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102. Diagnostic Accuracy of the InBios Scrub Typhus Detect™ ELISA for the Detection of IgM Antibodies in Chittagong, Bangladesh

Author

Stuart D. Blacksell, Hugh W. F. Kingston, Ampai Tanganuchitcharnchai, Meghna Phanichkrivalkosil, Mosharraf Hossain, Amir Hossain, Aniruddha Ghose, Stije J. Leopold, Arjen M. Dondorp, Nicholas P. J. Day, and Daniel H. Paris

Subjects
scrub typhus, diagnosis, ELISA, Bangladesh, Medicine
Abstract

Here we estimated the accuracy of the InBios Scrub Typhus Detect™ immunoglobulin M (IgM) ELISA to determine the optimal optical density (OD) cut-off values for the diagnosis of scrub typhus. Patients with undifferentiated febrile illness from Chittagong, Bangladesh, provided samples for reference testing using (i) qPCR using the Orientia spp. 47-kDa htra gene, (ii) IFA ≥1:3200 on admission, (iii) immunofluorescence assay (IFA) ≥1:3200 on admission or 4-fold rise to ≥3200, and (iv) combination of PCR and IFA positivity. For sero-epidemiological purposes (ELISA vs. IFA ≥1:3200 on admission or 4-fold rise to ≥3200), the OD cut-off for admission samples was ≥1.25, resulting in a sensitivity (Sn) of 91.5 (95% confidence interval (95% CI: 96.8–82.5) and a specificity (Sp) of 92.4 (95% CI: 95.0–89.0), while for convalescent samples the OD cut-off was ≥1.50 with Sn of 66.0 (95% CI: 78.5–51.7) and Sp of 96.0 (95% CI: 98.3–92.3). Comparisons against comparator reference tests (ELISA vs. all tests including PCR) indicated the most appropriate cut-off OD to be within the range of 0.75–1.25. For admission samples, the best Sn/Sp compromise was at 1.25 OD (Sn 91.5%, Sp 92.4%) and for convalescent samples at 0.75 OD (Sn 69.8%, Sp 89.5%). A relatively high (stringent) diagnostic cut-off value provides increased diagnostic accuracy with high sensitivity and specificity in the majority of cases, while lowering the cut-off runs the risk of false positivity. This study underlines the need for regional assessment of new diagnostic tests according to the level of endemicity of the disease given the high levels of residual or cross-reacting antibodies in the general population.

Published
2018
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106. Climate change and health in Southeast Asia – defining research priorities and the role of the Wellcome Trust Africa Asia Programmes

Author

A Bonell, Iqbal R. F. Elyazar, R van Doorn, Thanh Ngo-Duc, G Thwaites, D H Dang Giang, N T Xuan Chau, Mary Chambers, Arjen M. Dondorp, Louise Thwaites, P Quang Thai, Elizabeth A. Ashley, Damien Keng Yen Ming, Evelyne Kestelyn, H Ngoc Nhung, Sophie Yacoub, N V Vinh Chau, Marc Choisy, Henry Surendra, G N Thi, Angela McBride, M Evans, Rapeephan R. Maude, H Nguyen Quang, Rachel Lowe, H N Dan Thanh, C Ho Quang, Intensive Care Medicine, and Amsterdam institute for Infection and Immunity

Subjects
Community engagement, business.industry, Global warming, Climate change, Medicine (miscellaneous), Myanmar, Multiple methods, Public relations, Global heating, Thailand, General Biochemistry, Genetics and Molecular Biology, Unit (housing), Southeast asia, Vietnam, Indonesia, Laos, Data quality, Political science, Portfolio, business
Abstract

This article summarises a recent virtual meeting organised by the Oxford University Clinical Research Unit in Vietnam on the topic of climate change and health, bringing local partners, faculty and external collaborators together from across the Wellcome and Oxford networks. Attendees included invited local and global climate scientists, clinicians, modelers, epidemiologists and community engagement practitioners, with a view to setting priorities, identifying synergies and fostering collaborations to help define the regional climate and health research agenda. In this summary paper, we outline the major themes and topics that were identified and what will be needed to take forward this research for the next decade. We aim to take a broad, collaborative approach to including climate science in our current portfolio where it touches on infectious diseases now, and more broadly in our future research directions. We will focus on strengthening our research portfolio on climate-sensitive diseases, and supplement this with high quality data obtained from internal studies and external collaborations, obtained by multiple methods, ranging from traditional epidemiology to innovative technology and artificial intelligence and community-led research. Through timely agenda setting and involvement of local stakeholders, we aim to help support and shape research into global heating and health in the region.

