological infections. • Eleven studies were identified, with results demonstrating feasibility and potential for diagnosis of a range of aetiologies, including tuberculosis, West Nile virus infection and trypanosomiasis. • Six studies performed further work termed verification or validation. In two of these studies, it was possible to extract data on sensitivity and specificity of the biomarkers detected by ELISA, ranging from 89–94% and 58–92% respectively. • We highlight the need for strong interdisciplinary collaboration and investment in these studies, to ensure appropriate study design, and see biomarkers progress through to validation. • Successful CSF protein biomarkers could potentially be detected by MALDI-ToF, ELISA and point-of-care immunochromatographic tests., Summary Objectives Central nervous system (CNS) infections account for considerable death and disability every year. An urgent research priority is scaling up diagnostic capacity, and introduction of point-of-care tests. We set out to assess current evidence for the application of mass spectrometry (MS) peptide sequencing in identification of diagnostic biomarkers for CNS infections. Methods We performed a systematic review (PROSPERO—CRD42018104257) using PRISMA guidelines on use of MS to identify cerebrospinal fluid (CSF) biomarkers for diagnosing CNS infections. We searched PubMed, Embase, Web of Science, and Cochrane for articles published from 1 January 2000 to 1 February 2019, and contacted experts. Inclusion criteria involved primary research except case reports, on the diagnosis of infectious diseases except HIV, applying MS to human CSF samples, and English language. Results 4,620 papers were identified, of which 11 were included, largely confined to pre-clinical biomarker discovery, and eight (73%) published in the last five years. 6 studies performed further work termed verification or validation. In 2 of these studies, it was possible to extract data on sensitivity and specificity of the biomarkers detected by ELISA, ranging from 89–94% and 58–92% respectively. Conclusions The findings demonstrate feasibility and potential of the methods in a variety of infectious diseases, but emphasise the need for strong interdisciplinary collaborations to ensure appropriate study design and biomarker validation.

Published
2019

33. Antibacterial activity of sustainable composites derived from epoxidized natural rubber/silver-substituted zeolite/poly(lactic acid) blends

Author

Watanalai Panbangred, Mayura Janhom, Philippe Daniel, Phruedsaporn Taranamai, Pranee Phinyocheep, Department of Chemistry, Mahidol University (Department of Chemistry, Mahidol University), Mahidol University [Bangkok], Collaborative Research Center for Bioscience and Biotechnology (CRC), and Mahidol University [Bangkok]-Osaka University [Osaka]

Subjects
Absorption of water, Materials science, 020502 materials, Mechanical Engineering, technology, industry, and agriculture, Young's modulus, Izod impact strength test, 02 engineering and technology, Casting, Lactic acid, symbols.namesake, chemistry.chemical_compound, [CHIM.POLY]Chemical Sciences/Polymers, 0205 materials engineering, Natural rubber, chemistry, Mechanics of Materials, visual_art, symbols, visual_art.visual_art_medium, General Materials Science, Composite material, Antibacterial activity, Zeolite, ComputingMilieux_MISCELLANEOUS
Abstract

Sustainable composites derived from epoxidized natural rubber (ENR)/silver-substituted zeolite (AgZ)/poly(lactic acid) (PLA) blends possessing antibacterial activity were reported. ENR, herein, acted as an antibacterial promoter providing more hydrophilicity to the composites and facilitating water diffusion. Two methodologies were used to prepare composites, including solution casting (S) as well as solution casting followed by roll milling (SR). Both composites were compared in terms of morphology, AgZ dispersion, water absorption, and antibacterial activity. The shift of Tg and tan δ toward lower temperature of PLA composites consistently confirmed the compatibility between ENR and PLA by DSC and DMA results, respectively. The good AgZ distribution was observed in composites-SR, as confirmed by SEM/EDX. The results of agar disk diffusion susceptibility test showed that PLA, AgZ/PLA, and even ENR/AgZ/PLA composites-S showed no or less inhibition zone; meanwhile, ENR/AgZ/PLA composites-SR showed the significant inhibition zone against both Escherichia coli and Staphylococcus aureus. Besides, the antibacterial activity of the composites was required at least 5 wt% of AgZ. More than 98% inhibition of S. aureus growth by the composites-SR was observed during 2–24 h of cultivation, whereas AgZ/PLA provided the highest inhibition of only 75% at 24 h of cultivation. Hence, the incorporation of ENR enhances the bactericidal activity of the composites. In terms of mechanical properties, incorporating ENR into the composites decreased tensile modulus and strength, but increased the impact strength significantly. Therefore, the developed composites could be promising materials in food and biomedical fields in which antibacterial and impact resistance properties are required.

Published
2019

34. Author Correction:The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density

Author

Chris Drakeley, Ingrid Felger, Ogobara K. Doumbo, Endalamaw Gadisa, Naomi W. Lucchi, Ivo Mueller, Safiatou Doumbo, Bronner P. Gonçalves, Leanne J. Robinson, Natalie E. Hofmann, Robert W. Sauerwein, Mwinyi I. Msellem, Gonzalo J. Domingo, Cécile Nabet, Cristian Koepfli, Richard Paul, Teun Bousema, Jacklin F. Mosha, Anders Björkman, Eleanor M. Riley, Roly Gosling, Melissa C. Kapulu, Jackie Cook, Venkatachalam Udhayakumar, François Nosten, Alfred B. Tiono, Lucy C Okell, Mallika Imwong, Hannah C Slater, Daniel Chandramohan, André Lin Ouédraogo, Nicholas J. White, Renaud Piarroux, Kwadwo A. Koram, Smita Das, Felista Mwingira, Fitsum G. Tadesse, Ulrika Morris, Amanda Ross, Janet Midega, Seth Owusu-Agyei, Imperial College London, Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), The Walter and Eliza Hall Institute of Medical Research (WEHI), Papua New Guinea Institute for Medical Research (PNGIMR), University of Melbourne, Burnet Institute [Melbourne, Victoria], London School of Hygiene and Tropical Medicine (LSHTM), Karolinska Institutet [Stockholm, Sweden], Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), Institute for Disease Modeling (IDM), Mnazi Mmoja Hospital, Zanzibar, University of Notre Dame [Indiana] (UND), Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors, Institut Pasteur [Paris], Radboud University Medical Centre [Nijmegen, The Netherlands], Armauer Hansen Research Institute (AHRI), Addis Ababa University (AAU), Diagnostics Program [Seattle, WA, USA] (PATH), KEMRI-Wellcome Trust Research Programme (KWTRP), University of Oxford [Oxford], University of Health and Allied Sciences [Ho] (UHAS), Ecosystemes Amazoniens et Pathologie Tropicale (EPat), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Guyane (UG), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Epidemiology of Parasitic Diseases, Université de Bamako-Malaria Research and Training Centre, Noguchi Memorial Institute for Medical Research [Accra, Ghana] (NMIMR), University of Ghana, Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Mwanza Medical Research Centre (MITU), University of California, Dares Salaam University College of Education, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), University of Edinburgh, Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Mahidol University [Bangkok], Radboud university [Nijmegen], and MR/R015600/1/MRC_/Medical Research Council/United KingdomU19 AI129392/AI/NIAID NIH HHS/United States

Subjects
Time Factors, Science, Plasmodium falciparum, General Physics and Astronomy, Parasitemia, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MD Multidisciplinary, Diagnosis, Animals, Humans, Parasites, Malaria, Falciparum, lcsh:Science, Author Correction, Parasite density, 030304 developmental biology, Probability, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, Science & Technology, biology, 030306 microbiology, General Chemistry, biology.organism_classification, Malaria, Multidisciplinary Sciences, Germ Cells, Evolutionary biology, Science & Technology - Other Topics, lcsh:Q
Abstract

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.

