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496 results on '"Eijkman Institute for Molecular Biology"'

1. Prevalence and Serotype of Streptococcus Pneumoniae Hospitalized Adult With Community-Acquired Pneumonia (HACAP)

Author: Eijkman Institute for Molecular Biology and Gurmeet Singh, MD, Head Division Respirology and Critical Illness, Internal Medicine Department, Principal Investigator, Respirology and Critical Illness Consultant
Published: 2023

2. RapiGEN BIOCREDIT Malaria Ag RDTs WHO Prequalification Study

Author: University of Khartoum and Eijkman Institute for Molecular Biology
Published: 2023

3. Abbott NxTekTM Malaria RDT WHO Prequalification Study

Author: University of Khartoum, Eijkman Institute for Molecular Biology, and Universidad Peruana Cayetano Heredia
Published: 2023

4. Serological Screen and Treat Trial for Plasmodium Vivax (SSAT)

Author: Eijkman Institute for Molecular Biology, Eijkman Oxford Clinical Research Unit, Indonesia, Walter and Eliza Hall Institute of Medical Research, Rumah Sakit Umum Daerah Mimika, Universitas Sumatera Utara, and Inge Sutanto, Professor
Published: 2023

5. Convalescent Plasma as Adjunct Therapy for COVID-19 (PlaSenTer)

Author: Indonesian Red Cross and Eijkman Institute for Molecular Biology
Published: 2021

6. Convalescent Plasma Therapy in Patients With COVID-19

Author: Rumah Sakit Pusat Angkatan Darat Gatot Soebroto, Eijkman Institute for Molecular Biology, and dr. Marliana Sri Rejeki, Sp.FK, Medical doctor, clinical pharmacologist
Published: 2020

7. Malaria in Early Life Study

Author: Timika Research Facility, Indonesia, Eijkman Institute for Molecular Biology, Menzies School of Health Research, and Dr. Jeanne Rini Poespoprodjo, Maternal and Child Health Consultant
Published: 2018

8. Efficacy and Safety of Dihydroartemisinin-piperaquine (DHP) for the Treatment of Uncomplicated Malaria

Author: Eijkman Institute for Molecular Biology and World Health Organization
Published: 2017

9. Evaluation of Different G6PD Testing Platforms

Author: Eijkman Institute for Molecular Biology
Published: 2014

10. A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms

Author: Benoit Witkowski, Hans-Peter Fuehrer, Garib Das Thakur, Céline Barnadas, Djibrine Djalle, Michael Ramharter, Mindy Leelawong, Wasif Ali-Khan, Harald Noedl, Bouasy Hongvanthong, Mohammad Shafiul-Alam, Hypolite Muhindo-Mavoko, Abdillahi Mohamed Hassan, Judith Straimer, Nimol Khim, Kigbafori D. Silué, Kaknika Loch, Barbara H. Stokes, Maria Dorina Bustos, Laura Berne, Dylan R. Pillai, Ayola A. Adegnika, Lin Hua Tang, Rotha Eam, Saorin Kim, Alioune Dieye, Mei Li, Carole E. Eboumbou-Moukoko, Lydie Canier, Marian Warsame, Didier Menard, David A. Fidock, Yap Boum, Lyndes Wini, Abdiqani Sheikh-Omar, Patrick Tshibangu-Wa-Tshibangu, Maman Laminou Ibrahim, Mohammad Jahirul-Karim, Malen Ken, Monique A. Dorkenoo, Sócrates Herrera, Odile Mercereau-Puijalon, Lise Musset, Valentine Duru, Eric Legrand, Maniphone Khanthavong, Pascal Ringwald, Bruno Pradines, Sandrine Houzé, Rachida Tahar, Olukemi K. Amodu, Johann Beghain, Sandie Menard, Liwang Cui, Colin J. Sutherland, Jun Hu Chen, Kesara Na-Bangchang, Khin Lin, Michael Nambozi, Rithea Leang, Jean Christophe Barale, Milijaona Randrianarivelojosia, Marcus V. G. Lacerda, Sophy Chy, Frédéric Ariey, Jean-Bosco Ouédraogo, Isabelle Morlais, Maria de Fátima Ferreira-da-Cruz, Lubin Jiang, Christophe Rogier, Jun Cao, Peter G. Kremsner, Bui Quang-Phuc, Inès Vigan-Womas, Din Syafruddin, Jetsumon Sattabongkot, Shigeyuki Kano, Abebe A. Fola, Louis Collet, Karamoko Niaré, Thierry Fandeur, Sedigheh Zakeri, Sodiomon B. Sirima, Antoine Berry, Jean Baptiste Mazarati, Fe Espino, Ghulam Rahim-Awab, Chanra Khean, Offianan Andre Toure, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Génétique et Génomique des Insectes vecteurs, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Centre de Recherche Médicale de Lambaréné, Albert Schweitzer, Leiden University Medical Center (LUMC), Universiteit Leiden, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), University of Ibadan, Nangarhar University, Mahidol University [Bangkok], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Papua New Guinea Institute for Medical Research (PNGIMR), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mbarara University of Science and Technology [Mbarara] (MUST), Epicentre Ouganda [Mbarara] [Médecins Sans Frontières], Epicentre [Paris] [Médecins Sans Frontières], World Health Organization (WHO), country office for Thailand, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), JiangSu University, National Institute of Parasitic Diseases, Center for Disease Control, China, Centre Hospitalier de Mayotte, Pennsylvania State University (Penn State), Penn State System, Epidemiology and Disease Control division (EDCD), Ministry of Public Health [Nepal], Institut Pasteur de Dakar, Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Institut Pasteur de Bangui, Université de Lomé [Togo], Université de Douala, Centre Pasteur du Cameroun, Research Institute for Tropical Medicine, Centre International de Recherches Médicales de Franceville (CIRMF), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), University of Gondar, Institute of Parasitology [Vienna], University of Veterinary Medicine, Vienna, World Health Organisation (WHO), country office for Somalia, Caucaseco scientific research center = Centro de Investigación Científica Caucaseco, National Center for Malariology, Parasitology and Entomology, Ministry of Health [Mozambique], Hôpital Bichat - Claude Bernard, 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), Centre de Recherche Médicale et Sanitaire (Niamey, Niger) (CERMES), Directorate General of Health Services (DGHS), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), National Center for Global Health and Medicine [Japan] (NCGM), Institut Pasteur du Laos, Instituto Leônidas e Maria Deane - Fiocruz Amazônia [Manaus, Brésil] (ILMD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), National Center for Malaria Control, Parasitology and Entomology, Ministry of Health of Cambodgia, Henry M. Jackson Foundation for the Advancement of Military Medicine (HJM), U.S. Naval Medical Research, The Department of Medical Research (Upper Myanmar), Rwanda Biomedical Center (RBC), 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), Institut de Recherche pour le Développement [Yaoundé, Cameroun] (IRD [Cameroun]), Institut de Recherche pour le Développement (IRD), University of Kinshasa (UNIKIN), University of Antwerp (UA), Institut Pasteur de la Guyane, Thammasat University (TU), Tropical Diseases Research Center (TDRC), Université de Bamako, Medizinische Universität Wien = Medical University of Vienna, Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, Medicines for Malaria Venture (MMV), Université de Genève = University of Geneva (UNIGE), Global Malaria Programme, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence du Paludisme, Institut Pasteur de Madagascar, Ministry of Health and Human Services [Somalia], Centre Suisse de Recherches Scientifiques en Cote d'Ivoire [Abidjan] (CSRS-CI), Université Félix Houphouët-Boigny (UFHB), Groupe de recherche action en santé (GRAS), London School of Hygiene and Tropical Medicine (LSHTM), University of Hasanuddin, Eijkman Institute for Molecular Biology [Jakarta], Institut Pasteur de Côte d'Ivoire, Ministry of Health and Medical Services, Institut Pasteur d'Iran, Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR - laboratoire associé), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Columbia University Irving Medical Center (CUIMC), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Supported by the Institut Pasteur Paris, Institut Pasteur International Division, Institut Pasteur Cambodia, and the World Health Organization, by a grant (ANR-10-LABX-62-IBEID) from the French Government Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases', a grant from Natixis Banques, a grant (R01I109023, to Dr. Fidock) from the National Institutes of Health, grants from the Fiocruz Fundação Oswaldo Cruz, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Fundação de Amparo à Pesquisa do Estado do Amazonas, the Brazilian National Council for Scientific and Technological Development, the Agence Nationale de la Recherche (13-BSV3-0018-01 and11-BSV7-009-01), the Austrian Federal Ministry of Science, Research, and Econo-my, the Calgary Laboratory Services, the Centre International de Recherches Médicales de Franceville, the European and Developing Countries Clinical Trials Partnership (CT-2004-31070-001), the Drugs for Neglected Diseases Initiative, the Else Kroener Fresenius Stiftung, the Holger Poehlmann Stiftung, the European Community African–European Research Initiative 'IDEA' (HEALTH-F3-2009-241642), the Fonds Wetenschappelijk Onderzoek, the Vlaamse Interuniversitaire Raad–Universitaire Ontwikkelingssamenwerking, the Belgian Technical Cooperation in Democratic Republic of Congo, the European Community Seventh Framework Program (FP7/2007-2013, 242095, and 223601), the European Commission (REGPOT-CT-2011-285837-STRONGER), the Ministère de la Santé Publique du Niger (Laboratoire National de Référence Résistance aux Antipaludiques), the Foundation of National Science and Technology Major Program (2012ZX10004-220), the French Ministry of Health (Institut National de Veille Sanitaire), the Global Fund to Fight AIDS, Tuberculosis and Malaria, the 5% Initiative program (French Ministry of Foreign Affairs, France Expertise Internationale, 12INI109), the Institut Pasteur de Madagascar, the Government of the Philippines, the Institut de Recherche pour le Développement, the Foundation des Treilles, the Délégation Générale pour l’Armement (PDH-2-NRBC-4-B1-402), the Institut Pasteur de Bangui, the International Society for Health Research and Training, the Malaria Research Initiative Bandarban, Vienna, International Centre for Diarrhoeal Disease Research, Bangladesh, the Médecins sans Frontières (Centre Opérationnel Paris, France), Medicines for Malaria Venture, the National Research Council of Thailand, the Thammasat University, the National Natural Science Foundation of China (81271870, 81361120405, and 81271863), the Natural Science Foundation of Jiangsu Province (BK20130114 and BK20150001), the Jiangsu Science and Technology Department (BM2015024), the National Institutes of Health (R01 AI11646601, AI109023, and ICEMR U19AI089702, U19AI089672), the Pasteur Institute of Iran, the Malaria Division of the Iranian Center for Diseases Management and Control, Public Health England (Malaria Reference Service Contract), the Government of Rwanda, the U.S. Department of Defense Armed Forces Health Surveillance Center, Global Emerging Infections Surveillance and Response System (P0463-14-N6), the Fogarty International Center of the National Institutes of Health training (D43 TW007393), the Mahidol-Oxford Research Unit, the Government of Japan (Science and Technology Agency, Agency for Medical Research and Development, Japan International Cooperation Agency, and Science and Technology Research Partnership for Sustainable Development), and the President’s Malaria Initiative of the U.S. Agency for International Development., The KARMA Consortium, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-13-BSV3-0018,MALARTRES,Résistance de Plasmodium aux antipaludiques de la famille des artémisinines(2013), ANR-13-BSV7-0009,NEBEDIV,Le rôle des ennemis naturels dans la diversité béta des arbres tropicaux(2013), European Project: CT-2004-31070-001,EDCCTP, European Project: HEALTH-F3-2009-24164,IDEA, European Project: FP7/2007-2013, 24209,FP7, European Project: FP7/2007-2013, 22360,FP7, European Project: 285837,EC:FP7:REGPOT,FP7-REGPOT-2011-1,STRONGER(2011), European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009), European Project: 223601,EC:FP7:HEALTH,FP7-HEALTH-2007-B,MALVECBLOK(2009), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Fundação Oswaldo Cruz (FIOCRUZ), 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), Université de Genève (UNIGE), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR), Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia., Centre International de Recherches Médicales de Franceville, Caucaseco scientific research center, Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), National Center for Global Health and Medicine (NCGM), Instituto Leônidas e Maria Deane (ILMD), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement [Yaoundé], Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Eijkman Institute for Molecular Biology, Laboratoire de Parasitologie, Centre National de Référence du Paludisme - Région Antilles-Guyane, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-WHO Collaborating Center for Surveillance of Antimalarial Drug Resistance, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Van geertruyden, Jean-Pierre, and KARMA Consortium
Subjects: 0301 basic medicine, Nonsynonymous substitution, MESH: Sequence Analysis, DNA, Endemic Diseases, MESH: Asia, Southeastern, Drug Resistance, Protozoan Proteins, Drug resistance, MESH: Genotype, Lactones, 0302 clinical medicine, Genotype, Artemisinin, Malaria, Falciparum, MESH: Protozoan Proteins, Asia, Southeastern, MESH: Plasmodium falciparum, Genetics, biology, MESH: Malaria, Falciparum, General Medicine, Artemisinins, MESH: China, 3. Good health, MESH: Endemic Diseases, MESH: Drug Resistance, Algorithms, MESH: Lactones, medicine.drug, China, MESH: Mutation, 030231 tropical medicine, 030106 microbiology, Plasmodium falciparum, MESH: Algorithms, 03 medical and health sciences, parasitic diseases, MESH: Artemisinins, MESH: Polymorphism, Genetic, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Polymorphism, Genetic, MESH: Humans, Haplotype, Sequence Analysis, DNA, medicine.disease, biology.organism_classification, Virology, Mutation, Human medicine, Malaria
Abstract: Comment inK13-Propeller Mutations and Malaria Resistance, http://www.nejm.org/doi/full/10.1056/NEJMe1604520; International audience; BACKGROUND:Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale.METHODS:We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci.RESULTS:We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas--one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China--with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay.CONCLUSIONS:No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.).
Published: 2016