Published
2023

107. Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Author

Kartsonaki, Christiana, Baillie, J Kenneth, Barrio, Noelia García, Baruch, Joaquín, Beane, Abigail, Blumberg, Lucille, Bozza, Fernando, Broadley, Tessa, Burrell, Aidan, Carson, Gail, Citarella, Barbara Wanjiru, Dagens, Andrew, Dankwa, Emmanuelle A, Donnelly, Christl A, Dunning, Jake, Elotmani, Loubna, Escher, Martina, Farshait, Nataly, Goffard, Jean-Christophe, Gonçalves, Bronner P, Hall, Matthew, Hashmi, Madiha, Sim Lim Heng, Benedict, Ho, Antonia, Jassat, Waasila, Pedrera Jiménez, Miguel, Laouenan, Cedric, Lissauer, Samantha, Martin-Loeches, Ignacio, Mentré, France, Merson, Laura, Morton, Ben, Munblit, Daniel, Nekliudov, Nikita A, Nichol, Alistair D, Singh Oinam, Budha Charan, Ong, David, Panda, Prasan Kumar, Petrovic, Michele, Pritchard, Mark G, Ramakrishnan, Nagarajan, Ramos, Grazielle Viana, Roger, Claire, Sandulescu, Oana, Semple, Malcolm G, Sharma, Pratima, Sigfrid, Louise, Somers, Emily C, Streinu-Cercel, Anca, Taccone, Fabio, Vecham, Pavan Kumar, Kumar Tirupakuzhi Vijayaraghavan, Bharath, Wei, Jia, Wils, Evert-Jan, Ci Wong, Xin, Horby, Peter, Rojek, Amanda, Olliaro, Piero L, ISARIC Clinical Characterisation Group: Ali Abbas, Sheryl Ann Abdukahil, Nurul Najmee Abdulkadir, Ryuzo Abe, Laurent Abel, Lara Absil, Subhash Acharya, Andrew Acker, Elisabeth Adam, Diana Adrião, Saleh Al Ageel, Shakeel Ahmed, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Ait Hssain, Younes Ait Tamlihat, Takako Akimoto, Ernita Akmal, Eman Al Qasim, Razi Alalqam, Angela Alberti, Tala Al-Dabbous, Senthilkumar Alegesan, Cynthia Alegre, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman Al-Fares, Huda Alfoudri, Imran Ali, Adam Ali, Naseem Ali Shah, Kazali Enagnon Alidjnou, Jeffrey Aliudin, Qabas Alkhafajee, Clotilde Allavena, Nathalie Allou, Aneela Altaf, João Alves, Rita Alves, João Melo Alves, Maria Amaral, Nur Amira, Phoebe Ampaw, Roberto Andini, Claire Andréjak, Andrea Angheben, François Angoulvant, Séverine Ansart, Sivanesen Anthonidass, Massimo Antonelli, Carlos Alexandre Antunes de Brito, Ardiyan Apriyana, Yaseen Arabi, Irene Aragao, Francisco Arancibia, Carolline Araujo, Antonio Arcadipane, Patrick Archambault, Lukas Arenz, Jean-Benoît Arlet, Christel Arnold-Day, Lovkesh Arora, Rakesh Arora, Elise Artaud-Macari, Diptesh Aryal, Angel Asensio, Muhammad Ashraf, Namra Asif, Mohammad Asim, Jean Baptiste Assie, Amirul Asyraf, Anika Atique, A M Udara Lakshan Attanyake, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Laurène Azemar, Cecile Azoulay, Benjamin Bach, Delphine Bachelet, Claudine Badr, Nadia Baig, J Kevin Baird, Erica Bak, Agamemnon Bakakos, Nazreen Abu Bakar, Andriy Bal, Mohanaprasanth Balakrishnan, Valeria Balan, Firouzé Bani-Sadr, Renata Barbalho, Nicholas Yuri Barbosa, Wendy S Barclay, Saef Umar Barnett, Michaela Barnikel, Helena Barrasa, Audrey Barrelet, Cleide Barrigoto, Marie Bartoli, Mustehan Bashir, Romain Basmaci, Muhammad Fadhli Hassin Basri, Denise Battaglini, Jules Bauer, Diego Fernando Bautista Rincon, Denisse Bazan Dow, Alexandra Bedossa, Ker Hong Bee, Husna Begum, Sylvie Behilill, Albertus Beishuizen, Aleksandr Beljantsev, David Bellemare, Anna Beltrame, Beatriz Amorim Beltrão, Marine Beluze, Nicolas Benech, Lionel Eric Benjiman, Dehbia Benkerrou, Suzanne Bennett, Luís Bento, Jan-Erik Berdal, Delphine Bergeaud, Hazel Bergin, José Luis Bernal Sobrino, Giulia Bertoli, Lorenzo Bertolino, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Amar Bhatt, Krishna Bhavsar, Claudia Bianco, Farah Nadiah Bidin, Moirangthem Bikram Singh, Felwa Bin Humaid, Mohd Nazlin Bin Kamarudin, François Bissuel, Patrick Biston, Laurent Bitker, Jonathan Bitton, Pablo Blanco-Schweizer, Catherine Blier, Frank Bloos, Mathieu Blot, Filomena Boccia, Laetitia Bodenes, Alice Bogaarts, Debby Bogaert, Anne-Hélène Boivin, Pierre-Adrien Bolze, François Bompart, Aurelius Bonfasius, Diogo Borges, Raphaël Borie, Hans Martin Bosse, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Dounia Bouhmani, Damien Bouhour, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Anne-Sophie Boureau, John Bourke, Maude Bouscambert, Aurore Bousquet, Jason Bouziotis, Bianca