Published
2019

35. Management of Central Nervous System Infections, Vientiane, Laos, 2003–2011

Author

Phonelavanh Phoumin, Amphonesavanh Sengduangphachanh, Rattanaphone Phetsouvanh, Mary-Anne Burns, Scott B. Craig, Valy Keoluangkot, Audrey Dubot-Pérès, Olay Lattana, Khonesavanh Luangxay, Prasith Phimmasone, Koukeo Phommasone, Sue J. Lee, Manivanh Vongsouvath, Kongkham Sisout, David A. B. Dance, Amphaivanh Seubsanith, Catrin E. Moore, Mayfong Mayxay, Khamsai Detleuxay, Vilada Chansamouth, Viengmon Davong, Sabine Dittrich, Xavier de Lamballerie, S. M. Tulsiani, Stuart D. Blacksell, Inpanh Phouangsouvanh, Sayaphet Rattanavong, Phonepasith Panyanivong, Paul N. Newton, Anisone Chanthongthip, Bountoy Sibounheuang, Manivone Simmalavong, Joy Sirisouk, Davanh Sengdatka, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, University of Health Sciences, Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Nuffield Department of Clinical Medicine [Oxford], University of Oxford [Oxford], Mahosot Hospital, Queensland Health Forensic and Scientific Services, London School of Hygiene and Tropical Medicine (LSHTM), This work was supported by the Wellcome Trust of Great Britain, the Institute of Research for Development, AixMarseille University, and the European Union’s Horizon 2020 research and innovation program European Virus Archive global (grant agreement no. 653316)., European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Graduate School, AII - Infectious diseases, APH - Global Health, APH - Methodology, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford, BUISINE, Soline, and European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID

Subjects
Infectious Encephalitis, Male, Orientia tsutsugamushi, Epidemiology, encephalitis, Antibiotics, Cryptococcus, lcsh:Medicine, antibiotics, 0302 clinical medicine, 030212 general & internal medicine, Prospective Studies, Rickettsia, Child, bacteria, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Leptospira, Cross Infection, biology, diabetes, Mortality rate, Health Policy, meningitis, 3. Good health, Infectious Diseases, Laos, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Ceftriaxone, Female, meningitis/encephalitis, Meningitis, Encephalitis, medicine.drug, Microbiology (medical), Adult, medicine.medical_specialty, patient care management, Asia, Adolescent, medicine.drug_class, viral infections, 030231 tropical medicine, central nervous system infections, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Young Adult, Internal medicine, WHO meningitis, medicine, Humans, lcsh:RC109-216, viruses, antimicrobial medicines, business.industry, Research, lcsh:R, Infant, WHO encephalitis, Japanese encephalitis, medicine.disease, biology.organism_classification, mortality, Japanese encephalitis virus, bacterial infections, Lao, business
Abstract

International audience; During 2003-2011, we recruited 1,065 patients of all ages admitted to Mahosot Hospital (Vientiane, Laos) with suspected central nervous system (CNS) infection. Etiologies were laboratory confirmed for 42.3% of patients, who mostly had infections with emerging pathogens: viruses in 16.2% (mainly Japanese encephalitis virus [8.8%]); bacteria in 16.4% (including Orientia tsutsugamushi [2.9%], Leptospira spp. [2.3%], and Rickettsia spp. [2.3%]); and Cryptococcus spp. fungi in 6.6%. We observed no significant differences in distribution of clinical encephalitis and meningitis by bacterial or viral etiology. However, patients with bacterial CNS infection were more likely to have a history of diabetes than others. Death (26.3%) was associated with low Glasgow Coma Scale score, and the mortality rate was higher for patients with bacterial than viral infections. No clinical or laboratory variables could guide antibiotic selection. We conclude that high-dependency units and first-line treatment with ceftriaxone and doxycycline for suspected CNS infections could improve patient survival in Laos.

Published
2019

36. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: a cluster randomised trial

Author

Von Seidlein, L, Peto, TJ, Landier, J, Nguyen, T-N, Tripura, R, Phommasone, K, Pongvongsa, T, Lwin, KM, Keereecharoen, L, Kajeechiwa, L, Thwin, MM, Parker, DM, Wiladphaingern, J, Nosten, S, Proux, S, Corbel, V, Tuong-Vy, N, Phuc-Nhi, TL, Son, DH, Huong-Thu, PN, Tuyen, NTK, Tien, NT, Dong, LT, Hue, DV, Quang, HH, Nguon, C, Davoeung, C, Rekol, H, Adhikari, B, Henriques, G, Phongmany, P, Suangkanarat, P, Jeeyapant, A, Vihokhern, B, Van Der Pluijm, RW, Lubell, Y, White, LJ, Aguas, R, Promnarate, C, Sirithiranont, P, Malleret, B, Rénia, L, Onsjö, C, Chan, XH, Chalk, J, Miotto, O, Patumrat, K, Chotivanich, K, Hanboonkunupakarn, B, Jittmala, P, Kaehler, N, Cheah, PY, Pell, C, Dhorda, M, Imwong, M, Snounou, G, Mukaka, M, Peerawaranun, P, Lee, SJ, Simpson, JA, Pukrittayakamee, S, Singhasivanon, P, Grobusch, MP, Cobelens, F, Smithuis, F, Newton, PN, Thwaites, GE, Day, NPJ, Mayxay, M, Hien, TT, Nosten, FH, Dondorp, AM, White, NJ, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Department of Infectious Diseases [Amsterdam, Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA)-Center for Tropical and Travel Medicine [Amsterdam, Netherlands], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], Savannakhet Provincial Health Department [Lao People’s Democratic Republic], Savannakhet Province [Lao People’s Democratic Republic], Department of Clinical Tropical Medicine [Bangkok, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok], Department of Population Health and Disease Prevention [Irvine, CA, USA], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institute of Malariology, Parasitology, and Entomology [Ho Chi Minh City, Vietnam] (IMPE), Center for Malariology, Parasitology and Entomology [Ninh Thuan Province, Vietnam] (CMPE), Institute of Malariology, Parasitology, and Entomology [Quy Nhon, Vietnam] (IMPE), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Provincial Health Department [Battambang, Cambodia] (PHD), Department of Pathogen Molecular Biology [London, UK], London School of Hygiene and Tropical Medicine (LSHTM), WWARN Asia Regional Centre [Bangkok, Thailand], Department of Microbiology & Immunology [Singapore] (Yong Loo Lin School of Medicine), National University of Singapore (NUS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Department of Oncology, Clinical and Experimental Medicine, Faculty of Health Sciences [Linköping University ], Linköping University (LIU), Wellcome Trust Sanger Institute [Hinxton, UK], Department of Molecular Tropical Medicine and Genetics [Bangkok, Thailand] (Faculty of Tropical Medicine), Department of Tropical Hygiene [Bangkok, Thailand] (Faculty of Tropical Medicine), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Epidemiology and Biostatistics [Victoria, Australia], University of Melbourne-Melbourne School of Population and Global Health [Victoria, Australia], Royal Society of Thailand [Bangkok, Thailand], Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), NJW is the recipient of the Wellcome Trust Award Number: 101148/Z/13/Z. AMD is the recipient of the Bill and Melinda Gates Foundation Award Number: OPP1081420. JAS is the recipient of the National Health and Medical Research Council Award Number: 1104975., Dupuis, Christine, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Laboratoire de Lutte contre les Insectes Nuisibles, National Institute of Malariology, Parasitology and Entomology, National Center for Parasitology, Entomology, and Malaria Control, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Faculty of Tropical Medicine [Bangkok, Thailand], University of Oxford [Oxford], Faculty of Tropical Medicine, University of Oxford-Mahidol University [Bangkok], National Institute of Malariology, Parasitology and Entomology [Hanoi] (NIMPE), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford]-University of Oxford [Oxford], University of California [Irvine] (UCI), University of California-University of California, Graduate School, AII - Infectious diseases, APH - Aging & Later Life, APH - Global Health, APH - Methodology, Global Health, Infectious diseases, APH - Health Behaviors & Chronic Diseases, and APH - Quality of Care

Subjects
Male, Plasmodium, Myanmar, Medical and Health Sciences, Geographical Locations, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Cluster Analysis, Malaria, Falciparum, Child, Asia, Southeastern, ComputingMilieux_MISCELLANEOUS, Cross-Over Studies, Pharmaceutics, Drugs, Drug Resistance, Multiple, Vietnam, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, Mass Drug Administration, Female, Cambodia, Research Article, Adult, Drug Administration, Asia, Adolescent, Elimination, Plasmodium falciparum, Microbiology, Antimalarials, Young Adult, Drug Therapy, Microbial Control, General & Internal Medicine, Parasite Groups, parasitic diseases, Parasitic Diseases, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Disease Eradication, Pharmacology, Biology and Life Sciences, Tropical Diseases, Malaria, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, People and Places, Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antimicrobial Resistance, Apicomplexa
Abstract

Background The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People’s Democratic Republic, where artemisinin resistance is prevalent. Methods and findings After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Conclusions Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. Trial registration ClinicalTrials.gov NCT01872702, In a cluster-randomized trial, Lorenz von Seidlin & colleagues investigate whether mass drug administration can accelerate malaria elimination in the Greater Mekong Subregion., Author summary Why was this study done? The emergence and spread of multidrug resistance in the Greater Mekong Subregion (GMS) threaten regional and global malaria control. Mass drug administrations (MDAs) are controversial but could be useful in the control and elimination of malaria. We wanted to know whether well-resourced MDAs can accelerate malaria elimination in the GMS. What did the researchers do and find? We randomised 16 villages (clusters) to receive MDAs with antimalarial drugs (dihydroartemisinin-piperaquine [DP] plus low-dose primaquine) either in year 1 or year 2 of the study. The entire village population (except pregnant women and children under the age of 6 months) was invited to take 3 consecutive daily doses of antimalarial drugs 3 times at monthly intervals. Everyone was followed up for 1 year; all malaria cases were recorded, and quarterly malaria surveys were conducted using highly sensitive high-volume PCR detection. Most (87%) of the villagers completed at least 1 round of the antimalarial drugs, which were well tolerated. The intervention had a substantial impact on the prevalence of P. falciparum infections by month 3 after the start of the MDAs. Over the subsequent 9 months, P. falciparum infections returned but stayed below baseline levels. What do these findings mean? MDAs might be a useful tool to accelerate falciparum malaria elimination in low-endemicity settings. The effectiveness of MDAs depends on continued support for village health workers, adequate drug efficacy, high levels of community participation, and carefully planned roll out to minimise the risk of malaria reintroduction.