11. Repeatability and reproducibility of a handheld quantitative G6PD diagnostic

Author: Benedikt Ley, Ari Winasti Satyagraha, Mohammad Golam Kibria, Jillian Armstrong, Germana Bancone, Amy K. Bei, Greg Bizilj, Marcelo Brito, Xavier C. Ding, Gonzalo J. Domingo, Michael E. von Fricken, Gornpan Gornsawun, Brandon Lam, Didier Menard, Wuelton Monteiro, Stefano Ongarello, Sampa Pal, Lydia Visita Panggalo, Sunil Parikh, Daniel A. Pfeffer, Ric N. Price, Alessandra da Silva Orfano, Martina Wade, Mariusz Wojnarski, Kuntawunginn Worachet, Aqsa Yar, Mohammad Shafiul Alam, Rosalind E. Howes, Charles Darwin University [Australia], Eijkman Institute for Molecular Biology [Jakarta], International Center for Diarrheal Disease Research [Mohakhali, Bangladesh], Yale School of Public Health (YSPH), Mahidol University [Bangkok], University of Oxford, PATH [Seattle], Fundação de Medicina Tropical Dr Heitor Vieira Dourado [Manaus, Brazil], Foundation for Innovative New Diagnostics (FIND), George Mason University [Fairfax], Johns Hopkins University School of Medicine [Baltimore], Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), Laboratoire de Parasitologie et de Mycologie Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), 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), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), 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)-Université Paris Cité (UPCité), This study was funded by a grant from the Australian government (DFAT) to the Foundation for Innovative New Diagnostics (FIND). RNP is a Wellcome Senior Fellow in Clinical Science (200909), and GB and GG are in part unded by the Wellcome Trust (220211)., and univOAK, Archive ouverte
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Public Health, Environmental and Occupational Health, Reproducibility of Results, Biosensing Techniques, Glucosephosphate Dehydrogenase, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Infectious Diseases, Freeze Drying, Glucosephosphate Dehydrogenase Deficiency, Point-of-Care Testing, Spectrophotometry, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Female
Abstract: Background The introduction of novel short course treatment regimens for the radical cure of Plasmodium vivax requires reliable point-of-care diagnosis that can identify glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. While deficient males can be identified using a qualitative diagnostic test, the genetic make-up of females requires a quantitative measurement. SD Biosensor (Republic of Korea) has developed a handheld quantitative G6PD diagnostic (STANDARD G6PD test), that has approximately 90% accuracy in field studies for identifying individuals with intermediate or severe deficiency. The device can only be considered for routine care if precision of the assay is high. Methods and findings Commercial lyophilised controls (ACS Analytics, USA) with high, intermediate, and low G6PD activities were assessed 20 times on 10 Biosensor devices and compared to spectrophotometry (Pointe Scientific, USA). Each device was then dispatched to one of 10 different laboratories with a standard set of the controls. Each control was tested 40 times at each laboratory by a single user and compared to spectrophotometry results. When tested at one site, the mean coefficient of variation (CV) was 0.111, 0.172 and 0.260 for high, intermediate, and low controls across all devices respectively; combined G6PD Biosensor readings correlated well with spectrophotometry (rs = 0.859, ps = 0.604, p Conclusions Repeatability and inter-laboratory reproducibility of the Biosensor were good; though the device did not reliably discriminate between intermediate and low G6PD activities of the lyophilized specimens. Clinical studies are now required to assess the devices performance in practice.
Published: 2022

12. Episodes of Diversification and Isolation in Island Southeast Asian and Near Oceanian Male Lineages

Author: Monika Karmin, Rodrigo Flores, Lauri Saag, Georgi Hudjashov, Nicolas Brucato, Chelzie Crenna-Darusallam, Maximilian Larena, Phillip L Endicott, Mattias Jakobsson, J Stephen Lansing, Herawati Sudoyo, Matthew Leavesley, Mait Metspalu, François-Xavier Ricaut, Murray P Cox, Massey University, University of Tartu, Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Eijkman Institute for Molecular Biology [Jakarta], Uppsala University, Éco-Anthropologie (EA), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Complexity Science Hub Vienna (CSHV), University of Papua New Guinea (UPNG), James Cook University (JCU), and ANR-20-CE12-0003,PapuaEvol,Role évolutif de l'héritage génomique archaique dans la diversité humaine unique de Mélanésie(2020)
Subjects: Male, Evolutionary Biology, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Y chromosome, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, phylogeography, migration, DNA, Mitochondrial, Mitochondria, Evolutionsbiologi, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Asian People, human population genetics, Island Southeast Asia, Genetics, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Asia, Southeastern, Phylogeny
Abstract: Island Southeast Asia (ISEA) and Oceania host one of the world’s richest assemblages of human phenotypic, linguistic, and cultural diversity. Despite this, the region’s male genetic lineages are globally among the last to remain unresolved. We compiled ∼9.7 Mb of Y chromosome (chrY) sequence from a diverse sample of over 380 men from this region, including 152 first reported here. The granularity of this data set allows us to fully resolve and date the regional chrY phylogeny. This new high-resolution tree confirms two main population bursts: multiple rapid diversifications following the region’s initial settlement ∼50 kya, and extensive expansions
Published: 2022

13. Dynamics of G6PD activity in patients receiving weekly primaquine for therapy of Plasmodium vivax malaria

Author: Mavuto Mukaka, Saorin Kim, Eva Christophel, Sim Kheng, Sinoun Muth, Didier Menard, J. Kevin Baird, Alexandra Kerleguer, Walter R. J. Taylor, Lucio Luzzatto, Pety Tor, 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), WHO Regional Office for the Western Pacific, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Oxford, Muhimbili University of Health and Allied Sciences, Università degli Studi di Firenze = University of Florence (UniFI), Eijkman Institute for Molecular Biology [Jakarta], Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), Les Hôpitaux Universitaires de Strasbourg (HUS), and EC organised the funding of the study from WHO Headquarters. There is no reference number. At the time of the study, WRJT was part supported by France Expertise International through the 5% initiative as a consultant to CNM in operational research. JKB was supported by Wellcome Trust grant B9RJIXO and DM by the French Ministry of Foreign Affairs. S Kim was supported by an APMEN fellowship grant (103-09).
Subjects: Male, Plasmodium, Reticulocytes, Heredity, Erythrocytes, Primaquine, Tafenoquine, Epidemiology, Reticulocytosis, RC955-962, Gastroenterology, Hemoglobins, chemistry.chemical_compound, Medical Conditions, Dihydroartemisinin/piperaquine, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Red Blood Cells, Arctic medicine. Tropical medicine, Medicine and Health Sciences, Reticulocytopenia, Child, Glucose-6-Phosphate Dehydrogenase Deficiency, Heterozygosity, Drugs, Anemia, Hematology, Middle Aged, Haemolysis, Infectious Diseases, Genetic Diseases, Child, Preschool, Thalassemia, Female, Cellular Types, medicine.symptom, Public aspects of medicine, RA1-1270, Cambodia, Research Article, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Genotype, Bone Marrow Cells, Glucosephosphate Dehydrogenase, Hemolysis, Antimalarials, Young Adult, Autosomal Recessive Diseases, Internal medicine, Parasite Groups, parasitic diseases, Genetics, Parasitic Diseases, Malaria, Vivax, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Aged, Pharmacology, Clinical Genetics, Blood Cells, business.industry, Hemolytic Anemia, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Cell Biology, Tropical Diseases, medicine.disease, Malaria, Hemoglobinopathies, chemistry, Medical Risk Factors, Parasitology, business, Apicomplexa, Glucose-6-phosphate dehydrogenase deficiency
Abstract: Background Acute Plasmodium vivax malaria is associated with haemolysis, bone marrow suppression, reticulocytopenia, and post-treatment reticulocytosis leading to haemoglobin recovery. Little is known how malaria affects glucose-6-phosphate dehydrogenase (G6PD) activity and whether changes in activity when patients present may lead qualitative tests, like the fluorescent spot test (FST), to misdiagnose G6PD deficient (G6PDd) patients as G6PD normal (G6PDn). Giving primaquine or tafenoquine to such patients could result in severe haemolysis. Methods We investigated the G6PD genotype, G6PD enzyme activity over time and the baseline FST phenotype in Cambodians with acute P. vivax malaria treated with 3-day dihydroartemisinin piperaquine and weekly primaquine, 0·75 mg/kg x8 doses. Results Of 75 recruited patients (males 63), aged 5–63 years (median 24), 15 were G6PDd males (14 Viangchan, 1 Canton), 3 were G6PD Viangchan heterozygous females, and 57 were G6PDn; 6 patients had α/β-thalassaemia and 26 had HbE. Median (range) Day0 G6PD activities were 0·85 U/g Hb (0·10–1·36) and 11·4 U/g Hb (6·67–16·78) in G6PDd and G6PDn patients, respectively, rising significantly to 1·45 (0·36–5·54, p, Author summary At presentation of acute Plasmodium vivax malaria, glucose-6-phosphate dehydrogenase deficient (G6PDd) males have low G6PD activity that is unrelated to baseline reticulocyte counts; they were all detected by the qualitative fluorescent spot test. The number of G6PDd heterozygous females was too small to draw meaningful inferences. Enzyme activity rose in parallel with posttreatment reticulocytosis.
Published: 2021

14. Genetic Variants of Glucose-6-Phosphate Dehydrogenase and Their Associated Enzyme Activity: A Systematic Review and Meta-Analysis

Author: Pfeffer, DA, Satyagraha, AW, Sadhewa, A, Alam, MS, Bancone, G, Boum, Y, Brito, M, Cui, L, Deng, Z, Domingo, GJ, He, Y, Khan, WA, Kibria, MG, Lacerda, M, Menard, D, Monteiro, W, Pal, S, Parikh, S, Roca-Feltrer, A, Roh, M, Sirdah, MM, Wang, D, Huang, Q, Howes, RE, Price, RN, Ley, B, Charles Darwin University [Australia], Eijkman Institute for Molecular Biology [Jakarta], International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Mahidol University [Bangkok], University of Oxford, Mbarara University of Science and Technology [Mbarara] (MUST), Fundação de Medicina Tropical Dr Heitor Vieira Dourado [Manaus, Brazil], University of South Florida [Tampa] (USF), Kunming Medical University (KMU), 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), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), Yale School of Public Health (YSPH), University of California [San Francisco] (UC San Francisco), University of California (UC), Xiamen University, Foundation for Innovative New Diagnostics (FIND), and A.W.S. and A.S. were funded by the Ministry of Research and Technology/National Research and Innovation Agency of the Republic of Indonesia. GB and SMRU are supported by the Wellcome Trust [grant 220111]. GJD and PATH studies were funded by the United Kingdom’s Foreign, Commonwealth & Development Office (FCDO), grant number 204139 and, by the Bill & Melinda Gates Foundation [OPP1107113]. This research was funded by Wellcome Trust Senior Fellow in Clinical Science (200909 RNP) and by the Bill & Melinda Gates Foundation [SEPRA-INV-024389]. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Subjects: Microbiology (medical), G6PD genotype, G6PD activity, Infectious Diseases, General Immunology and Microbiology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, G6PD deficiency, glucose-6-phosphate dehydrogenase, Immunology and Allergy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Molecular Biology
Abstract: Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, individual patient data from studies reporting G6PD activity measured by spectrophotometry and corresponding the G6PD genotype were pooled (PROSPERO: CRD42020207448). G6PD activity was converted into percent normal activity applying study-specific definitions of 100%. In total, 4320 individuals from 17 studies across 10 countries were included, where 1738 (40.2%) had one of the 24 confirmed G6PD mutations, and 61 observations (3.5%) were identified as outliers. The median activity of the hemi-/homozygotes with A-(c.202G>A/c.376A>G) was 29.0% (range: 1.7% to 76.6%), 10.2% (range: 0.0% to 32.5%) for Mahidol, 16.9% (range 3.3% to 21.3%) for Mediterranean, 9.0% (range: 2.9% to 23.2%) for Vanua Lava, and 7.5% (range: 0.0% to 18.3%) for Viangchan. The median activity in heterozygotes was 72.1% (range: 16.4% to 127.1%) for A-(c.202G>A/c.376A>G), 54.5% (range: 0.0% to 112.8%) for Mahidol, 37.9% (range: 20.7% to 80.5%) for Mediterranean, 53.8% (range: 10.9% to 82.5%) for Vanua Lava, and 52.3% (range: 4.8% to 78.6%) for Viangchan. A total of 99.5% of hemi/homozygotes with the Mahidol mutation and 100% of those with the Mediterranean, Vanua Lava, and Viangchan mutations had A/c.376A>G), 55% of hemi/homozygotes had
Published: 2022

15. Hidden Biomass of Intact Malaria Parasites in the Human Spleen

Author: Nur I. Margyaningsih, Nicholas M. Anstey, Bruce Russell, Innocent Safeukui, Benediktus Andries, Pak Prayoga, Fabrice Chrétien, Leo Leonardo, Matthias Marti, Carmen Fernandez-Becerra, Tonia Woodberry, David Hardy, Labibah Qotrunnada, Ric N. Price, Dwi Apriyanti, Steven Kho, Nurjati Chairani Siregar, Benoit Henry, Papa Alioune Ndour, Gabriela Minigo, Leily Trianty, Tsin W. Yeo, Pierre Buffet, Hernando A. del Portillo, Aurélie Fricot, Agatha M. Puspitasari, Enny Kenangalem, Rintis Noviyanti, Elamaran Meibalan, Jeanne Rini Poespoprodjo, Putu A. I. Wardani, Menzies School of Health Research [Australia], Charles Darwin University, Eijkman Institute for Molecular Biology [Jakarta], Papuan Health and Community Development Foundation [Timika, Papua Indonesia], Rumah Sakit Umum Daerah Kabupaten Mimika [Timika, Papua, Indonesia], Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Institut Pasteur [Paris], University of Notre Dame [Indiana] (UND), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), University of Glasgow, University of Otago [Dunedin, Nouvelle-Zélande], Supported by program grant no. 1037304, by fellowship nos. 1042072 and 1135820, to Dr. Anstey, by a grant (no. 1131932) from Improving Health Outcomes in the Tropical North, and by the Australian Centre of Research Excellence in Malaria Elimination — all through the Australian National Health and Medical Research Council, by a grant from the Institut National de la Santé et de la Recherche Médicale, to Dr. Buffet, by a grant from the Wellcome Trust(no. 099875), to Dr. Poespoprodjo, by a Senior Wellcome Trust Fellowship in Clinical Science award(no. 200909), to Dr. Price, by an Australian Government Postgraduate Award Scholarship, to Dr. Kho, by a Royal Society Wolfson Research Merit award, to Dr. Marti, and by the Australian Department of Foreign Affairs and Trade., Hardy, David, Charles Darwin University [Australia], Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)
Subjects: biology, business.industry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Splenectomy, Spleen, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, biology.organism_classification, Plasmodium, Asymptomatic, Virology, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, parasitic diseases, medicine, 030212 general & internal medicine, medicine.symptom, business, Malaria, ComputingMilieux_MISCELLANEOUS
Abstract: Malaria and the Spleen In this report, patients living in a malaria-endemic area underwent trauma-related splenectomy. In these asymptomatic patients who were naturally infected with Plasmodium fal...
Published: 2021