Boxma, Marielle Boyer-Besseyre, Maria Boylan, Axelle Braconnier, Cynthia Braga, Timo Brandenburger, Filipa Brás Monteiro, Luca Brazzi, Patrick Breen, Dorothy Breen, Kathy Brickell, Shaunagh Browne, Alex Browne, Nicolas Brozzi, Marjolein Brusse-Keizer, Nina Buchtele, Christian Buesaquillo, Polina Bugaeva, Marielle Buisson, Danilo Buonsenso, Erlina Burhan, Ingrid G Bustos, Denis Butnaru, André Cabie, Susana Cabral, Eder Caceres, Cyril Cadoz, Mia Callahan, Kate Calligy, Jose Andres Calvache, João Camões, Valentine Campana, Paul Campbell, Josie Campisi, Cecilia Canepa, Mireia Cantero, Pauline Caraux-Paz, Sheila Cárcel, Chiara Simona Cardellino, Sofia Cardoso, Filipe Cardoso, Filipa Cardoso, Nelson Cardoso, Simone Carelli, Nicolas Carlier, Thierry Carmoi, Gayle Carney, Inês Carqueja, Marie-Christine Carret, François Martin Carrier, Ida Carroll, Maire-Laure Casanova, Mariana Cascão, Siobhan Casey, José Casimiro, Bailey Cassandra, Silvia Castañeda, Nidyanara Castanheira, Guylaine Castor-Alexandre, Henry Castrillón, Ivo Castro, Ana Catarino, François-Xavier Catherine, Paolo Cattaneo, Roberta Cavalin, Giulio Giovanni Cavalli, Alexandros Cavayas, Adrian Ceccato, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chakveatze, Adrienne Chan, Meera Chand, Christelle Chantalat Auger, Jean-Marc Chapplain, Julie Chas, Allegra Chatterjee, Mobin Chaudry, Jonathan Samuel Chávez Iñiguez, Anjellica Chen, Yih-Sharng Chen, Matthew Pellan Cheng, Antoine Cheret, Thibault Chiarabini, Julian Chica, Suresh Kumar Chidambaram, Leong Chin Tho, Catherine Chirouze, Davide Chiumello, Sung-Min Cho, Bernard Cholley, Marie-Charlotte Chopin, Ting Soo Chow, Yock Ping Chow, Hiu Jian Chua, Jonathan Chua, Jose Pedro Cidade, José Miguel Cisneros Herreros, Anna Ciullo, Jennifer Clarke, Emma Clarke, Rolando Claure-Del Granado, Sara Clohisey, Perren J Cobb, Cassidy Codan, Caitriona Cody, Alexandra Coelho, Megan Coles, Gwenhaël Colin, Michael Collins, Sebastiano Maria Colombo, Pamela Combs, Marie Connor, Anne Conrad, Sofía Contreras, Elaine Conway, Graham S Cooke, Mary Copland, Hugues Cordel, Amanda Corley, Sabine Cornelis, Alexander Daniel Cornet, Arianne Joy Corpuz, Andrea Cortegiani, Grégory Corvaisier, Emma Costigan, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Rachel Cregan, Charles Crepy D'Orleans, Cosimo Cristella, Sabine Croonen, Gloria Crowl, Jonathan Crump, Claudina Cruz, Juan Luis Cruz Berm, Jaime Cruz Rojo, Marc Csete, Ailbhe Cullen, Matthew Cummings, Gerard Curley, Elodie Curlier, Colleen Curran, Paula Custodio, Ana da Silva Filipe, Charlene Da Silveira, Al-Awwab Dabaliz, Darren Dahly, Heidi Dalton, Jo Dalton, Seamus Daly, Nick Daneman, Corinne Daniel, Jorge Dantas, Frédérick D'Aragon, Menno de Jong, Gillian de Loughry, Diego de Mendoza, Etienne De Montmollin, Rafael Freitas de Oliveira França, Ana Isabel de Pinho Oliveira, Rosanna De Rosa, Cristina De Rose, Thushan de Silva, Peter de Vries, Jillian Deacon, David Dean, Alexa Debard, Marie-Pierre Debray, Nathalie DeCastro, William Dechert, Lauren Deconninck, Romain Decours, Eve Defous, Isabelle Delacroix, Eric Delaveuve, Karen Delavigne, Nathalie M Delfos, Ionna Deligiannis, Andrea Dell'Amore, Christelle Delmas, Pierre Delobel, Corine Delsing, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Pieter Depuydt, Mehul Desai, Diane Descamps, Mathilde Desvallées, Santi Dewayanti, Pathik Dhanger, Alpha Diallo, Sylvain Diamantis, André Dias, Juan Jose Diaz, Priscila Diaz, Rodrigo Diaz, Kévin Didier, Jean-Luc Diehl, Wim Dieperink, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Yael Dishon, Félix Djossou, Annemarie B Docherty, Helen Doherty, Arjen M Dondorp, Andy Dong, Maria Donnelly, Sean Donohue, Yoann Donohue, Chloe Donohue, Peter Doran, Céline Dorival, Eric D'Ortenzio, James Joshua Douglas, Renee Douma, Nathalie Dournon, Triona Downer, Joanne Downey, Mark Downing, Tom Drake, Aoife Driscoll, Murray Dryden, Claudio Duarte Fonseca, Vincent Dubee, François Dubos, Alexandre Ducancelle, Toni Duculan, Susanne Dudman, Abhijit Duggal, Paul Dunand, Mathilde Duplaix, Emanuele Durante-Mangoni, Lucian Durham, Bertrand Dussol, Juliette Duthoit, Xavier Duval, Anne Margarita Dyrhol-Riise, Sim Choon