Published
2019

37. The tolerability of single low dose primaquine in glucose-6-phosphate deficient and normal falciparum-infected Cambodians

Author

Dysoley, L, Kim, S, Lopes, S, Khim, N, Bjorges, S, Top, S, Huch, C, Rekol, H, Westercamp, N, Fukuda, MM, Hwang, J, Roca-Feltrer, A, Mukaka, M, Menard, D, Taylor, WR, National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), School of Public Health [Phnom Penh, Cambodge], National Institute of Public Health [Phnom Penh, Cambodge], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Malaria Consortium [Phnom Penh, Cambodge], World Health Organization [Phnom Penh] (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Malaria Branch [Atlanta, GA, États-Unis], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention-Centers for Disease Control and Prevention, U.S. President's Malaria Initiative [Bangkok, Thaïlande], Division of Parasitic Diseases and Malaria [Bangkok, Thaïlande] (DPDM), Centers for Disease Control and Prevention [Bangkok, Thaïlande], Centers for Disease Control and Prevention-Centers for Disease Control and Prevention-Centers for Disease Control and Prevention [Bangkok, Thaïlande], U.S. President's Malaria Initiative [Atlanta, GA,], Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Centre for Tropical Medicine [Oxford, Royaume-Uni], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Malaria Genetics and Resistance Group [Paris], Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This research was made possible through support provided by the U.S. President’s Malaria Initiative via the Office of Health, Infectious Diseases, and Nutrition, Bureau for Global Health, U.S. Agency for International Development, under the terms of an Interagency Agreement with CDC and the Malaria Consortium., Bodescot, Myriam, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford-University of Oxford, and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Adolescent, Plasmodium falciparum, Glucose-6-Phosphate, [SDV.GEN] Life Sciences [q-bio]/Genetics, Primaquine, Parasitemia, lcsh:Infectious and parasitic diseases, Antimalarials, Young Adult, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, G6PD deficiency, Humans, lcsh:RC109-216, Malaria, Falciparum, Child, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Middle Aged, Artemisinins, Malaria, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Glucosephosphate Dehydrogenase Deficiency, Child, Preschool, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Transmission blocking, Cambodia, Research Article
Abstract

Background The WHO recommends single low-dose primaquine (SLDPQ, 0.25 mg/kg body weight) in falciparum-infected patients to block malaria transmission and contribute to eliminating multidrug resistant Plasmodium falciparum from the Greater Mekong Sub region (GMS). However, the anxiety regarding PQ-induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency (G6PDd) has hindered its use. Therefore, we assessed the tolerability of SLDPQ in Cambodia to inform national policy. Methods This open randomised trial of dihydroartemisinin-piperaquine (DHAPP) + SLDPQ vs. DHAPP alone recruited Cambodians aged ≥1 year with acute uncomplicated P. falciparum. Randomisation was 4:1 DHAPP+SLDPQ: DHAPP for G6PDd patients and 1:1 for G6PDn patients, according to the results of the qualitative fluorescent spot test. Definitive G6PD status was determined by genotyping. Day (D) 7 haemoglobin (Hb) concentration was the primary outcome measure. Results One hundred nine patients (88 males, 21 females), aged 4–76 years (median 23) were enrolled; 12 were G6PDd Viangchan (9 hemizygous males, 3 heterozygous females). Mean nadir Hb occurred on D7 [11.6 (range 6.4 ─ 15.6) g/dL] and was significantly lower (p = 0.040) in G6PDd (n = 9) vs. G6PDn (n = 46) DHAPP+SLDPQ recipients: 10.9 vs. 12.05 g/dL, Δ = -1.15 (95% CI: -2.24 ─ -0.05) g/dL. Three G6PDn patients had D7 Hb concentrations

Published
2019

38. Potential herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations

Author

Parker, D, Tun, S, White, L, Kajeechiwa, L, Thwin, M, Landier, J, Chaumeau, V, Corbel, V, Dondorp, A, Von Seidlein, L, White, N, Maude, R, Nosten, F, Dupuis, Christine, Department of Population Health and Disease Prevention [Irvine, CA, USA], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Mahidol Oxford Tropical Medicine Research Unit, University of Oxford-Mahidol University [Bangkok], Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Harvard T.H. Chan School of Public Health, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), University of California [Irvine] (UCI), University of California-University of California, University of Oxford [Oxford]-Mahidol University [Bangkok], University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, and University of Oxford [Oxford]-University of Oxford [Oxford]

Subjects
Rural Population, QH301-705.5, Science, infectious disease, Plasmodium falciparum, global health, Myanmar, P. falciparum, herd effect, Medication Adherence, Antimalarials, Spatio-Temporal Analysis, elimination, parasitic diseases, Cluster Analysis, Humans, human, Malaria, Falciparum, Biology (General), Microbiology and Infectious Disease, mass drug administration, microbiology, Epidemiology and Global Health, plasmodium, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, spatial epidemiology, Asymptomatic Diseases, Medicine, epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Research Article
Abstract

The global malaria burden has decreased over the last decade and many nations are attempting elimination. Asymptomatic malaria infections are not normally diagnosed or treated, posing a major hurdle for elimination efforts. One solution to this problem is mass drug administration (MDA), with success depending on adequate population participation. Here, we present a detailed spatial and temporal analysis of malaria episodes and asymptomatic infections in four villages undergoing MDA in Myanmar. In this study, individuals from neighborhoods with low MDA adherence had 2.85 times the odds of having a malaria episode post-MDA in comparison to those from high adherence neighborhoods, regardless of individual participation, suggesting a herd effect. High mosquito biting rates, living in a house with someone else with malaria, or having an asymptomatic malaria infection were also predictors of clinical episodes. Spatial clustering of non-adherence to MDA, even in villages with high overall participation, may frustrate elimination efforts., eLife digest The global burden of malaria has decreased over the last decade. Many countries now aim to banish malaria. One obstacle to elimination is people who carry malaria parasites without showing symptoms. These asymptomatic people are unlikely to be diagnosed and treated and may contribute to further spread of malaria. One way to clear all malaria infections would be to ask everyone in a community to take antimalarial drugs at the same time, even if they do not feel ill. This tactic is most likely to work in communities that are already reducing malaria infections by other means. For example, by treating symptomatic people and using bed nets to prevent bites from malaria-infected mosquitos. Several studies have shown that mass drug administration is a promising approach to reduce malaria infections. But its success depends on enough people participating. If enough community members take antimalarial drugs, then even those who cannot participate, such as young children or pregnant women, should be less likely to get malaria. This is called the herd effect. Now, Parker et al. demonstrate that mass antimalarial drug administration reduces infections with malaria caused by the parasite Plasmodium falciparum. The analysis looked at malaria infections among residents of four villages in the Kayin State of Myanmar that used mass antimalarial drug administration. People who lived in neighborhoods with high participation in mass drug administration were almost three times less likely to get malaria than people who lived in communities with low participation. Even people who did not take part benefited. The analysis suggests that mass antimalaria drug administration benefits individuals and their communities if enough people take part. To be successful, malaria elimination programs that wish to use mass drug administration should approach communities in a way that encourages high levels of participation.