16. Papua New Guinean genomes reveal the complex settlement of north Sahul

Author: Matthew Leavesley, Roxanne Tsang, Jean-François Deleuze, Mayukh Mondal, Jason Kariwiga, Lauri Saag, William Pomat, John Muke, Luca Pagani, Nicolas Brucato, Irene Gallego Romero, Mait Metspalu, Murray P. Cox, Mathilde André, François-Xavier Ricaut, Vincent Meyer, Anne Boland, Teppsy Beni, Herawati Sudoyo, Kylie Sesuki, Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), University of Tartu, Griffith University [Brisbane], University of Papua New Guinea (UPNG), University of Queensland [Brisbane], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Eijkman Institute for Molecular Biology [Jakarta], Dipartimento di Biologia, Università degli Studi di Padova = University of Padua (Unipd), University of Melbourne, Massey University, Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Universita degli Studi di Padova
Subjects: Demographic history, Human Migration, Sahul, Population, Oceania, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Biology, AcademicSubjects/SCI01180, Indigenous, Papua New Guinea, 03 medical and health sciences, 0302 clinical medicine, Ethnicity, Genetics, Humans, education, Molecular Biology, Phylogeny, Discoveries, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, geography, education.field_of_study, geography.geographical_feature_category, Human genome, Human migration, business.industry, Australia, AcademicSubjects/SCI01130, Papua New Guinean, Papuan, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Archipelago, Period (geology), Ethnology, business, Settlement (litigation), 030217 neurology & neurosurgery
Abstract: The settlement of Sahul, the lost continent of Oceania, remains one of the most ancient and debated human migrations. Modern New Guineans inherited a unique genetic diversity tracing back 50,000 years, and yet there is currently no model reconstructing their past population dynamics. We generated 58 new whole-genome sequences from Papua New Guinea, filling geographical gaps in previous sampling, specifically to address alternative scenarios of the initial migration to Sahul and the settlement of New Guinea. Here, we present the first genomic models for the settlement of northeast Sahul considering one or two migrations from Wallacea. Both models fit our data set, reinforcing the idea that ancestral groups to New Guinean and Indigenous Australians split early, potentially during their migration in Wallacea where the northern route could have been favored. The earliest period of human presence in Sahul was an era of interactions and gene flow between related but already differentiated groups, from whom all modern New Guineans, Bismarck islanders, and Indigenous Australians descend. The settlement of New Guinea was probably initiated from its southeast region, where the oldest archaeological sites have been found. This was followed by two migrations into the south and north lowlands that ultimately reached the west and east highlands. We also identify ancient gene flows between populations in New Guinea, Australia, East Indonesia, and the Bismarck Archipelago, emphasizing the fact that the anthropological landscape during the early period of Sahul settlement was highly dynamic rather than the traditional view of extensive isolation.
Published: 2021

17. Papuan mitochondrial genomes and the settlement of Sahul

Author: Pedro, Nicole, Brucato, Nicolas, Fernandes, Veronica, André, Mathilde, Saag, Lauri, Pomat, William, Besse, Céline, Boland, Anne, Deleuze, Jean-François, Clarkson, Chris, Sudoyo, Herawati, Metspalu, Mait, Stoneking, Mark, Cox, Murray P., Leavesley, Matthew, Pereira, Luisa, Ricaut, François-Xavier, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Human Genetics, Evolution et Diversité Biologique (EDB), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Lumière - Lyon 2 - UFR de Sciences économiques et de gestion (UL2 UFR SEG), Université Lumière - Lyon 2 (UL2), University of Tartu, Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National en Génomique Humaine, Institut de Génomique, CEA, Evry, France, University of Queensland [Brisbane], Eijkman Institute for Molecular Biology [Jakarta], Department of Evolutianory Genetics, Max-Planck-Institut, Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North 4442, New Zealand, Archaeology, School of Humanities &Social Sciences, University of Papua New Guinea, Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), 4200-135 Porto, Portugal, Centre National de la Recherche Scientifique (CNRS), Universidade do Porto = University of Porto, Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Institute of Genomics, University of Tartu, 51010 Tartu, Tartumaa, Estonia
Subjects: Adult, Male, Geological Phenomena, Likelihood Functions, New Guinea, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Population genetics, Human Migration, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Australia, Article, Tasmania, Papua New Guinea, Phylogeography, Mitochondrial genome, Haplotypes, Genome, Mitochondrial, Ethnicity, Humans, Female, Asia, Southeastern, History, Ancient, Phylogeny, ComputingMilieux_MISCELLANEOUS
Abstract: New Guineans represent one of the oldest locally continuous populations outside Africa, harboring among the greatest linguistic and genetic diversity on the planet. Archeological and genetic evidence suggest that their ancestors reached Sahul (present day New Guinea and Australia) by at least 55,000 years ago (kya). However, little is known about this early settlement phase or subsequent dispersal and population structuring over the subsequent period of time. Here we report 379 complete Papuan mitochondrial genomes from across Papua New Guinea, which allow us to reconstruct the phylogenetic and phylogeographic history of northern Sahul. Our results support the arrival of two groups of settlers in Sahul within the same broad time window (50–65 kya), each carrying a different set of maternal lineages and settling Northern and Southern Sahul separately. Strong geographic structure in northern Sahul remains visible today, indicating limited dispersal over time despite major climatic, cultural, and historical changes. However, following a period of isolation lasting nearly 20 ky after initial settlement, environmental changes postdating the Last Glacial Maximum stimulated diversification of mtDNA lineages and greater interactions within and beyond Northern Sahul, to Southern Sahul, Wallacea and beyond. Later, in the Holocene, populations from New Guinea, in contrast to those of Australia, participated in early interactions with incoming Asian populations from Island Southeast Asia and continuing into Oceania.
Published: 2020

18. 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

19. 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

20. Genetic homogeneity of Anopheles maculatus in Indonesia and origin of a novel species present in Central Java

Author: Triwibowo Ambar Garjito, Laurent Gavotte, Barandi Sapta Widartono, Mega Tyas Prihatin, Sylvie Manguin, Roger Frutos, Michael J. Bangs, Widiarti Widiarti, Riyani Setyaningsih, Mujiyono Mujiyono, Sitti Alfiah, Tri Baskoro Tunggul Satoto, Din Syafruddin, Umi Widiastuti, Institute for Vector and Reservoir Control Research and Development (NIHRD-MoH), Hydrosciences Montpellier (HSM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Universitas Gadjah Mada, Eijkman Institute for Molecular Biology [Jakarta], Department of Parasitology, Faculty of Medicine, Universitas Gadjah Mada, 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), Kasetsart University (KU), Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bordeaux (UB), Institut d’Electronique et des Systèmes (IES), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Kasetsart University - KU (THAILAND), Université de Bordeaux (UB)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)
Subjects: 0301 basic medicine, Entomology, Lineage (evolution), Anopheles maculatus, 0302 clinical medicine, Maculatus Group, Phylogeny, computer.programming_language, Islands, education.field_of_study, Anopheles, 3. Good health, Vecteur de maladie, Infectious Diseases, DNA, Intergenic, L20 - Écologie animale, Java, 030231 tropical medicine, Population, Allopatric speciation, Zoology, Mosquito Vectors, Biology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Variation génétique, parasitic diseases, Animals, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, education, Genetic diversity, Species name, Research, Genetic Variation, Taxonomie, L10 - Génétique et amélioration des animaux, biology.organism_classification, Malaria, 030104 developmental biology, Indonesia, Mutation, Cyclooxygenase 1, Parasitology, computer
Abstract: Background Anopheles maculatus (s.s.) is an important vector of malaria in Indonesia. Previously it was considered the only member of the Maculatus Group present in Indonesia. A novel species was recently identified in the Kulon Progo District in Central Java. Until recently, few investigations have been conducted looking at An. maculatus genetic diversity in Indonesia, including allopatric island populations. Methods Indonesian An. maculatus (s.l.) samples were collected in several locations in Java, Lesser Sunda Island group, Sumatra and in Kulon Progo (Yogyakarta, central Java) where a novel species has been identified. Samples from a 30-year-old colony of the Kulon Progo population were also included in the analysis. Maximum-likelihood analysis established the phylogenies of the ITS2 (nuclear) and cox1 (mitochondrial) markers. Putative times of separation were based on cox1 genetic distances. Results Two species of the Maculatus Group are present in Indonesia. The novel sibling species is more closely related to Anopheles dispar than to An. maculatus (s.s.). Anopheles maculatus (s.s.) samples are homogeneous based on the ITS2 sequences. Indonesian samples and An. dispar belong to the same cox1 maternal lineage and differ from all other known members of the Maculatus Group. Divergence time between the different populations found in Java was estimated using an established cox1 mutation rate. Conclusions A novel species within the Maculatus Group, most closely related to An. dispar, is confirmed present in the Kulon Progo area of Central Java. The divergence of this species from An. maculatus (s.s.) is explained by the stable refugia in the Kulon Progo area during the quaternary period of intense volcanic activity throughout most of Java. This novel species awaits detailed morphological description before applying a formal species name. For the interim, it is proposed that the Kulon Progo population be designated An. maculatus var. menoreh to distinguish it from An. maculatus (s.s.). Electronic supplementary material The online version of this article (10.1186/s13071-019-3598-1) contains supplementary material, which is available to authorized users.
Published: 2019

21. 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

22. 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

23. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study

Author: Rintis Noviyanti, Agatha M. Puspitasari, Papa Alioune Ndour, Nurjati Chairani Siregar, Benediktus Andries, Benoit Henry, Leo Leonardo, Dwi Apriyanti, Fabrice Chrétien, Bruce Russell, Nur I. Margyaningsih, Carmen Fernandez-Becerra, Aurélie Fricot, Matthias Marti, Nicholas M. Anstey, Tsin W. Yeo, Valentine Brousse, Labibah Qotrunnada, Ric N. Price, David Hardy, Pierre Buffet, Hernando A. del Portillo, Leily Trianty, Pak Prayoga, Enny Kenangalem, Elamaran Meibalan, Jeanne Rini Poespoprodjo, Innocent Safeukui, Putu A. I. Wardani, Tonia Woodberry, Steven Kho, Gabriela Minigo, Global and Tropical Health Division [Rocklands, Australia], Menzies School of Health Research [Australia], Charles Darwin University [Australia]-Charles Darwin University [Australia], Eijkman Institute for Molecular Biology [Jakarta], Papuan Health and Community Development Foundation [Timika, Papua Indonesia], Rumah Sakit Umum Daerah Kabupaten Mimika [Timika, Papua, Indonesia], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), University of Notre Dame [Indiana] (UND), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute (IGTP), Institució Catalana de Recerca i Estudis Avançats (ICREA), Harvard School of Public Health, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), University of Glasgow, University of Oxford, Mahidol University [Bangkok], University of Otago [Dunedin, Nouvelle-Zélande], Universitas Gadjah Mada, Universitas Indonesia (UI ), This work was supported by the Australian National Health and Medical Research Council (Program Grant #1037304, Fellowships to NA [#1042072 and #1135820], and ‘Improving Health Outcomes in the Tropical North (HOTNORTH): A multidisciplinary collaboration [#1131932], and the Australian Centre of Research Excellence in Malaria Elimination), the Paris Ile-de-France Region under « DIM Thérapie génique » and « DIM Maladies Infectieuses » initiatives (awarded to PAB and BH), the French Institut National de la Santé Et de la Recherche Médicale (INSERM), the University of Paris, the Laboratory of excellence GREx, the Bill and Melinda Gates Foundation (BMGF OPP1123683), and the « Sauver la Vie Foundation » (to PAB), the Wellcome Trust (Grant #099875 awarded to JRP and Senior Fellowship in Clinical Science awarded to RNP [#200909]), an Australian Government Postgraduate Award Scholarship and OzEMalaR Travel award (awarded to SK), a Royal Society Wolfson Research Merit award (awarded to MM), the Singapore National Medical Research Council (award to TWY [CSA INV 15nov007]), and the Australian Department of Foreign Affairs and Trade., We thank patients and relatives of patients in Indonesia and France for their participation and support, staff in the laboratory and operating theatre at RSUD hospital and French hospitals, Dr Daniel Lampah and Dr Freis Candrawati for clinical input, Dr Gregory Jouvion, Dr Sarah Auburn and Dr Jutta Marfurt for methodological and intellectual advice, Dr Grennady Wirjanata, Ms Aisah Resti Amelia and Mrs Magali Tichit for laboratory assistance, and Prof Yati Soenarto for facilitating the study. We are grateful to colleagues at the Timika Research Facility for their support., Hardy, David, Charles Darwin University-Charles Darwin University, Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Institut Pasteur [Paris]-Université de Paris (UP), and University of Oxford [Oxford]
Subjects: Male, 0301 basic medicine, Plasmodium, Reticulocytes, Physiology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Plasmodium vivax, Medical Conditions, 0302 clinical medicine, Reticulocyte, Animal Cells, Immune Physiology, Red Blood Cells, Medicine and Health Sciences, Blood and Lymphatic System Procedures, Prospective Studies, Asymptomatic Infections, Protozoans, biology, Malarial Parasites, Eukaryota, General Medicine, Middle Aged, Body Fluids, 3. Good health, [SDV] Life Sciences [q-bio], Blood, medicine.anatomical_structure, Splenectomy, Red pulp, Medicine, Female, Cellular Types, Anatomy, medicine.symptom, Research Article, Adult, Adolescent, 030231 tropical medicine, Bone Marrow Cells, Surgical and Invasive Medical Procedures, Spleen, Asymptomatic, Young Adult, 03 medical and health sciences, Parasite Groups, parasitic diseases, Malaria, Vivax, Parasitic Diseases, medicine, Humans, New Guinea, Blood Cells, Organisms, Biology and Life Sciences, Plasmodium falciparum, Cell Biology, Tropical Diseases, biology.organism_classification, medicine.disease, Parasitic Protozoans, Malaria, 030104 developmental biology, Indonesia, Immunology, Parasitology, Apicomplexa
Abstract: Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Dr. Anstey and co-authors found that P. vivax-infected immature reticulocytes and erythrocytes accumulate in the same splenic compartments, suggesting existence of a cryptic endosplenic lifecycle in chronic P. vivax infection that maximizes survival and replication in the spleen., Author summary Why was this study done? There is a surprisingly large biomass of intact Plasmodium vivax parasites in the spleen of people living in malaria endemic areas, greater than with Plasmodium falciparum. Why P. vivax accumulates so intensely in the spleen is not known. P. vivax requires very young red cells (immature reticulocytes) for invasion and replication. What did the researchers do and find? The accumulation of P. vivax and immature reticulocytes were evaluated in spleens from people undergoing splenectomy in malaria-endemic Papua. P. vivax parasites and immature reticulocytes accumulated in the same splenic compartments. All stages of P. vivax accumulated in the spleen at magnitudes unexplainable by replication occurring in the circulation alone, with the proportion of each stage in the spleen consistent with the duration in their lifecycle. What do these findings mean? Taking advantage of the large physiological splenic reservoir of immature reticulocytes, the majority of the P. vivax lifecycle can take place in the spleen in chronic malaria. Chronic vivax malaria should be considered predominantly an infection of the reticulocyte-rich spleen, with secondary involvement of the intravascular compartment. The spleen is not solely a compartment for parasite destruction and clearance. Specific adaptations have likely evolved to maximise P. vivax survival in the spleen.
Published: 2021