Ean, Marco Echeverria-Villalobos, Siobhan Egan, Carla Eira, Mohammed El Sanharawi, Subbarao Elapavaluru, Brigitte Elharrar, Jacobien Ellerbroek, Philippine Eloy, Tarek Elshazly, Iqbal Elyazar, Isabelle Enderle, Tomoyuki Endo, Chan Chee Eng, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Mariano Esperatti, Hélène Esperou, Marina Esposito-Farese, João Estevão, Manuel Etienne, Nadia Ettalhaoui, Anna Greti Everding, Mirjam Evers, Marc Fabre, Isabelle Fabre, Amna Faheem, Arabella Fahy, Cameron J Fairfield, Zul Fakar, Komal Fareed, Pedro Faria, Ahmed Farooq, Hanan Fateena, Arie Zainul Fatoni, Karine Faure, Raphaël Favory, Mohamed Fayed, Niamh Feely, Laura Feeney, Jorge Fernandes, Marília Andreia Fernandes, Susana Fernandes, François-Xavier Ferrand, Eglantine Ferrand Devouge, Joana Ferrão, Mário Ferraz, Sílvia Ferreira, Isabel Ferreira, Benigno Ferreira, Ricard Ferrer-Roca, Nicolas Ferriere, Céline Ficko, Claudia Figueiredo-Mello, William Finlayson, Juan Fiorda, Thomas Flament, Clara Flateau, Tom Fletcher, Letizia Lucia Florio, Deirdre Flynn, Claire Foley, Jean Foley, Victor Fomin, Tatiana Fonseca, Patricia Fontela, Simon Forsyth, Denise Foster, Giuseppe Foti, Erwan Fourn, Robert A Fowler, Marianne Fraher, Diego Franch-Llasat, John F Fraser, Christophe Fraser, Marcela Vieira Freire, Ana Freitas Ribeiro, Caren Friedrich, Ricardo Fritz, Stéphanie Fry, Nora Fuentes, Masahiro Fukuda, G Argin, Valérie Gaborieau, Rostane Gaci, Massimo Gagliardi, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Sérgio Gaião, Linda Gail Skeie, Phil Gallagher, Carrol Gamble, Yasmin Gani, Arthur Garan, Rebekha Garcia, Julia Garcia-Diaz, Esteban Garcia-Gallo, Navya Garimella, Denis Garot, Valérie Garrait, Basanta Gauli, Nathalie Gault, Aisling Gavin, Anatoliy Gavrylov, Alexandre Gaymard, Johannes Gebauer, Eva Geraud, Louis Gerbaud Morlaes, Nuno Germano, Praveen Kumar Ghisulal, Jade Ghosn, Marco Giani, Jess Gibson, Tristan Gigante, Morgane Gilg, Elaine Gilroy, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Daniel Glikman, Petr Glybochko, Eric Gnall, Geraldine Goco, François Goehringer, Siri Goepel, Jin Yi Goh, Jonathan Golob, Rui Gomes, Kyle Gomez, Joan Gómez-Junyent, Marie Gominet, Alicia Gonzalez, Patricia Gordon, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Margarite Grable, Jeronimo Graf, Edward Wilson Grandin, Pascal Granier, Giacomo Grasselli, Christopher A Green, Courtney Greene, William Greenhalf, Segolène Greffe, Domenico Luca Grieco, Matthew Griffee, Fiona Griffiths, Ioana Grigoras, Albert Groenendijk, Anja Grosse Lordemann, Heidi Gruner, Yusing Gu, Jérémie Guedj, Martin Guego, Dewi Guellec, Anne-Marie Guerguerian, Daniela Guerreiro, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Maisa Guimarães de Castro, Thomas Guimard, Marieke Haalboom, Daniel Haber, Hannah Habraken, Ali Hachemi, Amy Hackmann, Nadir Hadri, Fakhir Haidri, Sheeba Hakak, Adam Hall, Sophie Halpin, Jawad Hameed, Ansley Hamer, Raph L Hamers, Rebecca Hamidfar, Terese Hammond, Lim Yuen Han, Rashan Haniffa, Kok Wei Hao, Hayley Hardwick, Ewen M Harrison, Janet Harrison, Samuel Bernard Ekow Harrison, Alan Hartman, Mohd Shahnaz Hasan, Junaid Hashmi, Muhammad Hayat, Ailbhe Hayes, Leanne Hays, Jan Heerman, Lars Heggelund, Ross Hendry, Martina Hennessy, Aquiles Henriquez-Trujillo, Maxime Hentzien, Jaime Hernandez-Montfort, Andrew Hershey, Liv Hesstvedt, Astarini Hidayah, Eibhilin Higgins, Dawn Higgins, Rupert Higgins, Rita Hinchion, Samuel Hinton, Hiroaki Hiraiwa, Haider Hirkani, Hikombo Hitoto, Yi Bin Ho, Alexandre Hoctin, Isabelle Hoffmann, Wei Han Hoh, Oscar Hoiting, Rebecca Holt, Jan Cato Holter, Juan Pablo Horcajada, Koji Hoshino, Ikram Houas, Catherine L Hough, Stuart Houltham, Jimmy Ming-Yang Hsu, Jean-Sébastien Hulot, Stella Huo, Abby Hurd, Iqbal Hussain, Samreen Ijaz, Hajnal-Gabriela Illes, Patrick Imbert, Mohammad Imran, Rana Imran Sikander, Aftab Imtiaz, Hugo Inácio, Carmen Infante Dominguez, Yun Sii Ing, Elias Iosifidis, Mariachiara Ippolito, Sarah Isgett, Tiago Isidoro, Nadiah Ismail, Margaux Isnard, Junji Itai, Daniel Ivulich, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Clare Jackson, Nina Jamieson, Victoria Janes, Pierre Jaquet, Coline