Published
2019

39. Contribution of Asymptomatic Plasmodium Infections to the Transmission of Malaria in Kayin State, Myanmar

Author

Chaumeau, V, Kajeechiwa, L, Fustec, B, Landier, J, Naw Nyo, S, Nay Hsel, S, Phatharakokordbun, P, Kittiphanakun, P, Nosten, S, Thwin, MM, Win Tun, S, Wiladphaingern, J, Cottrell, G, Parker, DM, Minh, MC, Kwansomboon, K, Metaane, S, Montazeau, C, Kunjanwong, K, Sawasdichai, S, Andolina, C, Ling, C, Haohankhunnatham, W, Christiensen, P, Wanyatip, S, Konghahong, K, Cerqueira, D, Imwong, M, Dondorp, AM, Chareonviriyaphap, T, White, NJ, Nosten, FH, Corbel, V, Dupuis, Christine, Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Department of Population Health and Disease Prevention [Irvine, CA, USA], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Department of Entomology [Bangkok, Thailand] (Faculty of Agriculture), Kasetsart University (KU), Université de Rennes 1 - Faculté des sciences pharmaceutiques et biologiques (UR1 Pharmacie), Université de Rennes (UR), Nuffield (Nuffield), University of Oxford, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, This work was supported by the Wellcome Trust (grant 101148, support to the Shoklo Malaria Research Unit, via the Mahidol-Oxford University Research Unit), the Global Fund (grant THA-M-DDC), the Bill and Melinda Gates Foundation (grant GH OPP 1081420), and the Centre Hospitalier Universitaire de Montpellier (support to V. C.)., Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Rennes - Faculté des sciences pharmaceutiques et biologiques (UR Pharmacie), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford]-University of Oxford [Oxford], University of California [Irvine] (UCI), University of California-University of California, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Oxford [Oxford], and Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]

Subjects
Falciparum, primaquine, Plasmodium falciparum, malaria, Vivax, Mosquito Vectors, Myanmar, artemisinin resistance, Microbiology, Major Articles and Brief Reports, Antimalarials, Rare Diseases, elimination, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, Malaria, Vivax, Prevalence, 2.2 Factors relating to the physical environment, Humans, Parasites, Aetiology, Malaria, Falciparum, Asymptomatic Infections, Disease Reservoirs, entomological inoculation rate, Medical And Health Sciences, Incidence, Biological Sciences, Southeast Asia, Vector-Borne Diseases, Infectious Diseases, Good Health and Well Being, Mass drug administration, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, HIV/AIDS, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Seasons, Infection, Plasmodium vivax
Abstract

Background The objective of mass antimalarial drug administration (MDA) is to eliminate malaria rapidly by eliminating the asymptomatic malaria parasite reservoirs and interrupting transmission. In the Greater Mekong Subregion, where artemisinin-resistant Plasmodium falciparum is now widespread, MDA has been proposed as an elimination accelerator, but the contribution of asymptomatic infections to malaria transmission has been questioned. The impact of MDA on entomological indices has not been characterized previously. Methods MDA was conducted in 4 villages in Kayin State (Myanmar). Malaria mosquito vectors were captured 3 months before, during, and 3 months after MDA, and their Plasmodium infections were detected by polymerase chain reaction (PCR) analysis. The relationship between the entomological inoculation rate, the malaria prevalence in humans determined by ultrasensitive PCR, and MDA was characterized by generalized estimating equation regression. Results Asymptomatic P. falciparum and Plasmodium vivax infections were cleared by MDA. The P. vivax entomological inoculation rate was reduced by 12.5-fold (95% confidence interval [CI], 1.6–100-fold), but the reservoir of asymptomatic P. vivax infections was reconstituted within 3 months, presumably because of relapses. This was coincident with a 5.3-fold (95% CI, 4.8–6.0-fold) increase in the vector infection rate. Conclusion Asymptomatic infections are a major source of malaria transmission in Southeast Asia., This study demonstrates the major contribution of asymptomatic low-density Plasmodium infections to the transmission of malaria in Southeast Asian settings. Mass drug administration with dihydroartemisinin-piperaquine can interrupt malaria transmission rapidly in areas where the prevalence of asymptomatic infection is high.

Published
2019

40. Molecular characterization and mapping of glucose-6-phosphate dehydrogenase (G6PD) mutations in the Greater Mekong Subregion

Author

Bancone, G, Menard, D, Khim, N, Kim, S, Canier, L, Nguong, C, Phommasone, K, Mayxay, M, Dittrich, S, Vongsouvath, M, Fievet, N, Le Hesran, J-Y, Briand, V, Keomany, S, Newton, PN, Gorsawun, G, Tardy, K, Chu, CS, Rattanapalroj, O, Dong, LT, Quang, HH, Tam-Uyen, N, Thuy-Nhien, N, Hien, TT, Kalnoky, M, Nosten, F, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), Foundation for Innovative New Diagnostics (FIND), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salavan Provincial Hospital, Bureau of Vector Born Diseases [Bangkok, Thailande], Institute of Malariology, Parasitology, and Entomology [Ho Chi Minh City, Vietnam] (IMPE), Institute of Malariology, Parasitology, and Entomology [Quy Nhon, Vietnam] (IMPE), Hospital for Tropical Diseases - HTD [Ho Chi Minh City, Vietnam], Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Diagnostics Program [Seattle, WA, USA] (PATH), Institut Pasteur [Paris], Communautés d’universités et établissements Sorbonne Paris Cité (COMUE Sorbonne Paris Cité), Université Sorbonne Paris Cité (USPC)-Chimie ParisTech-Paris Sciences et Lettres (PSL), Santé de la mère et de l'enfant en milieu tropical : épidémiologie génétique et périnatale, Université Paris Descartes - Paris 5 (UPD5), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Centre National de la Recherche Scientifique (CNRS), National Institute of Malariology, Parasitology and Entomology, Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford]-University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Menard, Didier

Subjects
Adult, Male, lcsh:Arctic medicine. Tropical medicine, Adolescent, Genotype, lcsh:RC955-962, Research, Infant, Newborn, Genetic Variation, Infant, Glucosephosphate Dehydrogenase, Middle Aged, lcsh:Infectious and parasitic diseases, Young Adult, Glucosephosphate Dehydrogenase Deficiency, Child, Preschool, parasitic diseases, Prevalence, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:RC109-216, Female, Child, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Asia, Southeastern
Abstract

Background Plasmodium vivax malaria elimination can only be achieved by the deployment of 8-aminoquinolines (primaquine and tafenoquine) in combination with ACT to kill both blood and liver-stage parasites. However, primaquine and the other 8-aminoquinolines cause dose-dependent haemolysis in subjects with G6PD deficiency, an X-linked disorder of red blood cells that is very common in populations living in tropical and subtropical areas. In order to inform safer use of 8-aminoquinolines in the Greater Mekong Subregion, a multi-centre study was carried out to assess the prevalence of G6PD deficiency and to identify the main G6PD variants in samples collected in Cambodia, Lao PDR, Myanmar, Thailand and Vietnam. Methods Blood samples were collected in the five countries during National Malaria Surveys or during Population Surveys. During Population Surveys samples were characterized for G6PD phenotype using the Fluorescent Spot Test. Samples were then genotyped for a panel of G6PD mutations. Results G6PD deficiency was found to be common in the region with an overall mean prevalence of deficient or mutated hemizygous males of 14.0%, ranging from a mean 7.3% in Thailand, 8.1% in Lao PDR, 8.9% in Vietnam, 15.8% in Myanmar and 18.8% in Cambodia. Mahidol and Viangchan mutations were the most common and widespread variants found among the nine investigated. Conclusions Owing to the high prevalence of G6PD deficiency in the Greater Mekong Subregion, strategies for vivax malaria elimination should include point-of-care G6PD testing (both qualitative and quantitative) to allow safe and wide treatment with 8-aminoquinolines. Electronic supplementary material The online version of this article (10.1186/s12936-019-2652-y) contains supplementary material, which is available to authorized users.