24. Genomic landscape of human diversity across Madagascar

Author: Amal Arachiche, Mireille Mialy Rakotomalala, Veronica Pereda-Loth, Anne Boland, Mark Stoneking, Nelly Ranaivo Rabetokotany, Sander Adelaar, Sendra Lejamble, Laure Tonaso, Fulgence Fanony, Miakabola Andriamampianina Raharijesy, Olivier Thomas, Jean-François Deleuze, Herawati Sudoyo, François-Xavier Ricaut, Thierry Letellier, Lolona Razafindralambo, Philippe Grange, Bodo Ravololomanga, Chantal Radimilahy, Margit Heiske, Bako Rasoarifetra, Ramilisonina, Ahmed Mohamed Abdallah, Shengyu Ni, Jean-Aimé Rakotoarisoa, Lucien M.A. Rakotozafy, Stéphanie Schiavinato, Harilanto Razafindrazaka, Pradiptajati Kusuma, Ignace Rakoto, Denis Pierron, Nicolas Brucato, Philippe Beaujard, Michel Razafiarivony, Christophe Rocher, Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Université d'Antananarivo, Physiopathologie mitochondriale, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Eijkman Institute for Molecular Biology [Jakarta], Department of Pharmacy, Faculty of Science & Mathematics, Islamic University of Indonesia, Islamic University of Indonesia, Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Mondes Africains (IMAF), Université Paris 1 Panthéon-Sorbonne (UP1)-Institut de Recherche pour le Développement (IRD)-École des hautes études en sciences sociales (EHESS)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), La Rochelle Université (ULR), University of Melbourne, ANR-12-PDOC-0037,GENO-MIX,Admixture fonctionnelle : étude génomique des adaptations métaboliques lors d'un mélange de population.(2012), ANR-14-CE31-0013,OCEOADAPTO,Histoire des populations dans l'Océan Indien : Adaptation biologique des populations issu de la traite des esclaves et de la dispersion indonésienne vers Madagascar(2014), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, RICAUT, FRANCOIS-XAVIER, Retour Post-Doctorant - Admixture fonctionnelle : étude génomique des adaptations métaboliques lors d'un mélange de population. - - GENO-MIX2012 - ANR-12-PDOC-0037 - PDOC - VALID, Appel à projets générique - Histoire des populations dans l'Océan Indien : Adaptation biologique des populations issu de la traite des esclaves et de la dispersion indonésienne vers Madagascar - - OCEOADAPTO2014 - ANR-14-CE31-0013 - Appel à projets générique - VALID, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Paris 1 Panthéon-Sorbonne (UP1)-Institut de Recherche pour le Développement (IRD)-École des hautes études en sciences sociales (EHESS)-École pratique des hautes études (EPHE), and Université de La Rochelle (ULR)
Subjects: Male, 0301 basic medicine, media_common.quotation_subject, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Population, Ethnic group, Black People, Distribution (economics), Bantu languages, 030105 genetics & heredity, 03 medical and health sciences, Asian People, parasitic diseases, Ethnicity, Madagascar, Humans, genetics, Colonization, proto-globalization, education, Indian Ocean, Malagasy origins, Aged, media_common, education.field_of_study, Multidisciplinary, Middle East, Genome, Human, Ecology, business.industry, Genetic Variation, genome-wide data, Middle Aged, Genealogy, [SHS.ANTHRO-BIO] Humanities and Social Sciences/Biological anthropology, 030104 developmental biology, Geography, PNAS Plus, Genetic structure, Female, business, Genome-Wide Association Study, Diversity (politics)
Abstract: International audience; Although situated ∼400 km from the east coast of Africa, Madagascar exhibits cultural, linguistic, and genetic traits from both Southeast Asia and Eastern Africa. The settlement history remains contentious; we therefore used a grid-based approach to sample at high resolution the genomic diversity (including maternal lineages, paternal lineages, and genome-wide data) across 257 villages and 2,704 Malagasy individuals. We find a common Bantu and Austronesian descent for all Malagasy individuals with a limited paternal contribution from Europe and the Middle East. Admixture and demographic growth happened recently, suggesting a rapid settlement of Madagascar during the last millennium. However, the distribution of African and Asian ancestry across the island reveals that the admixture was sex biased and happened heterogeneously across Madagascar, suggesting independent colonization of Madagascar from Africa and Asia rather than settlement by an already admixed population. In addition, there are geographic influences on the present genomic diversity, independent of the admixture, showing that a few centuries is sufficient to produce detectable genetic structure in human populations.
Published: 2017

25. Defining the next generation of Plasmodium vivax diagnostic tests for control and elimination: Target product profiles

Author: Naomi W. Lucchi, Jack S. Richards, Xavier C. Ding, Maria Paz Ade, Arsène Ratsimbason, Sócrates Herrera, Mehul Dhorda, Iveth J. González, Ivo Mueller, Jetsumon Sattabongkot, Alfredo Mayor, Jane Cunningham, Marcel Tanner, Matthias Harbers, Chris Drakeley, Dionicia Gamboa, Ingrid Felger, Qin Cheng, J. Kevin Baird, Foundation for Innovative New Diagnostics (FIND), Pan American Health Organization, World Health Organization (PANAFTOSA), Eijkman Institute for Molecular Biology [Jakarta], Australian Army Malaria Institute, Global Malaria Programme, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Oxford, Churchill Hospital [Breast Care Unit], Churchill Hospital Oxford Centre for Haematology, London School of Hygiene and Tropical Medicine (LSHTM), Swiss Tropical and Public Health Institute [Basel], Universidad Peruana Cayetano Heredia (UPCH), RIKEN Center for Life Science Technologies (RIKEN CLST), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Caucaseco scientific research center = Centro de Investigación Científica Caucaseco, Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Barcelona Centre for International Health Research, Hospital Clinic (CRESIB), Universitat de Barcelona (UB), The Walter and Eliza Hall Institute of Medical Research (WEHI), Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors, Institut Pasteur [Paris] (IP), Mahidol University [Bangkok], Université d'Antananarivo, Burnet Institute [Melbourne, Victoria], University of Melbourne, University of Basel (Unibas), This work was supported by funds from the Department of Foreign Affairs and Trade, Australian Government., University of Oxford [Oxford], and Institut Pasteur [Paris]
Subjects: Plasmodium, Physiology, Plasmodium vivax, Psychological intervention, Plasmodium vivax/isolation & purification, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Epidemiology, Medicine and Health Sciences, 030212 general & internal medicine, Malaria, Falciparum, MESH: Plasmodium falciparum, Protozoans, biology, lcsh:Public aspects of medicine, MESH: Malaria, Falciparum, Malarial Parasites, Parasitic diseases, 3. Good health, MESH: Plasmodium vivax, MESH: Point-of-Care Systems, Body Fluids, Malalties parasitàries, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Blood, Infectious Diseases, Malaria, Vivax/diagnosis/parasitology/prevention & control, Anatomy, purl.org/pe-repo/ocde/ford#3.03.06 [https], Research Article, medicine.medical_specialty, lcsh:Arctic medicine. Tropical medicine, Infectious Disease Control, lcsh:RC955-962, Point-of-Care Systems, 030231 tropical medicine, Plasmodium falciparum, 03 medical and health sciences, Species Specificity, Diagnostic Medicine, parasitic diseases, Parasite Groups, medicine, Gametocyte, Malaria, Vivax, Parasitic Diseases, MESH: Species Specificity, Humans, Malaria, Falciparum/diagnosis/parasitology/prevention & control, Intensive care medicine, MESH: Diagnostic Tests, Routine, MESH: Humans, Plasmodium falciparum/isolation & purification, Diagnostic Tests, Routine, Public health, Public Health, Environmental and Occupational Health, Organisms, MESH: Malaria, Vivax, Biology and Life Sciences, lcsh:RA1-1270, medicine.disease, biology.organism_classification, Tropical Diseases, Parasitic Protozoans, Malaria, Parasitology, Immunology, Apicomplexa
Abstract: The global prevalence of malaria has decreased over the past fifteen years, but similar gains have not been realized against Plasmodium vivax because this species is less responsive to conventional malaria control interventions aimed principally at P. falciparum. Approximately half of all malaria cases outside of Africa are caused by P. vivax. This species places dormant forms in human liver that cause repeated clinical attacks without involving another mosquito bite. The diagnosis of acute patent P. vivax malaria relies primarily on light microscopy. Specific rapid diagnostic tests exist but typically perform relatively poorly compared to those for P. falciparum. Better diagnostic tests are needed for P. vivax. To guide their development, FIND, in collaboration with P. vivax experts, identified the specific diagnostic needs associated with this species and defined a series of three distinct target product profiles, each aimed at a particular diagnostic application: (i) point-of-care of acutely ill patients for clinical care purposes; (ii) point-of-care asymptomatic and otherwise sub-patent residents for public health purposes, e.g., mass screen and treat campaigns; and (iii) ultra-sensitive not point-of-care diagnosis for epidemiological research/surveillance purposes. This report presents and discusses the rationale for these P. vivax-specific diagnostic target product profiles. These contribute to the rational development of fit-for-purpose diagnostic tests suitable for the clinical management, control and elimination of P. vivax malaria., Author summary Plasmodium vivax is the second most prevalent Plasmodium species amongst the five that can infect humans and cause malaria. The control and elimination of P. vivax is complicated by its specific biology, such as hard-to-detect low densities of blood-circulating parasites in infected individuals, the existence of persistent liver forms causing relapse, or the early appearance of sexual stages of the parasite during the course of an infection, which facilitates its transmission. These difficulties are reinforced by the fact that most antimalarial tools have been developed primarily for P. falciparum, the most prevalent malaria species, and are not always as effective for P. vivax. Current tools for the diagnosis of P. vivax are of limited effectiveness. Rapid diagnostic tests exist but show, in average, lower performance than similar test for P. falciparum. P. vivax diagnosis often relies on light microscopy which is challenging to maintain at a high quality and not sensitive enough to detect a large fraction of all infections. Recognizing that better diagnostic tools for P. vivax are needed, we report in this study the development of new target product profiles to define the specific characteristics of such tests. The establishment of these consensus-based documents is an important first step to guide research and development efforts toward better diagnostic solutions for P. vivax malaria and to accelerate the elimination of this species alongside P. falciparum.
Published: 2016