Jaud-Fischer, Stéphane Jaureguiberry, Jeffrey Javidfar, Denise Jaworsky, Florence Jego, Anilawati Mat Jelani, Synne Jenum, Ruth Jimbo-Sotomayor, Ong Yiaw Joe, Ruth N Jorge García, Cédric Joseph, Mark Joseph, Swosti Joshi, Mercé Jourdain, Philippe Jouvet, Hanna Jung, Anna Jung, Dafsah Juzar, Ouifiya Kafif, Florentia Kaguelidou, Neerusha Kaisbain, Thavamany Kaleesvran, Sabina Kali, Alina Kalicinska, Smaragdi Kalomoiri, Muhammad Aisar Ayadi Kamaluddin, Zul Amali Che Kamaruddin, Nadiah Kamarudin, Paul Kambiya, Kavita Kamineni, Darshana Hewa Kandamby, Chris Kandel, Kong Yeow Kang, Darakhshan Kanwal, Pratap Karpayah, Todd Karsies, Daisuke Kasugai, Anant Kataria, Kevin Katz, Aasmine Kaur, Christy Kay, Hannah Keane, Seán Keating, Pulak Kedia, Claire Kelly, Yvelynne Kelly, Andrea Kelly, Niamh Kelly, Aoife Kelly, Sadie Kelly, Maeve Kelsey, Ryan Kennedy, Kalynn Kennon, Maeve Kernan, Younes Kerroumi, Sharma Keshav, Imrana Khalid, Osama Khalid, Antoine Khalil, Coralie Khan, Irfan Khan, Quratul Ain Khan, Sushil Khanal, Abid Khatak, Amin Khawaja, Krish Kherajani, Michelle E Kho, Saye Khoo, Ryan Khoo, Denisa Khoo, Nasir Khoso, Khor How Kiat, Yuri Kida, Peter Kiiza, Beathe Kiland Granerud, Anders Benjamin Kildal, Jae Burm Kim, Antoine Kimmoun, Detlef Kindgen-Milles, Alexander King, Nobuya Kitamura, Paul Klenerman, Rob Klont, Gry Kloumann Bekken, Stephen R Knight, Robin Kobbe, Chamira Kodippily, Malte Kohns Vasconcelos, Sabin Koirala, Mamoru Komatsu, Caroline Kosgei, Arsène Kpangon, Karolina Krawczyk, Vinothini Krishnan, Sudhir Krishnan, Oksana Kruglova, Deepali Kumar, Ganesh Kumar, Mukesh Kumar, Dinesh Kuriakose, Ethan Kurtzman, Demetrios Kutsogiannis, Galyna Kutsyna, Konstantinos Kyriakoulis, Marie Lachatre, Marie Lacoste, John G Laffey, Marie Lagrange, Fabrice Laine, Olivier Lairez, Sanjay Lakhey, Antonio Lalueza, Marc Lambert, François Lamontagne, Marie Langelot-Richard, Vincent Langlois, Eka Yudha Lantang, Marina Lanza, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Sakshi Lath, Naveed Latif, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Teresa Lawrence, Cassie Lawrence, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Paul Le Turnier, Ema Leal, Marta Leal Santos, Todd C Lee, James Lee, Jennifer Lee, Heng Gee Lee, Biing Horng Lee, Yi Lin Lee, Su Hwan Lee, Gary Leeming, Laurent Lefebvre, Bénédicte Lefebvre, Benjamin Lefevre, Sylvie LeGac, Jean-Daniel Lelievre, François Lellouche, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Gretchen Lemmink, Ha Sha Lene, Jenny Lennon, Rafael León, Marc Leone, Michela Leone, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Amy Lester-Grant, Bruno Levy, Yves Levy, Claire Levy-Marchal, Katarzyna Lewandowska, Erwan L'Her, Gianluigi Li Bassi, Janet Liang, Ali Liaquat, Geoffrey Liegeon, Wei Shen Lim, Kah Chuan Lim, Chantre Lima, Lim Lina, Bruno Lina, Andreas Lind, Maja Katherine Lingad, Guillaume Lingas, Sylvie Lion-Daolio, Keibun Liu, Marine Livrozet, Patricia Lizotte, Antonio Loforte, Navy Lolong, Leong Chee Loon, Diogo Lopes, Dalia Lopez-Colon, Jose W Lopez-Revilla, Anthony L Loschner, Paul Loubet, Bouchra Loufti, Guillame Louis, Silvia Lourenco, Lara Lovelace-Macon, Lee Lee Low, Marije Lowik, Jia Shyi Loy, Jean Christophe Lucet, Carlos Lumbreras Bermejo, Carlos M Luna, Olguta Lungu, Liem Luong, Nestor Luque, Dominique Luton, Nilar Lwin, Ruth Lyons, Olavi Maasikas, Oryane Mabiala, Moïse Machado, Gabriel Macheda, Hashmi Madiha, Guillermo Maestro de la Calle, Rafael Mahieu, Sophie Mahy, Ana Raquel Maia, Lars S Maier, Mylène Maillet, Thomas Maitre, Maximilian Malfertheiner, Nadia Malik, Paddy Mallon, Fernando Maltez, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Frank Manetta, Julie Mankikian, Edmund Manning, Aldric Manuel, Ceila Maria Sant Ana Malaque, Flávio Marino, Daniel Marino, Samuel Markowicz, Charbel Maroun Eid, Ana Marques, Catherine Marquis, Brian Marsh, Laura Marsh, Megan Marshal, John Marshall, Celina Turchi Martelli, Dori-Ann Martin, Emily Martin, Guillaume Martin-Blondel, Martin Martinot, Alejandro Martin-Quiros, João Martins, Ana Martins, Nuno Martins, Caroline Martins Rego, Gennaro Martucci, Olga Martynenko, Eva Miranda Marwali, Marsilla Marzukie, David