Published
2019

41. Performance of the Access Bio/CareStart rapid diagnostic test for the detection of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis

Author

Ric N. Price, Sunil Parikh, Daniel A. Pfeffer, Benedikt Ley, Germana Bancone, Michael E. von Fricken, Amalia Karahalios, Lorenz von Seidlein, Nicholas M. Douglas, Fe Espino, Ari W. Satyagraha, Gisela Henriques, Nwe Nwe Oo, Hisni Rahmat, Didier Menard, Menzies School of Health Research [Australia], Charles Darwin University [Australia], Eijkman Institute for Molecular Biology [Jakarta], George Mason University [Fairfax], Research Institute for Tropical Medicine [Muntinlupa City, Philippines], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Faculty of Infectious and Tropical Diseases [London], London School of Hygiene and Tropical Medicine (LSHTM), Department of Medical Research (Lower Myanmar) [Yangon], Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Yale School of Public Health (YSPH), Department of Epidemiology of Microbial Diseases [New Haven], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Charles Darwin University, University of Oxford [Oxford]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and Menard, Didier

Subjects
Male, Primaquine, Endemic Diseases, Physiology, 030204 cardiovascular system & hematology, Likelihood ratios in diagnostic testing, 0302 clinical medicine, Spectrum Analysis Techniques, Mathematical and Statistical Techniques, Medicine and Health Sciences, 030212 general & internal medicine, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Glucose-6-Phosphate Dehydrogenase Deficiency, Rapid diagnostic test, Statistics, Anemia, General Medicine, Venous blood, Hematology, Metaanalysis, Research Assessment, Haemolysis, 3. Good health, Body Fluids, Blood, Spectrophotometry, Meta-analysis, Physical Sciences, Medicine, Female, Anatomy, medicine.drug, Research Article, medicine.medical_specialty, Systematic Reviews, Point-of-Care Systems, Glucosephosphate Dehydrogenase, Research and Analysis Methods, Sensitivity and Specificity, 03 medical and health sciences, Internal medicine, medicine, Parasitic Diseases, Malaria, Vivax, Humans, Statistical Methods, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], business.industry, Diagnostic Tests, Routine, Hemolytic Anemia, Biology and Life Sciences, Gold standard (test), medicine.disease, Tropical Diseases, Capillaries, Malaria, Blood Counts, Glucosephosphate Dehydrogenase Deficiency, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiovascular Anatomy, Blood Vessels, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Mathematics, Glucose-6-phosphate dehydrogenase deficiency
Abstract

Background To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994). Methods and findings Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR−) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90–0.99) and a specificity of 0.95 (95% CI 0.92–0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94–1.00), with an LR+ and an LR− of 18.23 (95% CI 13.04–25.48) and 0.05 (95% CI 0.02–0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings. Conclusions The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR− render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings., In this systematic review and meta-analysis, Benedikt Ley and colleagues assess the performance of a point of care screening test for identifyint vivax malaria patients who are at risk of drug-induced haemolysis., Author summary Why was this study done? Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) is the key determinant of severe haemolysis following primaquine (PQ)-based radical cure of vivax malaria. A widely available reliable point-of-care diagnostic for G6PDd will improve patient safety of PQ treatment. A rapid diagnostic G6PD test from Access Bio (Somerset, NJ) has operational characteristics that render the test suitable for use at the bedside. What did the researchers do and find? We reviewed the literature systematically and identified studies that had evaluated the G6PD test and compared results with those generated by the gold standard spectrophotometry. Individual participant data (IPD), available from 5,777 participants, demonstrated that the test had a 96% sensitivity for detecting G6PD-deficient individuals with a specificity of 95%. What do these findings mean? Under research conditions, the G6PD test reliably confirms and excludes G6PDd in patients with G6PD activity of less than 30% (the most widely applied cut-off activity to guide PQ-based radical cure). These findings will have to be confirmed in routine clinical settings.

Published
2019

42. Hemolytic Dynamics of Weekly Primaquine Antirelapse Therapy Among Cambodians With Acute Plasmodium vivax Malaria With or Without Glucose-6-Phosphate Dehydrogenase Deficiency

Author

Taylor, Walter, Kheng, Sim, Muth, Sinoun, Tor, Pety, Kim, Saorin, Bjorge, Steven, Topps, Narann, Kosal, Khem, Sothea, Khon, Souy, Phum, Char, Chuor Meng, Vanna, Chan, Ly, Po, Khieu, Virak, Christophel, Eva, Kerleguer, Alexandra, Pantaleo, Antonella, Mukaka, Mavuto, Ménard, Didier, Baird, J Kevin, Menard, Didier, National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Hôpitaux Universitaires de Genève (HUG), Mahidol Oxford Tropical Medicine Research Unit, University of Oxford-Mahidol University [Bangkok], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), World Health Organization [Phnom Penh] (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Pailin Referral Hospital [Pailin, Cambodge], Anlong Veng Referral Hospital [Anlong Venh, Cambodge]., Pramoy Health Center [Veal Veng, Cambodge], WHO Regional Office for the Western Pacific, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Eijkman Oxford Clinical Research Unit [Jakarta, Indonesie], Eijkman Institute of Molecular Biology [Jakarta, Indonesie], University of Oxford [Oxford]-Mahidol University [Bangkok], University of Turin, Università degli Studi di Sassari [Sassari] (UNISS), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, University of Oxford [Oxford]-University of Oxford [Oxford], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
glucose-6-phosphate dehydrogenase deficiency, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, hemic and lymphatic diseases, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, parasitic diseases, malaria, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, hemoglobin E, Primaquine, Cambodia
Abstract

Background: Hemoglobin (Hb) data are limited in Southeast Asian glucose-6-phosphate dehydrogenase (G6PD) deficient (G6PD−) patients treated weekly with the World Health Organization–recommended primaquine regimen (ie, 0.75 mg/kg/week for 8 weeks [PQ 0.75]). Methods: We treated Cambodians who had acute Plasmodium vivax infection with PQ0.75 and a 3-day course of dihydroartemisinin/piperaquine and determined the Hb level, reticulocyte count, G6PD genotype, and Hb type. Results: Seventy-five patients (male sex, 63) aged 5–63 years (median, 24 years) were enrolled. Eighteen were G6PD deficient (including 17 with G6PD Viangchan) and 57 were not G6PD deficient; 26 had HbE (of whom 25 were heterozygous), and 6 had α-/β-thalassemia. Mean Hb concentrations at baseline (ie, day 0) were similar between G6PD deficient and G6PD normal patients (12.9 g/dL [range, 9‒16.3 g/dL] and 13.26 g/dL [range, 9.6‒16 g/dL], respectively; P = .46). G6PD deficiency (P = .000), higher Hb concentration at baseline (P = .000), higher parasitemia level at baseline (P = .02), and thalassemia (P = .027) influenced the initial decrease in Hb level, calculated as the nadir level minus the baseline level (range, −5.8–0 g/dL; mean, −1.88 g/dL). By day 14, the mean difference from the day 7 level (calculated as the day 14 level minus the day 7 level) was 0.03 g/dL (range, −0.25‒0.32 g/dL). Reticulocyte counts decreased from days 1 to 3, peaking on day 7 (in the G6PD normal group) and day 14 (in the G6PD deficient group); reticulocytemia at baseline (P = .001), G6PD deficiency (P = .000), and female sex (P = .034) correlated with higher counts. One symptomatic, G6PD-deficient, anemic male patient was transfused on day 4. Conclusions: The first PQ0.75 exposure was associated with the greatest decrease in Hb level and 1 blood transfusion, followed by clinically insignificant decreases in Hb levels. PQ0.75 requires monitoring during the week after treatment. Safer antirelapse regimens are needed in Southeast Asia.

Published
2019

43. Plasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum

Author

Bopp, S, Magistrado, P, Wong, W, Schaffner, S, Mukherjee, A, Lim, P, Dhorda, M, Amaratunga, C, Woodrow, C, Ashley, E, White, N, Dondorp, A, Fairhurst, R, Ariey, F, Menard, D, Wirth, D, Volkman, S, Harvard T.H. Chan School of Public Health, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), WWARN Asia Regional Centre [Bangkok, Thailand], Mahidol University [Bangkok], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford-Mahidol University [Bangkok], Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simmons college, This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health., We thank Courtney Edison for slide reading and subcloning the KH001_053 isolate., The computations in this paper were run on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University. N.J.W., C.J.W. were supported by Bill and Melinda Gates Foundation Global Health Grant Number OPP1040463, which also funded culture adaptation of the parasites described herein. Additional support was provided to DFW by the Bill and Melinda Gates Foundation Global Health Grant Number OPP1053604. This document is an output from a project of the Tracking Resistance to Artemisinin Collaboration funded by the UK Department for International Development (DFID) for the benefit of developing countries. However, the views expressed and information contained in it are not necessarily those of or endorsed by DFID, which can accept no responsibility for such views or for any reliance place on them., University of Oxford [Oxford]-Mahidol University [Bangkok], University of Oxford [Oxford]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Infectious-disease epidemiology, DNA Copy Number Variations, Whole Genome Sequencing, Cell Survival, Science, Plasmodium falciparum, Drug Resistance, Gene Dosage, Protozoan Proteins, Article, Malaria, Target validation, Isoenzymes, Antimalarials, parasitic diseases, Quinolines, Aspartic Acid Endopeptidases, Humans, lcsh:Q, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:Science, Cambodia, Antiparasitic agents
Abstract

Multidrug resistant Plasmodium falciparum in Southeast Asia endangers regional malaria elimination and threatens to spread to other malaria endemic areas. Understanding mechanisms of piperaquine (PPQ) resistance is crucial for tracking its emergence and spread, and to develop effective strategies for overcoming it. Here we analyze a mechanism of PPQ resistance in Cambodian parasites. Isolates exhibit a bimodal dose–response curve when exposed to PPQ, with the area under the curve quantifying their survival in vitro. Increased copy number for plasmepsin II and plasmepsin III appears to explain enhanced survival when exposed to PPQ in most, but not all cases. A panel of isogenic subclones reinforces the importance of plasmepsin II–III copy number to enhanced PPQ survival. We conjecture that factors producing increased parasite survival under PPQ exposure in vitro may drive clinical PPQ failures in the field., Piperaquine (PPQ) resistance of Plasmodium is an increasing problem. Here, Bopp et al. find a bimodal dose−response curve of Cambodian isolates exposed to PPQ, with the area under the curve correlating with in vitro PPQ resistance, and show the importance of Plasmepsin II–III copy number to PPQ resistance.