26. Genomic epidemiology of artemisinin resistant malaria

Author: Amato, Roberto, Miotto, Olivo, Woodrow, Charles J, Almagro-Garcia, Jacob, Sinha, Ipsita, Campino, Susana, Mead, Daniel, Drury, Eleanor, Kekre, Mihir, Sanders, Mandy, Amambua-Ngwa, Alfred, Amaratunga, Chanaki, Amenga-Etego, Lucas, Andrianaranjaka, Voahangy, Apinjoh, Tobias, Ashley, Elizabeth, Auburn, Sarah, Awandare, Gordon, Baraka, Vito, Barry, Alyssa, Boni, Maciej, Borrmann, Steffen, Bousema, Teun, Branch, Oralee, Bull, Peter, Chotivanich, Kesinee, Conway, David, Craig, Alister, Day, Nicholas, Djimde, Abdoulaye, Dolecek, Christiane, Dondorp, Arjen M, Drakeley, Chris, Duffy, Patrick, Echeverry, Diego F, Egwang, Thomas, Fairhurst, Rick, Faiz, Abul, Fanello, Caterina, Hien, Tran Tinh, Hodgson, Abraham, Imwong, Mallika, Ishengoma, Deus, Lim, Pharath, Lon, Chanthap, Marfurt, Jutta, Marsh, Kevin, Mayxay, Mayfong, Michon, Pascal, Mobegi, Victor, Mokuolu, Olugbenga, Montgomery, Jacqui, Mueller, Ivo, Kyaw, Myat Phone, Newton, Paul N, Nosten, François, Noviyanti, Rintis, Nzila, Alexis, Ocholla, Harold, Oduro, Abraham, Onyamboko, Marie, Ouédraogo, Jean-Bosco, Phyo, Aung, Plowe, Christopher, Price, Ric, Pukrittayakamee, Sasithon, Randrianarivelojosia, Milijaona, Ringwald, Pascal, Ruiz, Lastenia, Saunders, David, Shayo, Alex, Siba, Peter, Takala-Harrison, Shannon, Thanh, Thuy-Nhien, Thathy, Vandana, Verra, Federica, Wendler, Jason, White, Nicholas, Ye, Htut, Cornelius, Victoria, Giacomantonio, Rachel, Muddyman, Dawn, Henrichs, Christa, Malangone, Cinzia, Jyothi, Dushyanth, Pearson, Richard, Rayner, Julian, McVean, Gilean, Rockett, Kirk, Miles, Alistair, Vauterin, Paul, Jeffery, Ben, Manske, Magnus, Stalker, Jim, MacInnis, Bronwyn, Kwiatkowski, Dominic, The Wellcome Trust Sanger Institute [Cambridge], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Medical Research Council Unit The Gambia (MRC), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), G4 malaria group [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of Buéa, Global and Tropical Health Division [Rocklands, Australia], Menzies School of Health Research [Australia], Charles Darwin University-Charles Darwin University, West African Centre for Cell Biology of Infectious Pathogens [Legon, Ghana] (WACCBIP), University of Ghana, National Institute for Medical Research [Tanzania] (NIMR), The Walter and Eliza Hall Institute of Medical Research (WEHI), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), KEMRI-Wellcome Trust Research Programme (KWTRP), London School of Hygiene and Tropical Medicine (LSHTM), New York University School of Medicine, NYU System (NYU), Faculty of Tropical Medicine [Bangkok, Thailand], Mahidol University [Bangkok], Liverpool School of Tropical Medicine (LSTM), Faculté de Médecine, de pharmacie et d’Odonto-Stomatologie [Bamako, Mali] (FMPOS), Université de Bamako, Department of Entomology [West Lafayette], Purdue University [West Lafayette], Med Biotech Laboratories [Kampala, Ouganda] (MBL), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Faculty of Medicine and Health Sciences [Madang, Papouasie-Nouvelle-Guinée], Divine Word University [Papouasie-Nouvelle-Guinée] (DWU), University of Ilorin, Department of Entomology [University Park], Pennsylvania State University (Penn State), Penn State System-Penn State System, University of Melbourne, Ministry of health and sport [Yangon, Myanmar] (MoHS), Eijkman Institute for Molecular Biology [Jakarta], King Fahd University of Petroleum and Minerals (KFUPM), Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), Liverpool School of Tropical Medicine (LSTM)-University of Liverpool-Wellcome Trust-University of Malawi, University of Kinshasa (UNIKIN), Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, 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], University of Maryland School of Medicine, University of Maryland System, 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), Global Malaria Programme, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Universidad Nacional de la Amazonía Peruana [Loreto, Perou] (UNAP), University of Dodoma [Tanzanie] (UDOM), Papua New Guinea Institute of Medical Research (PNG-IMR), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], The sequencing, analysis, informatics and management of the Community Project are supported by the Wellcome Trust through Sanger Institute core funding (098051) and a Strategic Award (090770/Z/09/Z) and by the MRC Centre for Genomics and Global Health which is jointly funded by the Medical Research Council and the Department for International Development (DFID) (G0600718, M006212). AEB and IM acknowledge the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS., This study was conducted by the MalariaGEN Plasmodium falciparum Community Project, and was made possible by clinical parasite samples contributed by partner studies, whose investigators are represented in the author list. RA and OM contributed equally. In addition, the authors would like to thank the following individuals, who contributed to partner studies or to the MalariaGEN Resource Centre, making this study possible: James Abugri, Nicholas Amoako, Steven M Kiara, John Okombo, Rogelin Raherinjafy, Seheno Razanatsiorimalala, Hongying Jiang, Xin-zhuan Su., and MalariaGEN Plasmodium Falciparum C
Subjects: 0301 basic medicine, Drug resistance, Pharmacology, MESH: Asia, Southeastern/epidemiology, MESH: Malaria, Falciparum/epidemiology, Malaria, Falciparum, Artemisinin, Biology (General), GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Asia, Southeastern, Genetics, Molecular Epidemiology, Microbiology and Infectious Disease, education.field_of_study, MESH: Plasmodium falciparum/genetics, General Neuroscience, General Medicine, MESH: Artemisinins/pharmacology, Artemisinins, 3. Good health, Genomics and Evolutionary Biology, kelch13, Medicine, MESH: Plasmodium falciparum/drug effects, Research Article, medicine.drug, Combination therapy, plasmodium falciparum, QH301-705.5, infectious disease, MESH: Antimalarials/pharmacology, Science, 030106 microbiology, Population, malaria, MESH: Plasmodium falciparum/classification, MESH: Malaria, Falciparum/parasitology, Biology, General Biochemistry, Genetics and Molecular Biology, Antimalarials, 03 medical and health sciences, parasitic diseases, medicine, genomics, MESH: Molecular Epidemiology, education, MESH: Drug Resistance, [SDV.GEN]Life Sciences [q-bio]/Genetics, drug resistance, General Immunology and Microbiology, Molecular epidemiology, evolutionary biology, microbiology, Plasmodium falciparum, medicine.disease, biology.organism_classification, MESH: Africa/epidemiology, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, artemisinin, Infectious disease (medical specialty), Africa, Other, Human medicine, MESH: Plasmodium falciparum/isolation & purification, Malaria
Abstract: The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. DOI: http://dx.doi.org/10.7554/eLife.08714.001, eLife digest Malaria is an infectious disease caused by a microscopic parasite called Plasmodium, which is transferred between humans by mosquitos. One species of malaria parasite called Plasmodium falciparum can cause particularly severe and life-threatening forms of the disease. Currently, the most widely used treatment for P. falciparum infections is artemisinin combination therapy, a treatment that combines the drug artemisinin (or a closely related molecule) with another antimalarial drug. However, resistance to artemisinin has started to spread throughout Southeast Asia. Artemisinin resistance is caused by mutations in a parasite gene called kelch13, and researchers have identified over 20 different mutations in P. falciparum that confer artemisinin resistance. The diversity of mutations involved, and the fact that the same mutation can arise independently in different locations, make it difficult to track the spread of resistance using conventional molecular marker approaches. Here, Amato, Miotto et al. sequenced the entire genomes of more than 3,000 clinical samples of P. falciparum from Southeast Asia and Africa, collected as part of a global network of research groups called the MalariaGEN Plasmodium falciparum Community Project. Amato, Miotto et al. found that African parasites had independently acquired many of the same kelch13 mutations that are known to cause resistance to artemisinin in Southeast Asia. However the kelch13 mutations seen in Africa remained at low levels in the parasite population, and appeared to be under much less pressure for evolutionary selection than those found in Southeast Asia. These findings demonstrate that the emergence and spread of resistance to antimalarial drugs does not depend solely on the mutational process, but also on other factors that influence whether the mutations will spread in the population. Understanding how this is affected by different patterns of drug treatments and other environmental conditions will be important in developing more effective strategies for combating malaria. DOI: http://dx.doi.org/10.7554/eLife.08714.002
Published: 2016

27. Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency

Author: Phum Souy, Narann Tops, Saorin Kim, Khem Kosal, Eva Christophel, Chan Vanna, Sinoun Muth, Khon Sothea, Didier Menard, Pascal Ringwald, Sim Kheng, Chuor Meng Char, Po Ly, Alexandra Kerleguer, Walter R. J. Taylor, Pety Tor, Virak Khieu, John Kevin Baird, Steven Bjorge, National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Service de Médecine Tropicale et Humanitaire [Geneva, Suisse], Hôpitaux Universitaires de Genève (HUG), Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], 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]., Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Pramoy Health Centre [Cambodia], Eijkman Oxford Clinical Research Unit [Jakarta, Indonesie], Eijkman Institute of Molecular Biology [Jakarta, Indonesie], 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], Regional Office of the Western Pacific (WHO), Funding for this study was obtained by PR of WHO Geneva via a grant from UKAid without which this study would not have taken place. We record our profound gratitude to the taxpayers of the United Kingdom. WRJT was part supported by France Expertise International through the 5 % initiative as a consultant to CNM in operational research and he expresses 'ses remerciements profonds au peuple français.' JKB is supported by Wellcome Trust grant B9RJIXO. DM is supported the French Ministry of Foreign Affairs and SKim was part funded by a grant from the Asia Pacific Malaria Elimination Network. None of the funders had any role in study design, data collection, analysis, and interpretation, or writing of the manuscript or in the decision to submit the manuscript for publication., and We wish to express our sincere and profound thanks to the patients who took part in this study and to the nurses and laboratory staff who contributed to its successful and safe execution. We thank our DSMB who reviewed the G6PDd data in real time and provided very valuable and timely responses and advice: Drs Toby Leslie (Chairperson), Chanthap Lon, Isabella Ribeiro and Professor Lucio Luzzatto.
Subjects: Male, Primaquine, Blood transfusion, medicine.medical_treatment, Plasmodium vivax, MESH: Comorbidity, Comorbidity, Pharmacology, Gastroenterology, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Outcome Assessment, Health Care, Secondary Prevention, 030212 general & internal medicine, Child, Village Malaria Worker, Medicine(all), MESH: Middle Aged, MESH: Secondary Prevention, biology, General Medicine, MESH: Primaquine, Middle Aged, MESH: Plasmodium vivax, 3. Good health, MESH: Glucosephosphate Dehydrogenase Deficiency, Tolerability, Female, Cambodia, G6PD Activity, medicine.drug, Research Article, Adult, medicine.medical_specialty, Anemia, Hemolytic, Adolescent, Anemia, 030231 tropical medicine, Dihydroartemisinin, MESH: Blood Transfusion, MESH: Drug Administration Schedule, Drug Administration Schedule, 03 medical and health sciences, Antimalarials, Internal medicine, parasitic diseases, medicine, Malaria, Vivax, Humans, Blood Transfusion, MESH: Outcome Assessment, Health Care, MESH: Anemia, Hemolytic, MESH: Adolescent, MESH: Humans, business.industry, MESH: Cambodia, MESH: Malaria, Vivax, MESH: Adult, Thick Blood Film, medicine.disease, biology.organism_classification, MESH: Antimalarials, MESH: Male, Hemizygous Male, Regimen, Glucosephosphate Dehydrogenase Deficiency, business, MESH: Female, Glucose-6-phosphate dehydrogenase deficiency
Abstract: Background Primaquine is used to prevent Plasmodium vivax relapse; however, it is not implemented in many malaria-endemic countries, including Cambodia, for fear of precipitating primaquine-induced acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Reluctance to use primaquine is reinforced by a lack of quality safety data. This study was conducted to assess the tolerability of a primaquine regimen in Cambodian severely deficient G6PD variants to ascertain whether a weekly primaquine could be given without testing for G6PDd. Methods From January 2013 to January 2014, Cambodians with acute vivax malaria were treated with dihydroartemisinin/piperaquine on days (D) 0, 1 and 2 with weekly doses of primaquine 0.75 mg/kg for 8 weeks (starting on D0, last dose on D49), and followed until D56. Participants’ G6PD status was confirmed by G6PD genotype and measured G6PD activity. The primary outcome was treatment completion without primaquine toxicity defined as any one of: (1) severe anaemia (haemoglobin [Hb] 25 % fractional fall in Hb from D0, (3) the need for a blood transfusion, (4) haemoglobinuria, (5) acute kidney injury (an increase in baseline serum creatinine >50 %) or (6) methaemoglobinaemia >20 %. Results We enrolled 75 patients with a median age of 24 years (range 5–63); 63 patients (84 %) were male. Eighteen patients were G6PDd (17/18 had the Viangchan variant) and had D0 G6PD activity ranging from 0.1 to 1.5 U/g Hb (median 0.85 U/g Hb). In the 57 patients with normal G6PD (G6PDn), D0 G6PD activity ranged from 6.9 to 18.5 U/g Hb (median 12 U/g Hb). Median D0 Hb concentrations were similar (P = 0.46) between G6PDd (13 g/dL, range 9.6–16) and G6PDn (13.5 g/dL, range 9–16.3) and reached a nadir on D2 in both groups: 10.8 g/dL (8.2–15.3) versus 12.4 g/dL (8.8–15.2) (P = 0.006), respectively. By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049). One of these G6PDd patients required a blood transfusion (D0–D5 Hb, 10.0–7.2 g/dL). No patients developed severe anaemia, haemoglobinuria, a methaemoglobin concentration >4.9 %, or acute kidney injury. Conclusions Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion. Weekly primaquine in G6PDd patients mandates medical supervision and pre-treatment screening for G6PD status. The feasibility of implementing a package of G6PDd testing and supervised primaquine should be explored. Trial registration The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0441-1) contains supplementary material, which is available to authorized users.
Published: 2015

28. Spatial distribution of G6PD deficiency variants across malaria-endemic regions

Author: Howes, Rosalind E, Dewi, Mewahyu, Piel, Frédéric B, Monteiro, Wuelton M, Battle, Katherine E, Messina, Jane P, Sakuntabhai, Anavaj, Satyagraha, Ari W, Williams, Thomas N, Baird, J, Hay, Simon I, Spatial Ecology and Epidemiology Group, Department of Zoology, Eijkman-Oxford Clinical Research Unit, Evolutionary Ecology of Infectious Disease Group, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, University of the State of Amazonas, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Eijkman Institute for Molecular Biology [Jakarta], Kenya Medical Research Institute (KEMRI), Department of Medicine, Imperial College London, Nuffield Department of Clinical Medicine [Oxford], University of Oxford, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Oxford [Oxford]
Subjects: Spatial Analysis, Genetic variants, Research, Glucose-6-phosphate dehydrogenase deficiency, Genetic Variation, Haemolysis, Malaria elimination, Primaquine, Global Health, Risk Assessment, Plasmodium viva, Antimalarials, Infectious Diseases, Glucosephosphate Dehydrogenase Deficiency, Gene Frequency, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, Malaria, Vivax, Humans, Parasitology, Topography, Medical, Spatial distribution, Malaria, Falciparum, Plasmodium vivax, G6PD
Abstract: International audience; BACKGROUND: Primaquine is essential for malaria control and elimination since it is the only available drug preventing multiple clinical attacks by relapses of Plasmodium vivax. It is also the only therapy against the sexual stages of Plasmodium falciparum infectious to mosquitoes, and is thus useful in preventing malaria transmission. However, the difficulties of diagnosing glucose-6-phosphate dehydrogenase deficiency (G6PDd) greatly hinder primaquine's widespread use, as this common genetic disorder makes patients susceptible to potentially severe and fatal primaquine-induced haemolysis. The risk of such an outcome varies widely among G6PD gene variants. METHODS: A literature review was conducted to identify surveys of G6PD variant frequencies among representative population groups. Informative surveys were assembled into two map series: (1) those showing the relative proportions of the different variants among G6PDd individuals; and (2) those showing allele frequencies of G6PD variants based on population surveys without prior G6PDd screening. RESULTS: Variants showed conspicuous geographic patterns. A limited repertoire of variants was tested for across sub-Saharan Africa, which nevertheless indicated low genetic heterogeneity predominated by the G6PD A-202A mutation, though other mutations were common in western Africa. The severe G6PD Mediterranean variant was widespread across western Asia. Further east, a sharp shift in variants was identified, with high variant heterogeneity in the populations of China and the Asia-Pacific where no single variant dominated. CONCLUSIONS: G6PD variants exhibited distinctive region-specific distributions with important primaquine policy implications. Relative homogeneity in the Americas, Africa, and western Asia contrasted sharply with the heterogeneity of variants in China, Southeast Asia and Oceania. These findings will inform rational risk assessments for primaquine in developing public health strategies for malaria control and elimination, and support the future development of regionally targeted policies. The major knowledge gaps highlighted here strongly advocate for further investigation of G6PD variant diversity and their primaquine-sensitivity phenotypes.
Published: 2013

29. Thrombocytopenia in early malaria is associated with GP1b shedding in absence of systemic platelet activation and consumptive coagulopathy

Author: De Mast, Quirijn, De Groot, Philip G., Van Heerde, Waander, Roestenberg, Meta, Van Velzen, Jeroen F, Verbruggen, Bert, Roest, Mark, McCall, Matthew, Nieman, An-Emmie, Westendorp, Josien, Syafruddin, Din, Fijnheer, Rob, Van Dongen-Lases, Edmee C, R, Sauerwein, Van Der Ven, Andre J., General Internal Medicine, Radboud University Medical Center [Nijmegen], Clinical Chemistry and Hematology, University Medical Center [Utrecht], Laboratory Medicine, Medical Microbiology, Malaria research, and Eijkman Institute for Molecular Biology [Jakarta]
Subjects: parasitic diseases, Medicine
Abstract: International audience; Thrombocytopenia develops early in malaria, but the underlying mechanisms remain incompletely understood. We studied the etiology of malaria-associated thrombocytopenia in volunteers experimentally infected with Plasmodium falciparum malaria, in Indonesian malaria patients and in ex vivo studies. In experimental human malaria, the decrease in platelet numbers was associated with a concurrent rise in young platelets (immature platelet fraction) and thrombopoietin. D-dimer concentrations were moderately elevated without a prolongation in APTT or decrease in fibrinogen. There was no increase in expression of the platelet surface markers CD62P, PAC-1 and CD63 and in plasma concentrations of the platelet factors P-selectin, CXCR4, CXCL7, RANTES and CD40L. In contrast, concentrations of soluble glycoprotein-1b (sGP1b), the external domain of the platelet receptor for von Willebrand factor (VWF), increased early. Indonesian malaria patients also had elevated concentrations of sGP1b, which correlated with VWF concentrations. Finally, incubation of platelets with parasitized erythrocytes in vitro failed to induce platelet aggregation or activation. We conclude that neither a compromised platelet production nor platelet activation or consumptive coagulopathy are responsible for the early thrombocytopenia in malaria. We hypothesize that the increase in sGP1b concentrations results from VWF-mediated GP1b shedding; a process that may prevent excessive adhesion of platelets and parasitized erythrocytes
Published: 2010

30. Spectrum of respiratory viruses identified from SARS-CoV-2-negative human respiratory tract specimens in Watansoppeng, Indonesia.