Maslove, Sabina Mason, Sobia Masood, Basri Mat Nor, Moshe Matan, Meghena Mathew, Daniel Mathieu, Mathieu Mattei, Romans Matulevics, Laurence Maulin, Michael Maxwell, Javier Maynar, Thierry Mazzoni, Natalie Mc Evoy, Lisa Mc Sweeney, Colin McArthur, Anne McCarthy, Aine McCarthy, Colin McCloskey, Rachael McConnochie, Sherry McDermott, Sarah E McDonald, Aine McElroy, Samuel McElwee, Victoria McEneany, Allison McGeer, Chris McKay, Johnny McKeown, Kenneth A McLean, Paul McNally, Bairbre McNicholas, Elaine McPartlan, Edel Meaney, Cécile Mear-Passard, Maggie Mechlin, Maqsood Meher, Omar Mehkri, Ferruccio Mele, Luis Melo, Kashif Memon, Joao Joao Mendes, Ogechukwu Menkiti, Kusum Menon, Alexander J Mentzer, Emmanuelle Mercier, Noémie Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Blake Mergler, António Mesquita, Roberta Meta, Osama Metwally, Agnès Meybeck, Dan Meyer, Alison M Meynert, Vanina Meysonnier, Amina Meziane, Mehdi Mezidi, Céline Michelanglei, Isabelle Michelet, Efstathia Mihelis, Vladislav Mihnovit, Hugo Miranda-Maldonado, Nor Arisah Misnan, Tahira Jamal Mohamed, Nik Nur Eliza Mohamed, Asma Moin, David Molina, Elena Molinos, Brenda Molloy, Mary Mone, Agostinho Monteiro, Claudia Montes, Giorgia Montrucchio, Shona C Moore, Sarah Moore, Lina Morales Cely, Lucia Moro, Catherine Motherway, Ana Motos, Hugo Mouquet, Clara Mouton Perrot, Julien Moyet, Caroline Mudara, Aisha Kalsoom Mufti, Ng Yong Muh, Dzawani Muhamad, Jimmy Mullaert, Fredrik Müller, Karl Erik Müller, Syed Muneeb, Nadeem Munir, Laveena Munshi, Aisling Murphy, Lorna Murphy, Marlène Murris, Srinivas Murthy, Himed Musaab, Himasha Muvindi, Gugapriyaa Muyandy, Dimitra Melia Myrodia, Farah Nadia Mohd-Hanafiah, Dave Nagpal, Alex Nagrebetsky, Mangala Narasimhan, Nageswaran Narayanan, Rashid Nasim Khan, Alasdair Nazerali-Maitland, Nadège Neant, Holger Neb, Erni Nelwan, Raul Neto, Emily Neumann, Pauline Yeung Ng, Wing Yiu Ng, Anthony Nghi, Duc Nguyen, Orna Ni Choileain, Niamh Ni Leathlobhair, Prompak Nitayavardhana, Stephanie Nonas, Nurul Amani Mohd Noordin, Marion Noret, Nurul Faten Izzati Norharizam, Lisa Norman, Alessandra Notari, Mahdad Noursadeghi, Karolina Nowicka, Adam Nowinski, Saad Nseir, Jose I Nunez, Nurnaningsih Nurnaningsih, Dwi Utomo Nusantara, Elsa Nyamankolly, Fionnuala O Brien, Annmarie O Callaghan, Annmarie O'Callaghan, Giovanna Occhipinti, Derbrenn OConnor, Max O'Donnell, Tawnya Ogston, Takayuki Ogura, Tak-Hyuk Oh, Sophie O'Halloran, Katie O'Hearn, Shinichiro Ohshimo, Agnieszka Oldakowska, João Oliveira, Larissa Oliveira, Jee Yan Ong, Wilna Oosthuyzen, Anne Opavsky, Peter Openshaw, Saijad Orakzai, Claudia Milena Orozco-Chamorro, Jamel Ortoleva, Javier Osatnik, Linda O'Shea, Miriam O'Sullivan, Siti Zubaidah Othman, Nadia Ouamara, Rachida Ouissa, Eric Oziol, Maïder Pagadoy, Justine Pages, Mario Palacios, Amanda Palacios, Massimo Palmarini, Giovanna Panarello, Hem Paneru, Lai Hui Pang, Mauro Panigada, Nathalie Pansu, Aurélie Papadopoulos, Rachael Parke, Melissa Parker, Briseida Parra, Taha Pasha, Jérémie Pasquier, Bruno Pastene, Fabian Patauner, Drashti Patel, Mohan Dass Pathmanathan, Luís Patrão, Patricia Patricio, Juliette Patrier, Lisa Patterson, Rajyabardhan Pattnaik, Mical Paul, Christelle Paul, Jorge Paulos, William A Paxton, Jean-François Payen, Kalaiarasu Peariasamy, Giles J Peek, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Mare Pejkovska, Paolo Pelosi, Ithan D Peltan, Rui Pereira, Daniel Perez, Luis Periel, Thomas Perpoint, Antonio Pesenti, Vincent Pestre, Lenka Petrou, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Scott Pharand, Michael Piagnerelli, Walter Picard, Olivier Picone, Maria de Piero, Carola Pierobon, Djura Piersma, Carlos Pimentel, Raquel Pinto, Catarina Pires, Isabelle Pironneau, Lionel Piroth, Ayodhia Pitaloka, Riinu Pius, Laurent Plantier, Hon Shen Png, Julien Poissy, Ryadh Pokeerbux, Maria Pokorska-Spiewak, Sergio Poli, Georgios Pollakis, Diane Ponscarme, Jolanta Popielska, Diego Bastos Porto, Andra-Maris Post, Douwe F Postma, Pedro Povoa, Diana Póvoas, Jeff Powis, Sofia Prapa, Sébastien Preau, Christian Prebensen, Jean-Charles Preiser, Anton Prinssen, Gamage Dona Dilanthi Priyadarshani, Lucia