Published
2018

44. Operational Performance of a Plasmodium falciparum Ultrasensitive Rapid Diagnostic Test for Detection of Asymptomatic Infections in Eastern Myanmar

Author

Jordi Landier, Peter R. Christensen, Gilles Delmas, Jathee Raksuansak, Pase Phattharakokoedbun, François Nosten, Gonzalo J. Domingo, Kamonchanok Konghahong, Jacher Wiladphaingern, Smita Das, May Myo Thwin, Ladda Kajeechiwa, Stephane Proux, Warat Haohankhunnatham, Khin Maung Lwin, Ihn Kyung Jang, Clare Ling, Mallika Imwong, Dupuis, Christine, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Diagnostics Program [Seattle, WA, USA] (PATH), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, This work was supported by the Wellcome Trust (041843), the Bill and Melinda Gates Foundation (OPP1117507 and OPP1135840), the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria). SMRU is part of the Mahidol Oxford University Research Unit, supported by the Wellcome Trust of Great Britain., Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and University of Oxford [Oxford]-University of Oxford [Oxford]

Subjects
Male, Protozoan Proteins, Myanmar, Parasitemia, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Prevalence, Medicine, Multiplex, 030212 general & internal medicine, Malaria, Falciparum, Asymptomatic Infections, rapid tests, Microscopy, Rapid diagnostic test, biology, Middle Aged, 3. Good health, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, medicine.symptom, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Adult, Microbiology (medical), Plasmodium falciparum, 030231 tropical medicine, malaria, Antigens, Protozoan, Enzyme-Linked Immunosorbent Assay, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Asymptomatic, 03 medical and health sciences, parasitic diseases, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Mass screening, asymptomatic infection, Diagnostic Tests, Routine, business.industry, ultrasensitive RDT, low density parasitemia, biology.organism_classification, medicine.disease, Virology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Parasitology, business, low transmission setting, Asymptomatic carrier, Malaria
Abstract

In the Greater Mekong Subregion in Southeast Asia, malaria elimination strategies need to target all Plasmodium falciparum parasites, including those carried asymptomatically. More than 70% of asymptomatic carriers are not detected by current rapid diagnostic tests (RDTs) or microscopy., In the Greater Mekong Subregion in Southeast Asia, malaria elimination strategies need to target all Plasmodium falciparum parasites, including those carried asymptomatically. More than 70% of asymptomatic carriers are not detected by current rapid diagnostic tests (RDTs) or microscopy. An HRP2-based ultrasensitive RDT (uRDT) developed to improve the detection of low-density infections was evaluated during prevalence surveys within a malaria elimination program in a low-transmission area of eastern Myanmar. Surveys were conducted to identify high-prevalence villages. Two-milliliter venous blood samples were collected from asymptomatic adult volunteers and transported to the laboratory. Plasmodium parasites were detected by RDT, uRDT, microscopy, ultrasensitive qPCR (uPCR), and multiplex enzyme-linked immunosorbent assay (ELISA). The sensitivity, specificity, and predictive positive and negative values of RDT and uRDT were calculated compared to uPCR and ELISA. Parasite and antigen concentrations detected by each test were defined using uPCR and ELISA, respectively. A total of 1,509 samples, including 208 P. falciparum-positive samples were analyzed with all tests. The sensitivity of the uRDT was twofold higher than that of RDT, 51.4% versus 25.2%, with minor specificity loss, 99.5% versus 99.9%, against the combined reference (uPCR plus ELISA). The geometric mean parasitemia detected by uRDT in P. falciparum monospecific infections was 3,019 parasites per ml (95% confidence interval [95% CI], 1,790 to 5,094; n = 79) compared to 11,352 parasites per ml (95% CI, 5,643 to 22,837; n = 38) by RDT. The sensitivities of uRDT and RDT dropped to 34.6% and 15.1%, respectively, for the matched tests performed in the field. The uRDT performed consistently better than RDT and microscopy at low parasitemias. It shows promising characteristics for the identification of high-prevalence communities and warrants further evaluation in mass screening and treatment interventions.

Published
2018

45. Indirect neonatal hyperbilirubinemia in hospitalized neonates on the Thai-Myanmar border: a review of neonatal medical records from 2009 to 2014

Author

François Nosten, B. van Overmeire, Jordi Landier, E Wouda, Borimas Hanboonkunupakarn, T Prins, M. Mu, C. Po, Claudia Turner, Laurence Thielemans, Rose McGready, T. Hannay, Verena I. Carrara, Candy Beau, Margreet Trip-Hoving, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Neonatology-Pediatrics [Brussels] (Cliniques Universitaires de Bruxelles), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Cambodia-Oxford Medical Research Unit [Siem Reap, Cambodia], Angkor Hospital for Children (AHC), Angkor Hospital for Children [Siem Reap, Cambodia], University of Groningen [Groningen], University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of Glasgow, Funding was obtained from ‘The Belgian Kids'’ Fund for Pediatric Research., Dupuis, Christine, Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford]-University of Oxford [Oxford], and Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]

Subjects
Pediatrics, medicine.medical_treatment, Exchange transfusion, Infant, Premature, Diseases, Myanmar, Limited access, Indirect neonatal hyperbilirubinemia, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, Resource-limited setting, 030212 general & internal medicine, Neonatal Disorder, Medical record, lcsh:RJ1-570, Jaundice, Thailand, 3. Good health, Hospitalization, Blood Group Incompatibility, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hyperbilirubinemia, Neonatal, medicine.symptom, Research Article, medicine.medical_specialty, Refugee, Pédiatrie, Led phototherapy, ABO Blood-Group System, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, (LED-) phototherapy, 030225 pediatrics, medicine, Humans, Mortality, Risk factor, Low-resource, Retrospective Studies, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Infant, Newborn, Neonates, Migrant, lcsh:Pediatrics, Odds ratio, Phototherapy, Glucosephosphate Dehydrogenase Deficiency, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Pediatrics, Perinatology and Child Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background: Indirect neonatal hyperbilirubinemia (INH) is a common neonatal disorder worldwide which can remain benign if prompt management is available. However there is a higher morbidity and mortality risk in settings with limited access to diagnosis and care. The manuscript describes the characteristics of neonates with INH, the burden of severe INH and identifies factors associated with severity in a resource-constrained setting. Methods: We conducted a retrospective evaluation of anonymized records of neonates hospitalized on the Thai-Myanmar border. INH was defined according to the National Institute for Health and Care Excellence guidelines as 'moderate' if at least one serum bilirubin (SBR) value exceeded the phototherapy threshold and as 'severe' if above the exchange transfusion threshold. Results: Out of 2980 records reviewed, 1580 (53%) had INH within the first 14days of life. INH was moderate in 87% (1368/1580) and severe in 13% (212/1580). From 2009 to 2011, the proportion of severe INH decreased from 37 to 15% and the mortality dropped from 10% (8/82) to 2% (7/449) coinciding with the implementation of standardized guidelines and light-emitting diode (LED) phototherapy. Severe INH was associated with: prematurity (, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

46. Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis

Author

Kloprogge, F, Workman, Borrmann, Tékété, Lefèvre, Hamed, Piola, Ursing, Kofoed, Mårtensson, Ngasala, Björkman, Ashton, Hietala, Aweeka, Parikh, Mwai, Davis, Karunajeewa, Salman, Checchi, Fogg, Newton, PN, Mayxay, M, Deloron, Faucher, Nosten, F, Ashley, E, McGready, R, Vugt, v, Proux, S, Price, R, Karbwang, Ezzet, Bakshi, Stepniewska, K, White, N, Guerin, P, Barnes, Tarning, J, Institute for Global Health, Imperial College London, Institute for Tropical Medicine [Tübingen, Germany], University of Tübingen [Germany], Département d'Epidémiologie des Affections parasitaires, Malaria Research and training center Université de Bamako, Mali, Université de Bamako, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Department of Microbiology, Tumour and Cell biology [Stockholm, Sweden] (Malaria Research), Karolinska Institutet [Stockholm], Bandim Health Project, International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH Network), Department of Women's and Children's Health [Uppsala, Sweden], Uppsala University-International Maternal and Child Healt [Uppsala, Sweden] (IMCH), Muhimbili University of Health and Allied Sciences, University of Gothenburg (GU), Université d'Uppsala et Gothenburg, University of California [San Francisco] (UCSF), University of California, Yale School of Public Health (YSPH), Kenya Medical Research Institute (KEMRI), Medical School [Australian National University - ANU], Australian National University (ANU), The Walter and Eliza Hall Institute of Medical Research, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (LSHTM), Epicentre [Paris] [Médecins Sans Frontières], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration, Mahosot Hospital-Microbiology Laboratory, Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies infectieuses et tropicales [CHU Limoges], CHU Limoges, Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford [Oxford], Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Global Health Division, Menzies School of Health Research, Nagasaki University, Centre for Tropical Medicine and Global Health, University of Oxford, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Institute for Tropical Medicine = Institut für Tropenmedizin, Reisemedizin, Humanparasitolgie [Tübingen, Allemagne] (ITM), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Department of Women and Children's Health, Uppsala University, The Walter and Eliza Hall Institute of Medical Research (WEHI), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, Infectious diseases, APH - Global Health, APH - Quality of Care, AII - Infectious diseases, Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and Beeson, James G.

Subjects
Male, Artemether, Lumefantrine Drug Combination/pharmacokinetics, Antimalarials/pharmacokinetics, Fluorenes/metabolism, Antimalarials, Pregnancy, Health Sciences, Humans, Malaria, Falciparum, Fluorenes, Dose-Response Relationship, Drug, Ethanolamines/metabolism, Malaria, Falciparum/drug therapy, Artemether, Lumefantrine Drug Combination, Infant, Newborn, Infant, Public Health, Global Health, Social Medicine and Epidemiology, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Models, Chemical, Ethanolamines, Child, Preschool, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female
Abstract

Background - The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.Methods and findings - A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing Conclusions - Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Published
2018

47. Effect of generalised access to early diagnosis and treatment and targeted mass drug administration on Plasmodium falciparum malaria in Eastern Myanmar : an observational study of a regional elimination programme

Author

Jordi Landier, Daniel M Parker, Aung Myint Thu, Khin Maung Lwin, Gilles Delmas, François H Nosten, Chiara Andolina, Ricardo Aguas, Saw Moe Ang, Ei Phyo Aung, Naw Baw Baw, Saw Aye Be, Saw B'Let, Hay Bluh, Craig A. Bonnington, Victor Chaumeau, Miasa Chirakiratinant, Win Cho Cho, Peter Christensen, Vincent Corbel, Nicholas PJ Day, Saw Hsa Dah, Mehul Dhorda, Arjen M Dondorp, Jean Gaudart, Gornpan Gornsawun, Warat Haohankhunnatham, Saw Kyaw Hla, Saw Nay Hsel, Gay Nay Htoo, Saw Nay Htoo, Mallika Imwong, Saw John, Ladda Kajeechiwa, Lily Kereecharoen, Praphan Kittiphanakun, Keerati Kittitawee, Kamonchanok Konghahong, Saw Diamond Khin, Saw Win Kyaw, Clare Ling, Khine Shwe War Lwin, Naw K' Yin Ma, Alexandra Marie, Cynthia Maung, Ed Marta, Myo Chit Minh, Olivo Miotto, Paw Khu Moo, Ku Ler Moo, Merry Moo, Naw Na Na, Mar Nay, François H. Nosten, Suphak Nosten, Slight Naw Nyo, Eh Kalu Shwe Oh, Phu Thit Oo, Tun Pyit Oo, Daniel M. Parker, Eh Shee Paw, Choochai Phumiya, Aung Pyae Phyo, Kasiha Pilaseng, Stéphane Proux, Santisuk Rakthinthong, Wannee Ritwongsakul, Kloloi Salathibuphha, Armon Santirad, Sunisa Sawasdichai, Lorenz von Seidlein, Paw Wah Shee, Paw Bway Shee, Decha Tangseefa, May Myo Thwin, Saw Win Tun, Chode Wanachaloemlep, Lisa J White, Nicholas J White, Jacher Wiladphaingern, Saw Nyunt Win, Nan Lin Yee, Daraporn Yuwapan, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Population Health and Disease Prevention [Irvine, CA, USA], University of California [Irvine] (UCI), University of California-University of California, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], This work was supported by the Wellcome Trust (041843), the Bill & Melinda Gates Foundation (OPP1117507), and the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria)., Malaria Elimination Task Force Group : Andolina C, Aguas R, Ang SM, Aung EP, Baw NB, Be SA, B'Let S, Bluh H, Bonnington CA, Chaumeau V, Chirakiratinant M, Cho WC, Christensen P, Corbel V, Day NP, Dah SH, Delmas G, Dhorda M, Dondorp AM, Gaudart J, Gornsawun G, Haohankhunnatham W, Hla SK, Hsel SN, Htoo GN, Htoo SN, Imwong M, John S, Kajeechiwa L, Kereecharoen L, Kittiphanakun P, Kittitawee K, Konghahong K, Khin SD, Kyaw SW, Landier J, Ling C, Lwin KM, Lwin KSW, Ma NKY, Marie A, Maung C, Marta E, Minh MC, Miotto O, Moo PK, Moo KL, Moo M, Na NN, Nay M, Nosten FH, Nosten S, Nyo SN, Oh EKS, Oo PT, Oo TP, Parker DM, Paw ES, Phumiya C, Phyo AP, Pilaseng K, Proux S, Rakthinthong S, Ritwongsakul W, Salathibuphha K, Santirad A, Sawasdichai S, von Seidlein L, Shee PW, Shee PB, Tangseefa D, Thu AM, Thwin MM, Tun SW, Wanachaloemlep C, White LJ, White NJ, Wiladphaingern J, Win SN, Yee NL, Yuwapan D., Dupuis, Christine, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), and University of Oxford-University of Oxford

Subjects
Male, Rural Population, Primaquine, Drug Resistance, Myanmar, Drug resistance, Rate ratio, Health Services Accessibility, State Medicine, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Prevalence, 030212 general & internal medicine, Artemether, Malaria, Falciparum, Artemisinin, 2. Zero hunger, biology, Incidence, 1. No poverty, General Medicine, Artemisinins, 3. Good health, Drug Combinations, Treatment Outcome, Ethanolamines, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Mass Drug Administration, Female, medicine.drug, 030231 tropical medicine, Article, Antimalarials, 03 medical and health sciences, parasitic diseases, medicine, Humans, Mass drug administration, Fluorenes, business.industry, Artemether, Lumefantrine Drug Combination, Plasmodium falciparum, medicine.disease, biology.organism_classification, Malaria, Early Diagnosis, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Demography
Abstract

Summary Background Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria. Methods The programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar. Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether–lumefantrine plus single low-dose primaquine. Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum ) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post. During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults. Hotspots received targeted mass drug administration with dihydroartemisinin–piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts. The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model. Malaria prevalence was measured in the hotspots 12 months after mass drug administration. Findings Between May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals. Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified. By April 2017, 50 hotspots were treated with mass drug administration. Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2·7, 95% CI 1·8–4·4). Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0·82, 95% CI 0·76–0·88 per quarter) and in other villages (0·75, 0·73–0·78 per quarter). Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0·19, 95% CI 0·13–0·26). By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months. The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631). Interpretation Providing early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar. Targeted mass drug administration significantly reduced malaria incidence in hotspots. If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum . Funding The Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust.