Author: Idris I, Wahid I, Antonjaya U, Johar E, Kleib FH, Sriyani IY, Dewantari AK, Daming O, Duharing M, Sappe F, Hasan H, Yudhaputri FA, Syafruddin D, and Myint KSA
Abstract: Respiratory infections account for millions of hospital admissions worldwide. The aetiology of respiratory infections can be attributed to a diverse range of pathogens including viruses, bacteria and fungi. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)-negative specimens from Wattansoppeng city, South Sulawesi, were analysed to study the spectrum of respiratory viruses. Samples were screened for influenza virus, enterovirus, Paramyxoviridae, Nipah virus, Coronaviridae and Pneumoviridae. Of 210 specimens, 19 were positive for respiratory syncytial virus (RSV)-A, RSV-B, human parainfluenza virus type 1 (HPIV-1), HPIV-2, human rhinovirus (HRV)-A, HRV-B, HRV-C, human metapneumovirus (HMPV), influenza A virus (IAV) and coxsackievirus A6 (CV-A6). Influenza virus was of seasonal H3N2 subtype. The HMPVs were of genotypes B1 and A2a, while one RSV-A was of the ON-1 genotype. The viruses mostly affected children with unknown severity., Competing Interests: The authors declare that there are no conflicts of interest. K.S.A. Myint receives research support from the US CDC. The findings and conclusions expressed in this report do not necessarily represent the views of the US Center for Disease Control and Prevention., (Copyright © 2024 The Authors.)
Published: 2024
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31. Early intervention of 5% albumin shown superior control of vascular integrity and function compared to ringer's lactatein hospitalized adult with grade I & II Dengue hemorrhagic fever: a multicenter randomized controlled trial in Indonesia.

Author: Bur R, Suwarto S, Pohan HT, Prihartono J, Harahap AR, Dewi BE, Sadikin M, Rachman A, and Yusuf H
Abstract: Background: Dengue virus remains a major public health problem with one of the hallmark pathologies is the vascular leakage caused by endothelial dysfunction which can lead to Dengue Hemorrhagic Fever (DHF) manifestation. In the status quo, no specific therapy has been discovered but rather heavily relies on judicious and frequent monitoring of intravenous fluids administration. The current guideline has discussed the roles of fluid therapy during the Dengue Shock Syndrome (DSS) stage, however, administration of early fluid intervention for DHF grade I and II remains uncharted territory. In addition, the choice and timing of colloid administration remains underexplored. As one of the widely available colloids, 5% albumin has known physiological properties that potentially minimize plasma leakage. Therefore, this study aimed to evaluate the benefit of early intervention of 5% albumin in adults with DHF in the hope of preventing the lethal progression to DSS and further, shorten the length of stay (LOS) for patients., Methods: We conducted a multicenter, open-labeled, randomized controlled trial in Jakarta and Banten to compare the effect of early intervention with 5% albumin in adult patients with DHF compared to Ringer's Lactate (RL). Statistical analyses were conducted using unpaired t-test and Mann-Whitney for normally and abnormally distributed data respectively., Results: Adult patients with a diagnosis of DHF grade I and II that being hospitalized to receive the early intervention of 5% albumin had significantly lower levels of hemoconcentration 4, 12, and 24 h (p = 0.002, 0.001, 0.003, respectively), higher platelet counts 4 h (p = 0.036), higher serum albumin levels 48 h (p = 0.036), lower proteinuria 24 and 48 h post-albumin administration (p < 0.001, < 0.001, respectively), and shorter LOS (p < 0.001) when compared to the RL group., Conclusion: Early intervention of 5% albumin showed better control on vascular integrity and function compared to ringer lactate in hospitalized adults with grade I & II DHF, thus halting the progression of DHF into DSS and other related complications which leads to faster recovery and shorter length of stay., Trial Registration: The study was registered to www., Clinicaltrial: gov with trial registration number NCT04076254, and registration date October 31st 2016., (© 2024. The Author(s).)
Published: 2024
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32. Vitamin D and gut microbiome in preterm infants.

Author: Marsubrin PMT, Firmansyah A, Rohsiswatmo R, Purwosunu Y, Bardosono S, Malik SG, Munasir Z, Timan IS, Yuniati T, and Yulindhini M
Subjects: Humans, Infant, Newborn, Female, Male, Cohort Studies, Indonesia epidemiology, Feces microbiology, Gastrointestinal Microbiome, Vitamin D blood, Vitamin D analogs & derivatives, Vitamin D Deficiency epidemiology, Infant, Premature, Dysbiosis
Abstract: Background: The incidence of vitamin D deficiency among pregnant women remains high and is associated with vitamin D deficiency in infants. In normally breastfed infants, Bifidobacteriaceae and Lactobacillaceae are known to help in maintaining immunotolerance and prevent infection. Vitamin D in the gastrointestinal tract plays a role in determining the composition and function of intestinal bacteria. Preterm infants are vulnerable to intestinal dysbiosis and sepsis due to bacterial translocation. This study aimed to determine the association between vitamin D levels and intestinal dysbiosis., Methods: It was a cohort study conducted in the Neonatal Unit, Cipto Mangunkusumo Hospital, Tertiary hospital in Indonesia, from November 2019 to January 2021. The inclusion criteria in this study were preterm infants with a gestational age of less than 32 weeks or a birth weight of less than 1500 g. Total 25-hydroxyvitamin D (25(OH)D) levels were collected from the umbilical cords of very preterm or very low birth weight infants. A fecal examination was performed on the seventh day of life to assess intestinal bacteria using real-time PCR for four bacterial genera: Bifidobacteriaceae, Lactobacillaceae, Enterobacteriaceae, and Clostridiaceae., Results: A total of 43 infants were included in this study. Among the subjects, 53.4% had vitamin D deficiency. There was no association identified between vitamin D deficiency and intestinal dysbiosis (RR 0.67; 95% CI (0.15-2.82), p-value = 0.531). However, the ratio of Lactobacillacecae to Enterobacteriaceae was lower in those with vitamin D deficiency., Conclusion: Vitamin D deficiency was not associated with dysbiosis in preterm infants. However, this study found that the ratio of Lactobacillaceae to Enterobacteriaceae in those with vitamin D deficiency was lower than in those without vitamin D deficiency. Further research is warranted to confirm this finding., (© 2024. The Author(s).)
Published: 2024
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33. A description of lineage 1 Mycobacterium tuberculosis from papua, Indonesia.

Author: Djunaedy HAK, Febinia CA, Hamers RL, Baird K, Elyazar I, Thuong NTT, Trimarsanto H, Malik SG, Thwaites G, van Crevel R, Alisjahbana B, Chaidir L, and Ashton PM
Abstract: Indonesia has the third highest number of tuberculosis (TB) patients infected with Mycobacterium tuberculosis (MTB) Lineage 1 (L1). Most of these MTB L1 cases can be found in Indonesia's remote easternmost province of Papua, one of Indonesia's most underdeveloped provinces with a particularly high burden for TB. In this study, we sequenced and described 42 MTB L1 isolates from a well-characterized cohort of patients. We found a genetically diverse MTB L1 population with no association between pathogen genetic relatedness and place of residence or pathogen genetic relatedness and patient ethnicity, which could reflect mixing between different locales and ethnicities or our low sampling fraction. Only a small number showed genetic variants associated with drug resistance (5/42, 11.9 %), probably due to a lack of effective treatment programs. The Papuan isolates showed similarities to other Island Southeast Asian Countries due to the high proportion of L1.2.1.2.1 (30/42, 71.4 %), especially East Timor and the Philippines. This study fills a research gap of MTB L1 in Indonesian Papua and should serve as a stepping stone for further research in the region., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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34. On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity.

Author: Edgar RCS, Malcolm TR, Siddiqui G, Giannangelo C, Counihan NA, Challis M, Duffy S, Chowdhury M, Marfurt J, Dans M, Wirjanata G, Noviyanti R, Daware K, Suraweera CD, Price RN, Wittlin S, Avery VM, Drinkwater N, Charman SA, Creek DJ, de Koning-Ward TF, Scammells PJ, and McGowan S
Subjects: Animals, Mice, Drug Resistance, Humans, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Protozoan Proteins antagonists & inhibitors, Protozoan Proteins metabolism, Protozoan Proteins genetics, Female, Antimalarials pharmacology, Plasmodium falciparum drug effects, Plasmodium falciparum enzymology, Plasmodium vivax drug effects, Plasmodium vivax enzymology, Aminopeptidases antagonists & inhibitors, Aminopeptidases metabolism
Abstract: To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound MMV1557817 is a selective, nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. MMV1557817 can kill sexual-stage P. falciparum , is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. MMV1557817 -resistant P. falciparum exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlights the potential of dual inhibition of M1 and M17 as an effective multi-species drug-targeting strategy.IMPORTANCEEach year, malaria infects approximately 240 million people and causes over 600,000 deaths, mostly in children under 5 years of age. For the past decade, artemisinin-based combination therapies have been recommended by the World Health Organization as the standard malaria treatment worldwide. Their widespread use has led to the development of artemisinin resistance in the form of delayed parasite clearance, alongside the rise of partner drug resistance. There is an urgent need to develop and deploy new antimalarial agents with novel targets and mechanisms of action. Here, we report a new and potent antimalarial compound, known as MMV1557817 , and show that it targets multiple stages of the malaria parasite lifecycle, is active in a preliminary mouse malaria model, and has a novel mechanism of action. Excitingly, resistance to MMV15578117 appears to be self-limiting, suggesting that development of the compound may provide a new class of antimalarial., Competing Interests: The authors declare no conflict of interest.
Published: 2024
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35. Cancer Stem Cells (CD44 + /CD24 - ), RAD6, DDB2 Immunohistochemistry Expression and IHC-UNEDO Scoring System As Predictor of Ovarian Cancer Chemoresistance.

Author: Sihombing UHM, Andrijono A, Purwoto G, Gandamihardja S, Harahap AR, Rustamadji P, Kekalih A, Widyawati R, and Fuady DR
Abstract: Backgrounds: Ovarian cancer is a deadly women cancer with many chemoresistance after standard treatment. Ovarian cancer tissues' CD44 + /CD24 - (CSCs), RAD6 overexpression and DDB2 underexpression are associated with chemoresistance, recurrence, and poor prognosis of the disease because of the existence of cancer stem cells (CSCs). We tried to analyze the expression of those three proteins while building a predictor scoring system to predict the ovarian cancer chemoresistance from the ovarian cancer tissue immunohistochemistry., Materials and Methods: We conducted a cohort study of 64 patients divided into two groups (32 patients in each group) at the Cipto Mangunkusumo, Tarakan, Dharmais, and Fatmawati Hospital which are located in Jakarta city, Indonesia. The patients underwent cytoreductive debulking and histopathological examination continued by six series of chemotherapy followed by six months of observation. We divided the groups into chemoresistant and chemosensitive by using Response Criteria in Solid Tumors (RECIST) criteria. Ovarian cancer tissue immunohistochemistry tests were then performed to count the CSCs, RAD6 and DDB2 expressions., Results: We found relationship between increased CSCs, RAD6 and reduced DDB2 ( p < 0.05) expression in ovarian cancer tissue with the chemoresistance. A possible predictor scoring system named IHC-UNEDO scoring was built to aid the ovarian cancer chemoresistance prediction., Conclusions: The conclusion is that CSCs, RAD6 and DDB2 expressions are significantly associated with ovarian cancer chemoresistance, and IHC-UNEDO scoring should be considered as a tool to predict ovarian cancer chemoresistance., Competing Interests: Conflict of interestAll authors report there are no competing interests to declare. Unedo Hence Markus Sihombing: no competing interests to declare. Andrijono: no competing interests to declare.Gatot Purwoto: no competing interests to declare.Supriadi Gandamihardja: no competing interests to declare.Alida R. Harahap: no competing interests to declare. Primariadewi Rustamadji: no competing interests to declare.Aria Kekalih: no competing interests to declare.Retno Widyawati: no competing interests to declare.Dzicky Rifqi Fuady: no competing interests to declare., (© Federation of Obstetric & Gynecological Societies of India 2023, corrected publication 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
Published: 2024
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36. Effectiveness of an Unsupervised Primaquine Regimen for Preventing Plasmodium vivax Malaria Relapses in Northeast Myanmar: A Single-Arm Nonrandomized Observational Study.

Author: Malla P, Wang Z, Brashear A, Yang Z, Lo E, Baird K, Wang C, and Cui L
Subjects: Humans, Myanmar epidemiology, Male, Adult, Female, Young Adult, Middle Aged, Adolescent, Recurrence, Child, Chloroquine therapeutic use, Chloroquine administration & dosage, Genotype, Secondary Prevention methods, Treatment Outcome, Aged, Child, Preschool, Primaquine therapeutic use, Primaquine administration & dosage, Malaria, Vivax drug therapy, Malaria, Vivax prevention & control, Malaria, Vivax epidemiology, Antimalarials therapeutic use, Antimalarials administration & dosage, Plasmodium vivax drug effects, Plasmodium vivax genetics
Abstract: Background: Plasmodium vivax presents a significant challenge for malaria elimination in the Greater Mekong Subregion. We evaluated the effectiveness of primaquine for reducing relapses of vivax malaria., Methods: Patients with uncomplicated P vivax malaria from eastern Myanmar received chloroquine (25-mg base/kg given in 3 days) plus unsupervised PQ (0.25 mg/kg/d for 14 days) without screening for glucose-6-phosphate dehydrogenase deficiency and were followed for a year., Results: A total of 556 patients were enrolled to receive the chloroquine/primaquine treatment from February 2012 to August 2013. During the follow-up, 38 recurrences were detected, presenting a cumulative recurrence rate of 9.1% (95% CI, 4.1%-14.1%). Genotyping at the pvmsp1 and pvmsp3α loci by amplicon deep sequencing and model prediction indicated that 13 of the 27 recurrences with genotyping data were likely due to relapses. Notably, all confirmed relapses occurred within the first 6 months., Conclusions: The unsupervised standard dose of primaquine was highly effective as a radical cure for P vivax malaria in eastern Myanmar. The high presumed effectiveness might have benefited from the health messages delivered during the enrollment and follow-up activities. Six-month follow-ups in the Greater Mekong Subregion are sufficient for detecting most relapses., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Published: 2024
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37. Higher peripheral blood mitochondrial DNA copy number and relative telomere length in under 48 years Indonesian breast cancer patients.