Proença, Sravya Pudota, Oriane Puéchal, Bambang Pujo Semedi, Mathew Pulicken, Gregory Purcell, Luisa Quesada, Vilmaris Quinones-Cardona, Víctor Quirós González, Else Quist-Paulsen, Mohammed Quraishi, Maia Rabaa, Christian Rabaud, Ebenezer Rabindrarajan, Aldo Rafael, Marie Rafiq, Gabrielle Ragazzo, Mutia Rahardjani, Rozanah Abd Rahman, Ahmad Kashfi Haji Ab Rahman, Arsalan Rahutullah, Fernando Rainieri, Giri Shan Rajahram, Pratheema Ramachandran, Ahmad Afiq Ramli, Blandine Rammaert, Asim Rana, Rajavardhan Rangappa, Ritika Ranjan, Christophe Rapp, Aasiyah Rashan, Thalha Rashan, Ghulam Rasheed, Menaldi Rasmin, Indrek Rätsep, Cornelius Rau, Tharmini Ravi, Ali Raza, Andre Real, Stanislas Rebaudet, Sarah Redl, Brenda Reeve, Attaur Rehman, Liadain Reid, Dag Henrik Reikvam, Renato Reis, Jordi Rello, Jonathan Remppis, Martine Remy, Hongru Ren, Hanna Renk, Anne-Sophie Resseguier, Matthieu Revest, Oleksa Rewa, Luis Felipe Reyes, Tiago Reyes, Maria Ines Ribeiro, Antonia Ricchiuto, David Richardson, Denise Richardson, Laurent Richier, Siti Nurul Atikah Ahmad Ridzuan, Jordi Riera, Ana L Rios, Asgar Rishu, Patrick Rispal, Karine Risso, Maria Angelica Rivera Nuñez, Nicholas Rizer, Chiara Robba, André Roberto, Stephanie Roberts, David L Robertson, Olivier Robineau, Ferran Roche-Campo, Paola Rodari, Simão Rodeia, Bernhard Roessler, Pierre-Marie Roger, Emmanuel Roilides, Juliette Romaru, Roberto Roncon-Albuquerque, Mélanie Roriz, Manuel Rosa-Calatrava, Michael Rose, Dorothea Rosenberger, Nurul Hidayah Mohammad Roslan, Andrea Rossanese, Matteo Rossetti, Bénédicte Rossignol, Patrick Rossignol, Stella Rousset, Carine Roy, Benoît Roze, Desy Rusmawatiningtyas, Clark D Russell, Maria Ryan, Maeve Ryan, Steffi Ryckaert, Aleksander Rygh Holten, Isabela Saba, Sairah Sadaf, Musharaf Sadat, Valla Sahraei, Maximilien Saint-Gilles, Pranya Sakiyalak, Nawal Salahuddin, Leonardo Salazar, Jodat Saleem, Gabriele Sales, Stéphane Sallaberry, Charlotte Salmon Gandonniere, Hélène Salvator, Olivier Sanchez, Angel Sanchez-Miralles, Vanessa Sancho-Shimizu, Gyan Sandhu, Zulfiqar Sandhu, Pierre-François Sandrine, Marlene Santos, Shirley Sarfo-Mensah, Bruno Sarmento Banheiro, Iam Claire E Sarmiento, Benjamine Sarton, Ankana Satya, Sree Satyapriya, Rumaisah Satyawati, Egle Saviciute, Parthena Savvidou, Yen Tsen Saw, Justin Schaffer, Tjard Schermer, Arnaud Scherpereel, Marion Schneider, Stephan Schroll, Michael Schwameis, Gary Schwartz, Brendan Scicluna, Janet T Scott, James Scott-Brown, Nicholas Sedillot, Tamara Seitz, Jaganathan Selvanayagam, Mageswari Selvarajoo, Caroline Semaille, Rasidah Bt Senian, Eric Senneville, Claudia Sepulveda, Filipa Sequeira, Tânia Sequeira, Ary Serpa Neto, Pablo Serrano Balazote, Ellen Shadowitz, Syamin Asyraf Shahidan, Mohammad Shamsah, Anuraj Shankar, Shaikh Sharjeel, Catherine A Shaw, Victoria Shaw, Ashraf Sheharyar, Rohan Shetty, Rajesh Mohan Shetty, Haixia Shi, Nisreen Shiban, Mohiuddin Shiekh, Nobuaki Shime, Hiroaki Shimizu, Keiki Shimizu, Sally Shrapnel, Pramesh Sundar Shrestha, Shubha Kalyan Shrestha, Hoi Ping Shum, Nassima Si Mohammed, Ng Yong Siang, Jeanne Sibiude, Atif Siddiqui, Piret Sillaots, Catarina Silva, Rogério Silva, Maria Joao Silva, Wai Ching Sin, Dario Sinatti, Punam Singh, Budha Charan Singh, Pompini Agustina Sitompul, Karisha Sivam, Vegard Skogen, Sue Smith, Benjamin Smood, Coilin Smyth, Michelle Smyth, Morgane Snacken, Dominic So, Tze Vee Soh, Joshua Solomon, Tom Solomon, Agnès Sommet, Rima Song, Tae Song, Jack Song Chia, Michael Sonntagbauer, Azlan Mat Soom, Alberto Sotto, Edouard Soum, Marta Sousa, Ana Chora Sousa, Maria Sousa Uva, Vicente Souza-Dantas, Alexandra Sperry, Elisabetta Spinuzza, B P Sanka Ruwan Sri Darshana, Shiranee Sriskandan, Sarah Stabler, Thomas Staudinger, Stephanie-Susanne Stecher, Trude Steinsvik, Ymkje Stienstra, Birgitte Stiksrud, Eva Stolz, Amy Stone, Adrian Streinu-Cercel, David Stuart, Ami Stuart, Decy Subekti, Gabriel Suen, Jacky Y Suen, Asfia Sultana, Charlotte Summers, Dubravka Supic, Deepashankari Suppiah, Magdalena Surovcová, Suwarti Suwarti, Andrey Svistunov, Sarah Syahrin, Konstantinos Syrigos, Jaques Sztajnbok, Konstanty Szuldrzynski, Shirin Tabrizi, Lysa Tagherset, Shahdattul