Published
2018

48. Contribution to Malaria Transmission of Symptomatic and Asymptomatic Parasite Carriers in Cambodia

Author

Eakpor Piv, Sophy Chy, Nimol Khim, Saorin Kim, Laura Berne, Dysoley Lek, Didier Menard, Amélie Vantaux, Reingsey Samreth, Sovannaroth Siv, Walter R. J. Taylor, Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Xeno Cell Innovations [Plzen, République tchèque], National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), National Institute of Public Health [Phnom Penh, Cambodge], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Institut Pasteur in Cambodia, France Expertise Internationale 5% initiative (grant no. 12INI211), Rotary Club (grant no. GG1523934), United States Agency for International Development/President’s Malaria Initiative/Centers for Disease Control and Prevention through Malaria Consortium, and Dedonder Clayton (grant no. EC/MAM/N°325/14). A. V. was supported by a postdoctoral fellowship from the International Direction, Institut Pasteur, Paris, France., Malaria Molecular Epidemiology (MMEU), University of Oxford-Mahidol University [Bangkok], University of Oxford-University of Oxford, and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Plasmodium vivax, Prevalence, 0302 clinical medicine, Anopheles dirus, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Immunology and Allergy, MESH: Animals, 030212 general & internal medicine, Malaria, Falciparum, Child, MESH: Plasmodium falciparum, Infectivity, MESH: Middle Aged, biology, MESH: Malaria, Falciparum, Anopheles, Middle Aged, 3. Good health, MESH: Plasmodium vivax, Infectious Diseases, MESH: Young Adult, Female, MESH: Mosquito Vectors, medicine.symptom, Cambodia, Adult, Plasmodium falciparum, 030231 tropical medicine, Mosquito Vectors, Asymptomatic, MESH: Anopheles, Young Adult, 03 medical and health sciences, parasitic diseases, Malaria, Vivax, medicine, Animals, Humans, Parasites, MESH: Parasites, MESH: Prevalence, MESH: Humans, business.industry, MESH: Cambodia, MESH: Malaria, Vivax, MESH: Adult, biology.organism_classification, medicine.disease, Virology, MESH: Male, business, Asymptomatic carrier, MESH: Female, Malaria
Abstract

International audience; Background:Eliminating falciparum malaria in Cambodia is a top priority, requiring the implementation of novel tools and strategies to interrupt its transmission. To date, few data are available regarding the contributions to malaria transmission of symptomatic and asymptomatic carriers.Methods:Direct-membrane and skin feeding assays (DMFAs, SFAs) were performed, using Anopheles minimus and Anopheles dirus, to determine infectivity of symptomatic falciparum-infected patients and malaria asymptomatic carriers; a subset of the latter were followed up for 2 months to assess their transmission potential.Results:By microscopy and real-time polymerase chain reaction, Plasmodium falciparum gametocyte prevalence rates were, respectively, 19.3% (n = 21/109) and 44% (n = 47/109) on day (D) 0 and 17.9% (n = 5/28) and 89.3% (n = 25/28) in recrudescent patients (Drec) (RT-PCR Drec vs D0 P = .002). Falciparum malaria patient infectivity was low on D0 (6.2%; n = 3/48) and in Drec (8.3%; n = 1/12). Direct-membrane feeding assays and SFAs gave similar results. None of the falciparum (n = 0/19) and 3 of 28 Plasmodium vivax asymptomatic carriers were infectious to mosquitoes, including those that were followed up for 2 months. Overall, P. falciparum gametocytemias were low except in a few symptomatic carriers.Conclusions:Only symptomatic falciparum malaria patients were infectious to mosquito vectors at baseline and recrudescence, highlighting the need to detect promptly and treat effectively P. falciparum patients.

Published
2018

49. Characterization of hydrometeorological events in the tropical volcanic Island of Tahiti

Author

Sichoix, Lydie, Laurent, V., Beau, C., Arapari-Hargous, R., Buisson, G., Géopôle du Pacifique Sud (GePaSUD), Université de la Polynésie Française (UPF), Territoires, Environnement, Télédétection et Information Spatiale (UMR TETIS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-AgroParisTech-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Centre National de la Recherche Scientifique (CNRS), Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), and Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]

Subjects
Tropical volcanic Island, Franch Polynesia, Hydrometeorological events, Tahiti, [SDU.STU.ME]Sciences of the Universe [physics]/Earth Sciences/Meteorology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

50. Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome

Author

Bruno Cavadas, Luísa Pereira, Fanny Koeth, Etienne Simon-Loriere, Marisa Oliveira, Isabelle Casademont, Worachart Lert-itthiporn, Prida Malasit, Orlando Anunciação, Prapat Suriyaphol, Marina Penova, Richard Paul, Fumihiko Matsuda, Chiea Chuen Khor, Ampaiwan Chuansumrit, Kanchana Tangnararatchakit, Anavaj Sakuntabhai, Verónica Fernandes, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Siriraj Hospital, Mahidol University, Mahidol University [Bangkok], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics [Kyoto, Japan], Institut Pasteur [Paris], Department of Pediatrics, Faculty of Medicine, Mahidol University [Bangkok]-Ramathibodi Hospital, National University of Singapore (NUS), French National Research Agency (ANR-10–INSB–04, Investments for the Future)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Instituto de Investigação e Inovação em Saúde, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Universidade do Porto = University of Porto, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Universidade do Porto [Porto], Genome Institute of Singapore (GIS), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de Génotypage (CNG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Male, Heredity, Basic Helix-Loop-Helix Transcription Factors / genetics, Thai People, Viral Nonstructural Proteins / genetics, MESH: Asia, Southeastern, Genome-wide association study, Genome, Viral / genetics, Dengue virus, MESH: Dengue Virus, Biochemistry, MESH: Genotype, 0302 clinical medicine, MESH: Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Ethnicities, Protein Phosphatase 2, MESH: Nerve Tissue Proteins, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Asian Continental Ancestry Group, MESH: Protein Phosphatase 2, Genomics, Genomic Databases, Severe Dengue / ethnology, MESH: Infant, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, MESH: Repressor Proteins, MESH: Young Adult, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Metabolic Pathways, Carrier Proteins / genetics, MESH: Cell Nucleus, MESH: Gene Expression, Genotype, Bioinformatics, lcsh:RC955-962, Single-nucleotide polymorphism, MESH: Severe Dengue, MESH: Carrier Proteins, Serogroup, 03 medical and health sciences, Viral Proteins, Asian People, Sequence Motif Analysis, Cell Nucleus / virology, Genetic predisposition, Genetics, Xenobiotic Metabolism, Humans, MESH: Adolescent, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Computational Biology, Infant, MESH: Adult, lcsh:RA1-1270, Dengue Virus, medicine.disease, Tropical Diseases, MESH: Sulfotransferases, MESH: Cell Line, 030104 developmental biology, Severe Dengue / genetics, MESH: Genome-Wide Association Study, MESH: Viral Nonstructural Proteins, Population Groupings, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Carrier Proteins, MESH: Female, 030217 neurology & neurosurgery, 0301 basic medicine, Viral Diseases, Gene Expression, Repressor Proteins / genetics, MESH: Dengue, Viral Nonstructural Proteins, medicine.disease_cause, Dengue fever, Dengue Fever, Geographical Locations, Dengue, Cohort Studies, Database and Informatics Methods, Medicine and Health Sciences, Basic Helix-Loop-Helix Transcription Factors, Nerve Tissue Proteins / genetics, MESH: Cohort Studies, Asia, Southeastern, Type C Phospholipases / genetics, lcsh:Public aspects of medicine, MESH: Genetic Predisposition to Disease, Thailand, Phenotype, Europe, Genetic Mapping, Infectious Diseases, Dengue Virus / genetics, Asian Continental Ancestry Group / genetics, Female, Sulfotransferases, MESH: Genome, Viral, MESH: Type C Phospholipases, Sequence Analysis, Research Article, Neglected Tropical Diseases, Adult, lcsh:Arctic medicine. Tropical medicine, Adolescent, Dengue / virology, Dengue / genetics, Nerve Tissue Proteins, Genome, Viral, Biology, Genetic Predisposition, Research and Analysis Methods, Cell Line, Young Adult, medicine, Viral Proteins / genetics, Genetic Predisposition to Disease, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Severe Dengue, MESH: Thailand, Cell Nucleus, Protein Phosphatase 2 / genetics, MESH: Serogroup, Genome Analysis, MESH: Viral Proteins, MESH: Male, MESH: Odds Ratio, Repressor Proteins, Biological Databases, Metabolism, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Type C Phospholipases, People and Places, Genetics of Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS., Author summary Dengue fever is endemic in tropical and subtropical areas of East Asia and America, but globalization and climate changes are introducing vector and virus to the naïve regions of Europe and North America. In this work we conducted a statistically robust, coupled association-admixture test in two dengue cohorts from Thailand (classical dengue fever, DF, and dengue shock syndrome, DSS) and a published Vietnamese (DSS only) cohort. We identified new candidate genes associated with DF risk and confirmed known gene family association with DSS risk. In DF, phosphatase control is crucial, including through binding to viral proteins, as we showed for PPP2R5E protein co-localization with DENV1 and DENV2-NS5 proteins within liver cells and differential cellular localizations along time. In DSS, cytokine dynamics, inflammation and activation of vascular endothelium cells are dominant features. The particular genetic risk conferred by these genes indicates that Southeast and Northeast Asians are highly susceptible to both phenotypes, while Africans are best protected against DSS, and Europeans best protected against DF but the most susceptible against DSS.

Published
2018

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