Author: Limardi PC, Panigoro SS, Siregar NC, Sutandyo N, Witjaksono F, Priliani L, Oktavianthi S, and Malik SG
Subjects: Humans, Female, Indonesia, Middle Aged, Case-Control Studies, Adult, Telomere Homeostasis, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Aged, Breast Neoplasms genetics, Breast Neoplasms blood, DNA, Mitochondrial blood, DNA, Mitochondrial genetics, DNA Copy Number Variations genetics, Telomere genetics
Abstract: Objective: Breast cancer is the leading cause of cancer incidence and mortality among Indonesian women. A comprehensive investigation is required to enhance the early detection of this disease. Mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) have been proposed as potential biomarkers for several cancer risks, as they are linked through oxidative stress mechanisms. We conducted a case-control study to examine peripheral blood mtDNA-CN and RTL patterns in Indonesian breast cancer patients (n = 175) and healthy individuals (n = 181). The relative ratios of mtDNA-CN and RTL were determined using quantitative real-time PCR (qPCR)., Results: Median values of mtDNA-CN and RTL were 1.62 and 0.70 in healthy subjects and 1.79 and 0.73 in breast cancer patients, respectively. We found a positive association between peripheral blood mtDNA-CN and RTL (p < 0.001). In under 48 years old breast cancer patients, higher peripheral blood mtDNA-CN (mtDNA-CN ≥ 1.73 (median), p = 0.009) and RTL (continuous variable, p = 0.010) were observed, compared to the corresponding healthy subjects. We also found a significantly higher 'High-High' pattern of mtDNA-CN and RTL in breast cancer patients under 48 years old (p = 0.011). Our findings suggest that peripheral blood mtDNA-CN and RTL could serve as additional minimally invasive biomarkers for breast cancer risk evaluation., (© 2024. The Author(s).)
Published: 2024
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38. Whole-Genome Sequencing and Mutation Analyses of SARS-CoV-2 Isolates from Indonesia.

Author: Oktavianthi S, Lages AC, Kusuma R, Kurniasih TS, Trimarsanto H, Andriani F, Rustandi D, Meriyanti T, Yusuf I, Malik SG, Jo J, and Suriapranata I
Abstract: The SARS-CoV-2 infection that caused the COVID-19 pandemic has become a significant public health concern. New variants with distinct mutations have emerged, potentially impacting its infectivity, immune evasion capacity, and vaccine response. A whole-genome sequencing study of 292 SARS-CoV-2 isolates collected from selected regions of Indonesia between January and October 2021 was performed to identify the distribution of SARS-CoV-2 variants and common mutations in Indonesia. During January-April 2021, Indonesian lineages B.1.466.2 and B.1.470 dominated, but from May 2021, Delta's AY.23 lineage outcompeted them. An analysis of 7515 published sequences from January 2021 to June 2022 revealed a decline in Delta in November 2021, followed by the emergence of Omicron variants in December 2021. We identified C241T (5'UTR), P314L (NSP12b), F106F (NSP3), and D614G (Spike) mutations in all sequences. The other common substitutions included P681R (76.4%) and T478K (60%) in Spike, D377Y in Nucleocapsid (61%), and I82T in Membrane (60%) proteins. Breakthrough infection and prolonged viral shedding cases were associated with Delta variants carrying the Spike T19R, G142D, L452R, T478K, D614G, P681R, D950N, and V1264L mutations. The dynamic of SARS-CoV-2 variants in Indonesia highlights the importance of continuous genomic surveillance in monitoring and identifying potential strains leading to disease outbreaks.
Published: 2024
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39. Granulocyte Colony-stimulating Factor Improves Innate Immunity in Pediatric Pretransplant Patients.

Author: Rahayatri TH, Oswari H, Kekalih A, Harahap A, Hendarto A, Munasir Z, Setiabudy R, and Taher A
Abstract: Background: Children with decompensated cirrhosis (DC) awaiting LT suffer from infection linked to high pediatric end-stage liver disease (PELD) scores and mortality. Granulocyte colony-stimulating factor (G-CSF) therapy has shown promising results in adult DC. Our study investigated G-CSF as an optimizing treatment for pre-transplant DC, exploring its effect on cytokine activity., Methods: An open-label, randomized controlled trial included DC patients aged 3 months-12 years. The intervention group (n=26) received 12 G-CSF courses injected subcutaneously (5 μg/kg/day) plus DC standard medical treatment (SMT). The control group (n = 24) received SMT. We obtained PELD scores, tumor necrosis factor (TNF)-α, interleukin (IL)-10, hepatocyte growth factor (HGF), CD34+ mobilization, liver function, leukocyte and neutrophil counts. Infection and side effects were documented., Results: There was no significant difference in PELD scores between the groups after 3 months G-CSF treatment. Decreased TNF-α (p < 0.001) and increased IL-10 and HGF (p = 0.003 for both markers) were shown 1 month following G-CSF treatment. Alanine aminotransferase (ALT) levels improved significantly (p = 0.038). Significant increase in leucocyte and neutrophil counts (p < 0.001) and a lower incidence of sepsis (p = 0.04) were shown after intervention. There was no significant difference in survival (p = 0.372)., Conclusion: Following 3 months of G-CSF treatment, PELD scores did not show significant improvement. G-CSF reversed the cytokine profiles in DC, resulting in reduced TNF-α and increased IL-10. HGF significantly improved, indicating hepatic regeneration. Significantly decreased occurrence of sepsis following G-CSF treatment indicated improved clinical outcome., (© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Published: 2024
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40. Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria.

Author: Kho S, Siregar NC, Qotrunnada L, Fricot A, Sissoko A, Shanti PAI, Candrawati F, Kambuaya NN, Rini H, Andries B, Hardy D, Margyaningsih NI, Fadllan F, Rahmayenti DA, Puspitasari AM, Aisah AR, Leonardo L, Yayang BTG, Margayani DS, Prayoga P, Trianty L, Kenangalem E, Price RN, Yeo TW, Minigo G, Noviyanti R, Poespoprodjo JR, Anstey NM, and Buffet PA
Subjects: Humans, Splenomegaly etiology, Erythrocytes, Plasmodium falciparum, Anemia complications, Malaria complications, Malaria, Falciparum complications, Malaria, Vivax complications
Abstract: Splenomegaly frequently occurs in patients with Plasmodium falciparum (Pf) or P. vivax (Pv) malarial anemia, but mechanisms underlying this co-occurrence are unclear. In malaria-endemic Papua, Indonesia, we prospectively analyzed red blood cell (RBC) concentrations in the spleen and spleen-mimetic retention in 37 subjects splenectomized for trauma or hyperreactive splenomegaly, most of whom were infected with Plasmodium. Splenomegaly (median 357 g [range: 80-1918 g]) was correlated positively with the proportion of red-pulp on histological sections (median 88.1% [range: 74%-99.4%]; r = .59, p = .0003) and correlated negatively with the proportion of white-pulp (median 8.3% [range: 0.4%-22.9%]; r = -.50, p = .002). The number of RBC per microscopic field (>95% uninfected) was correlated positively with spleen weight in both Pf-infected (r = .73; p = .017) and Pv-infected spleens (r = .94; p = .006). The median estimated proportion of total-body RBCs retained in Pf-infected spleens was 8.2% (range: 1.0%-33.6%), significantly higher than in Pv-infected (2.6% [range: 0.6%-23.8%]; p = .015) and PCR-negative subjects (2.5% [range: 1.0%-3.3%]; p = .006). Retained RBCs accounted for over half of circulating RBC loss seen in Pf infections. The proportion of total-body RBC retained in Pf- and Pv-infected spleens correlated negatively with hemoglobin concentrations (r = -.56, p = .0003), hematocrit (r = -.58, p = .0002), and circulating RBC counts (r = -.56, p = .0003). Splenic CD71-positive reticulocyte concentrations correlated with spleen weight in Pf (r = 1.0; p = .003). Retention rates of peripheral and splenic RBCs were correlated negatively with circulating RBC counts (r = -.69, p = .07 and r = -.83, p = .008, respectively). In conclusion, retention of mostly uninfected RBC in the spleen, leading to marked congestion of the red-pulp, was associated with splenomegaly and is the major mechanism of anemia in subjects infected with Plasmodium, particularly Pf., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
Published: 2024
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41. Forest-goers as a heterogeneous population at high-risk for malaria: a case-control study in Aceh Province, Indonesia.

Author: Gallalee S, Zarlinda I, Silaen MG, Cotter C, Cueto C, Elyazar IRF, Jacobson JO, Gosling R, Hsiang MS, Bennett A, Coutrier FN, and Smith JL
Subjects: Male, Humans, Indonesia epidemiology, Case-Control Studies, Forests, Malaria prevention & control, Malaria, Vivax epidemiology, Malaria, Vivax prevention & control
Abstract: Background: A major challenge to malaria elimination is identifying and targeting populations that are harbouring residual infections and contributing to persistent transmission. In many near-elimination settings in Southeast Asia, it is known that forest-goers are at higher risk for malaria infection, but detailed information on their behaviours and exposures is not available., Methods: In Aceh Province, Indonesia, a near-elimination setting where a growing proportion of malaria is due to Plasmodium knowlesi, a case-control study was conducted to identify risk factors for symptomatic malaria, characteristics of forest-goers, and key intervention points. From April 2017 to September 2018, cases and controls were recruited and enrolled in a 1:3 ratio. Cases had confirmed malaria infection by rapid diagnostic test or microscopy detected at a health facility (HF). Gender-matched controls were recruited from passive case detection among individuals with suspected malaria who tested negative at a health facility (HF controls), and community-matched controls were recruited among those testing negative during active case detection. Multivariable logistic regression (unconditional for HF controls and conditional for community controls) was used to identify risk factors for symptomatic malaria infection., Results: There were 45 cases, of which 27 were P. knowlesi, 17 were Plasmodium vivax, and one was not determined. For controls, 509 and 599 participants were recruited from health facilities and the community, respectively. Forest exposures were associated with high odds of malaria; in particular, working and sleeping in the forest (HF controls: adjusted odds ratio (aOR) 21.66, 95% CI 5.09-92.26; community controls: aOR 16.78, 95% CI 2.19-128.7) and having a second residence in the forest (aOR 6.29, 95% CI 2.29-17.31 and 13.53, 95% CI 2.10-87.12). Male forest-goers were a diverse population employed in a variety of occupations including logging, farming, and mining, sleeping in settings, such as huts, tents, and barracks, and working in a wide range of group sizes. Reported use of protective measures, such as nets, hammock nets, mosquito coils, and repellents was low among forest-goers and interventions at forest residences were absent., Conclusions: Second residences in the forest and gaps in use of protective measures point to key malaria interventions to improve coverage in forest-going populations at risk for P. knowlesi and P. vivax in Aceh, Indonesia. Intensified strategies tailored to specific sub-populations will be essential to achieve elimination., (© 2024. The Author(s).)
Published: 2024
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42. Genomic analysis of Plasmodium vivax describes patterns of connectivity and putative drivers of adaptation in Ethiopia.

Author: Kebede AM, Sutanto E, Trimarsanto H, Benavente ED, Barnes M, Pearson RD, Siegel SV, Erko B, Assefa A, Getachew S, Aseffa A, Petros B, Lo E, Mohammed R, Yilma D, Rumaseb A, Nosten F, Noviyanti R, Rayner JC, Kwiatkowski DP, Price RN, Golassa L, and Auburn S
Subjects: Humans, Plasmodium vivax, Ethiopia epidemiology, Chloroquine pharmacology, Chloroquine therapeutic use, Genomics, Protozoan Proteins genetics, Protozoan Proteins metabolism, Drug Resistance genetics, Plasmodium falciparum metabolism, Malaria, Vivax parasitology, Malaria, Falciparum parasitology, Antimalarials pharmacology, Antimalarials therapeutic use
Abstract: Ethiopia has the greatest burden of Plasmodium vivax in Africa, but little is known about the epidemiological landscape of parasites across the country. We analysed the genomic diversity of 137 P. vivax isolates collected nine Ethiopian districts from 2012 to 2016. Signatures of selection were detected by cross-country comparisons with isolates from Thailand (n = 104) and Indonesia (n = 111), representing regions with low and high chloroquine resistance respectively. 26% (35/137) of Ethiopian infections were polyclonal, and 48.5% (17/35) of these comprised highly related clones (within-host identity-by-descent > 25%), indicating frequent co-transmission and superinfection. Parasite gene flow between districts could not be explained entirely by geographic distance, with economic and cultural factors hypothesised to have an impact on connectivity. Amplification of the duffy binding protein gene (pvdbp1) was prevalent across all districts (16-75%). Cross-population haplotype homozygosity revealed positive selection in a region proximal to the putative chloroquine resistance transporter gene (pvcrt-o). An S25P variant in amino acid transporter 1 (pvaat1), whose homologue has recently been implicated in P. falciparum chloroquine resistance evolution, was prevalent in Ethiopia (96%) but not Thailand or Indonesia (35-53%). The genomic architecture in Ethiopia highlights circulating variants of potential public health concern in an endemic setting with evidence of stable transmission., (© 2023. The Author(s).)
Published: 2023
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43. Central nervous system infection in a pediatric population in West Java.

Author: Alisjahbana DH, Nurmawati S, Milanti M, Djauhari H, Ledermann JP, Antonjaya U, Dewi YP, Johar E, Wiyatno A, Sriyani IY, Alisjahbana B, Safari D, Myint KSA, Powers AM, and Hakim DD
Subjects: Humans, Child, Indonesia epidemiology, Central Nervous System Infections epidemiology, Central Nervous System Viral Diseases cerebrospinal fluid, Central Nervous System Viral Diseases complications, Viruses, Tuberculosis complications
Abstract: Central nervous system (CNS) viral infections are critical causes of morbidity and mortality in children; however, comprehensive data on etiology is lacking in developing countries such as Indonesia. To study the etiology of CNS infections in a pediatric population, 50 children admitted to two hospitals in Bandung, West Java, during 2017-2018 were enrolled in a CNS infection study. Cerebrospinal fluid and serum specimens were tested using molecular, serological, and virus isolation platforms for a number of viral and bacteriological agents. Causal pathogens were identified in 10 out of 50 (20%) and included cytomegalovirus (n = 4), Streptococcus pneumoniae (n = 2), tuberculosis (n = 2), Salmonella serotype Typhi (n = 1) and dengue virus (n = 1). Our study highlights the importance of using a wide range of molecular and serological detection methods to identify CNS pathogens, as well as the challenges of establishing the etiology of CNS infections in pediatric populations of countries with limited laboratory capacity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
Published: 2023
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44. Genomics of Plasmodium vivax in Colombia reveals evidence of local bottle-necking and inter-country connectivity in the Americas.

Author: Sutanto E, Pava Z, Echeverry DF, Lopera-Mesa TM, Montenegro LM, Yasnot-Acosta MF, Benavente ED, Pearson RD, Herrera S, Arévalo-Herrera M, Trimarsanto H, Rumaseb A, Noviyanti R, Kwiatkowski DP, Price RN, and Auburn S
Subjects: Humans, Plasmodium vivax genetics, Colombia epidemiology, Protozoan Proteins genetics, Drug Resistance genetics, Genomics, Antimalarials pharmacology, Malaria, Vivax epidemiology, Malaria, Vivax drug therapy, Malaria, Falciparum
Abstract: Colombia aims to eliminate malaria by 2030 but remains one of the highest burden countries in the Americas. Plasmodium vivax contributes half of all malaria cases, with its control challenged by relapsing parasitaemia, drug resistance and cross-border spread. Using 64 Colombian P. vivax genomes collected between 2013 and 2017, we explored diversity and selection in two major foci of transmission: Chocó and Córdoba. Open-access data from other countries were used for comparative assessment of drug resistance candidates and to assess cross-border spread. Across Colombia, polyclonal infections were infrequent (12%), and infection connectivity was relatively high (median IBD = 5%), consistent with low endemicity. Chocó exhibited a higher frequency of polyclonal infections (23%) than Córdoba (7%), although the difference was not significant (P = 0.300). Most Colombian infections carried double pvdhfr (95%) and single pvdhps (71%) mutants, but other drug resistance mutations were less prevalent (< 10%). There was no evidence of selection at the pvaat1 gene, whose P. falciparum orthologue has recently been implicated in chloroquine resistance. Global population comparisons identified other putative adaptations. Within the Americas, low-level connectivity was observed between Colombia and Peru, highlighting potential for cross-border spread. Our findings demonstrate the potential of molecular data to inform on infection spread and adaptation., (© 2023. The Author(s).)
Published: 2023
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45. Significant increase in anti-SARS-CoV-2 antibodies after administration of heterologous mRNA-based vaccine booster in individuals receiving two doses of inactivated COVID-19 vaccine: A single-center study in healthcare workers in Jakarta, Indonesia.

Author: Setiadi W, Effendi Q, Johar E, Yohan B, Wibowo DP, Syahrani L, Pramono AA, Kartapradja HH, Yudhaputri FA, Dewi BE, Malik SG, Myint KSA, Soebandrio A, and Safari D
Subjects: Humans, 2019-nCoV Vaccine mRNA-1273, Indonesia epidemiology, Retrospective Studies, SARS-CoV-2, Health Personnel, Antibodies, Viral, RNA, Messenger, Immunoglobulin A, COVID-19 Vaccines, COVID-19 prevention & control
Abstract: Background: Vaccine plays an important role in breaking SARS-CoV-2 transmission and accelerating the path to pandemic recovery. Currently, there is still limited data on heterologous COVID-19 booster vaccination efficacy and effectiveness in Indonesia., Methods: Antibody response was retrospectively analyzed from 156 serum collected from healthcare workers that have received mRNA-1273 vaccine as the booster against SARS-CoV-2. These individuals had previously received the full two doses of inactivated anti-SARS-CoV-2 vaccine. Serological analysis was performed to measure total antibody, as well as IgA and IgG antibodies specific to spike (S) protein using ECLIA and ELISA methods., Results: A significant increase in total, IgA, and IgG antibody titers was reported in vaccine receiving a third heterologous booster dose of mRNA-based COVID-19 vaccine following two doses of inactivated type., Conclusion: The third heterologous booster dose of vaccine may be beneficial to individuals with or without previous history of SARS-CoV-2 infection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2023
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46. Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study.

Author: Sutanto I, Soebandrio A, Ekawati LL, Chand K, Noviyanti R, Satyagraha AW, Subekti D, Santy YW, Crenna-Darusallam C, Instiaty I, Budiman W, Prasetya CB, Lardo S, Elyazar I, Duparc S, Cedar E, Rolfe K, Fernando D, Berni A, Jones S, Kleim JP, Fletcher K, Sharma H, Martin A, Taylor M, Goyal N, Green JA, Tan LK, and Baird JK
Subjects: Humans, Primaquine therapeutic use, Drug Therapy, Combination, Chloroquine therapeutic use, Plasmodium vivax, Malaria, Vivax drug therapy, Malaria, Vivax prevention & control, Antimalarials, Quinolines therapeutic use, Artemisinins adverse effects, Malaria drug therapy
Abstract: Background: Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin-piperaquine for the radical cure of P vivax malaria., Methods: In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin-piperaquine alone, dihydroartemisinin-piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin-piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin-piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed., Findings: Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4-22) in patients treated with dihydroartemisinin-piperaquine alone versus 21% (11-34) in patients treated with tafenoquine plus dihydroartemisinin-piperaquine (hazard ratio 0·44; 95% CI [0·29-0·69]) and 52% (37-65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin-piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin-piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin-piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively., Interpretation: Although tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria., Funding: ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK., Translation: For the Indonesian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests IS reports grants or contracts from Menzies School of Health Research, Darwin and the National Health and Medical Research Council, and funding from Medicines for Malaria Venture (MMV) and GSK. AS, KC, RN, DS, YWS, II, WB, CBP, and SL report that they or their institutions received funding from MMV to do the study and editorial support from GSK for this publication. LLE and AWS report institutional funding from Menzies School of Health Research, MMV, and GSK. CC-D reports institutional funding from MMV, GSK, and the Chan Zuckerberg Initiative. IE reports institutional funding from MMV, GSK, WHO, SPARK (University of Melbourne), and honoraria from the Indonesian Ministry of Health. SD is an employee of MMV; his institution received funding from ExxonMobil, the Bill & Melinda Gates Foundation (grant number INV-007155/19-BMGF-006), Newcrest Mining, and the UK Government to fund the INSPECTOR study. EC is a former independent contractor at GSK and holds shares in the company. EC developed the first draft of the manuscript and provided editorial services as an independent medical writer funded by GSK. KR, DF, AB, SJ, KF, HS, AM, MT, and LKT are employees of GSK and hold shares in the company. J-PK, NG, and JAG are former employees of GSK and hold shares in GSK. JKB reports institutional research funding from MMV, GSK, the Wellcome Trust, the Gates Foundation, FIND, Sanaria, UKAid, University of Oxford, US Centers for Disease Control and Prevention, and the Chinese Center for Disease Control; travel and speaking fees from the Belgian Society of Tropical Medicine, the International Conference of Tropical Medicine and Malariology, and Singapore Malaria Group Conference; and participation on the US National Health Institute Data Safety Monitoring Board., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Published: 2023
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47. Polo-like kinase-1 mediates hepatitis C virus-induced cell migration, a drug target for liver cancer.

Author: El-Khobar KE, Tay E, Diefenbach E, Gloss BS, George J, and Douglas MW
Subjects: Humans, Hepacivirus, Actins, Cell Movement genetics, Polo-Like Kinase 1, Carcinoma, Hepatocellular genetics, Liver Neoplasms genetics, Hepatitis C
Abstract: Polo-like kinase 1 (PLK1) is a regulator of cell mitosis and cytoskeletal dynamics. PLK1 overexpression in liver cancer is associated with tumour progression, metastasis, and vascular invasion. Hepatitis C virus (HCV) NS5A protein stimulates PLK1-mediated phosphorylation of host proteins, so we hypothesised that HCV-PLK1 interactions might be a mechanism for HCV-induced liver cancer. We used a HCV cell-culture model (Jc1) to investigate the effects of virus infection on the cytoskeleton. In HCV-infected cells, a novel posttranslational modification in β-actin was observed with phosphorylation at Ser239. Using in silico and in vitro approaches, we identified PLK1 as the mediating kinase. In functional experiments with a phosphomimetic mutant form of β-actin, Ser239 phosphorylation influences β-actin polymerization and distribution, resulting in increased cell motility. The changes were prevented by treating cells with the PLK1 inhibitor volasertib. In HCV-infected hepatocytes, increased cell motility contributes to cancer cell migration, invasion, and metastasis. PLK1 is an important mediator of these effects and early treatment with PLK1 inhibitors may prevent or reduce HCC progression, particularly in people with HCV-induced HCC., (© 2023 El Khobar et al.)
Published: 2023
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48. Effect of elevated temperature on SARS-CoV-2 viability.

Author: Harapan H, Johar E, Maroef CN, Sriyani IY, Iqhrammullah M, Kusuma HI, Syukri M, Razali R, Hamdani H, Kurniawan R, Irwansyah I, Sofyan SE, Myint KS, Mahlia TMI, and Rizal S
Subjects: Humans, SARS-CoV-2, Temperature, COVID-19, Hyperthermia, Induced
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide disruption of global health putting healthcare workers at high risk. To reduce the transmission of SARS-CoV-2, in particular during treating the patients, our team aims to develop an optimized isolation chamber. The present study was conducted to evaluate the role of temperature elevation against SARS-CoV-2 viability, where the information would be used to build the isolation chamber. 0.6 mL of the Indonesian isolate of SARS-CoV-2 strain 20201012747 (approximately 10 13 PFU/mL) was incubated for one hour with a variation of temperatures: 25, 30, 35, 40, 45, 50, 55, 60, and 65°C in digital block heater as well as at room temperature (21-23°C) before used to infect Vero E6 cells. The viability was determined using a plaque assay. Our data found a significant reduction of the viral viability from 10 13 PFU/mL to 10 9 PFU/mL after the room temperature was increase to 40°C. Further elevation revealed that 55°C and above resulted in the total elimination of the viral viability. Increasing the temperature 40°C to reduce the SARS-CoV-2 survival could create mild hyperthermia conditions in a patient which could act as a thermotherapy. In addition, according to our findings, thermal sterilization of the vacant isolation chamber could be conducted by increasing the temperature to 55°C. In conclusion, elevating the temperature of the isolation chamber could be one of the main variables for developing an optimized isolation chamber for COVID-19 patients., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Harapan H et al.)
Published: 2023
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49. The determinants of thyroid function among vegetable farmers with primary exposure to chlorpyrifos: A cross-sectional study in Central Java, Indonesia.

Author: Liem JF, Subekti I, Mansyur M, Soemarko DS, Kekalih A, Suyatna FD, Suryandari DA, Malik SG, and Pangaribuan B
Abstract: Objectives: Occupational pesticide exposure, chlorpyrifos (CPF) in particular, may adversely affect the thyroid. The purpose of this study was to evaluate the determinants of thyroid function as indicated by the serum concentration of thyroid-stimulating hormone (TSH) among Indonesian vegetable farmers with primary exposure to CPF., Methods: A total of 151 vegetable farmers participated in this study. The sociodemographic and occupational characteristics of the participants were obtained using a structured interviewer-administered questionnaire. A validated quantitative method was used to estimate the cumulative exposure level (CEL). Serum TSH, thyroglobulin (Tg), free thyroxine (FT4), and urinary iodine excretion (UIE) were measured in the laboratory. The difference in TSH concentrations according to CEL and other characteristics were analysed using the Mann-Whitney U test. A multiple linear regression model was used to evaluate the potential determinants of TSH., Results: The mean age was 50 (SD 9.4) years. The median concentrations of TSH, FT4, and Tg/FT4 ratio were 1.46 mIU/L, 1.17 ng/dL, and 6.23 × 10 2 , respectively. We observed that higher TSH concentrations were found among those with a higher Tg/FT4 ratio, were classified as high CEL, and had lower UIE or FT4., Conclusions: Our findings show that Tg/FT4 ratio, CEL, FT4, UIE concentrations, and post-spraying days were determinants of TSH concentrations among farmers with primary exposure to CPF. These results indicate that farmers are exposed to agents with thyroid-disrupting properties, thus supporting previous evidence showing the potential for thyroid disorders in agricultural populations exposed to pesticides., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)
Published: 2023
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50. The role of genetic polymorphisms of interleukin-1 (IL-1R1 and IL-1RN) in primary knee osteoarthritis in Indonesia.

Author: Budhiparama NC, Lumban-Gaol I, Sudoyo H, Magetsari R, and Wibawa T
Subjects: Female, Humans, Case-Control Studies, Indonesia, Interleukin 1 Receptor Antagonist Protein genetics, Interleukin-1 genetics, Obesity, Polymorphism, Single Nucleotide, Osteoarthritis, Knee diagnostic imaging, Osteoarthritis, Knee genetics
Abstract: This study aimed to evaluate the association of SNPs of the IL-1 family with the clinical severity of knee OA. This case‒control study was performed among 100 healthy knees and 130 osteoarthritis (OA) knees of people aged ≥ 50 years with a BMI ≥ 25 kg/m 2 . The possible correlations among clinical findings, radiographic evaluations, serum levels of IL-1R1 and IL-1Ra, and genotype analyses were evaluated. Three SNPs of IL-1R1, rs871659, rs3771202, and rs3917238, were associated with primary knee OA. Females with IL-1R1 SNP rs871659 allele A had a higher prevalence of primary knee OA. No correlation was found between SNPs of IL-1R1 and IL-1RN and clinical or radiologic severity or serum concentrations of IL-1R1 and IL-1Ra (p > 0.05). BMI and IL-1R1 rs3917238 genotype C/C were correlated with moderate-severe VAS scores. A correlation was also found between the EQ-5D-3L self-care dimension and obesity and between the EQ-5D-3L pain and usual activity dimensions and age ≥ 60 and obesity (p < 0.05). Radiologic severity was only associated with age ≥ 60 years (p < 0.05). We found the IL-1R1 SNPs rs871659, rs3771202, and rs3917238 to be predisposing factors for primary knee osteoarthritis. The clinical findings, radiographic severity, and serum concentrations of IL-1R1 and IL-1Ra were not correlated with these gene polymorphisms., (© 2023. The Author(s).)
Published: 2023
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