Mawarni Taib, Ewa Talarek, Sara Taleb, Jelmer Talsma, Renaud Tamisier, Maria Lawrensia Tampubolon, Kim Keat Tan, Yan Chyi Tan, Taku Tanaka, Hiroyuki Tanaka, Hayato Taniguchi, Huda Taqdees, Arshad Taqi, Coralie Tardivon, Pierre Tattevin, M Azhari Taufik, Hassan Tawfik, Richard S Tedder, Tze Yuan Tee, João Teixeira, Sofia Tejada, Marie-Capucine Tellier, Sze Kye Teoh, Vanessa Teotonio, François Téoulé, Pleun Terpstra, Olivier Terrier, Nicolas Terzi, Hubert Tessier-Grenier, Adrian Tey, Alif Adlan Mohd Thabit, Anand Thakur, Zhang Duan Tham, Suvintheran Thangavelu, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Jananee Thirumanickam, Shaun Thompson, Emma C Thomson, David Thomson, Surain Raaj Thanga Thurai, Ryan S Thwaites, Paul Tierney, Vadim Tieroshyn, Peter S Timashev, Jean-François Timsit, Noémie Tissot, Jordan Zhien Yang Toh, Maria Toki, Kristian Tonby, Sia Loong Tonnii, Margarida Torres, Antoni Torres, Rosario Maria Torres Santos-Olmo, Hernando Torres-Zevallos, Michael Towers, Tony Trapani, Théo Treoux, Cécile Tromeur, Ioannis Trontzas, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Helen Tuite, Jean-Marie Turmel, Lance C W Turtle, Anders Tveita, Pawel Twardowski, Makoto Uchiyama, P G Ishara Udayanga, Andrew Udy, Roman Ullrich, Alberto Uribe, Asad Usman, Timothy M Uyeki, Cristinava Vajdovics, Piero Valentini, Luís Val-Flores, Amélie Valran, Stijn Van de Velde, Marcel van den Berge, Machteld Van der Feltz, Job van der Palen, Paul van der Valk, Nicky Van Der Vekens, Peter Van der Voort, Sylvie Van Der Werf, Laura van Gulik, Jarne Van Hattem, Carolien van Netten, Frank van Someren Greve, Ilonka van Veen, Hugo Van Willigen, Noémie Vanel, Henk Vanoverschelde, Pooja Varghese, Michael Varrone, Shoban Raj Vasudayan, Charline Vauchy, Shaminee Veeran, Aurélie Veislinger, Sebastian Vencken, Sara Ventura, Annelies Verbon, James Vickers, José Ernesto Vidal, César Vieira, Deepak Vijayan, Joy Ann Villanueva, Judit Villar, Pierre-Marc Villeneuve, Andrea Villoldo, Gayatri Vishwanathan, Benoit Visseaux, Hannah Visser, Chiara Vitiello, Harald Vonkeman, Fanny Vuotto, Suhaila Abdul Wahab, Noor Hidayu Wahab, Nadirah Abdul Wahid, Marina Wainstein, Wan Fadzlina Wan Muhd Shukeri, Chih-Hsien Wang, Steve Webb, Katharina Weil, Tan Pei Wen, Sanne Wesselius, T Eoin West, Murray Wham, Bryan Whelan, Nicole White, Paul Henri Wicky, Aurélie Wiedemann, Surya Otto Wijaya, Keith Wille, Suzette Willems, Virginie Williams, Calvin Wong, Yew Sing Wong, Teck Fung Wong, Natalie Wright, Gan Ee Xian, Lim Saio Xian, Kuan Pei Xuan, Ioannis Xynogalas, Siti Rohani Binti Mohd Yakop, Masaki Yamazaki, Yazdan Yazdanpanah, Nicholas Yee Liang Hing, Cécile Yelnik, Chian Hui Yeoh, Stephanie Yerkovich, Toshiki Yokoyama, Hodane Yonis, Obada Yousif, Saptadi Yuliarto, Akram Zaaqoq, Marion Zabbe, Kai Zacharowski, Masliza Zahid, Maram Zahran, Nor Zaila Binti Zaidan, Maria Zambon, Miguel Zambrano, Alberto Zanella, Konrad Zawadka, Nurul Zaynah, Hiba Zayyad, Alexander Zoufaly, David Zucman, Kartsonaki, Christiana, Baillie, J Kenneth, Barrio, Noelia García, Baruch, Joaquín, Beane, Abigail, Blumberg, Lucille, Bozza, Fernando, Broadley, Tessa, Burrell, Aidan, Carson, Gail, Citarella, Barbara Wanjiru, Dagens, Andrew, Dankwa, Emmanuelle A, Donnelly, Christl A, Dunning, Jake, Elotmani, Loubna, Escher, Martina, Farshait, Nataly, Goffard, Jean-Christophe, Gonçalves, Bronner P, Hall, Matthew, Hashmi, Madiha, Sim Lim Heng, Benedict, Ho, Antonia, Jassat, Waasila, Pedrera Jiménez, Miguel, Laouenan, Cedric, Lissauer, Samantha, Martin-Loeches, Ignacio, Mentré, France, Merson, Laura, Morton, Ben, Munblit, Daniel, Nekliudov, Nikita A, Nichol, Alistair D, Singh Oinam, Budha Charan, Ong, David, Panda, Prasan Kumar, Petrovic, Michele, Pritchard, Mark G, Ramakrishnan, Nagarajan, Ramos, Grazielle Viana, Roger, Claire, Sandulescu, Oana, Semple, Malcolm G, Sharma, Pratima, Sigfrid, Louise, Somers, Emily C, Streinu-Cercel, Anca, Taccone, Fabio, Vecham, Pavan Kumar, Kumar Tirupakuzhi Vijayaraghavan, Bharath, Wei, Jia, Wils, Evert-Jan, Ci Wong, Xin, Horby, Peter, Rojek, Amanda, Olliaro, Piero L, ISARIC Clinical Characterisation Group: Ali Abbas, Sheryl Ann Abdukahil, Nurul Najmee Abdulkadir, Ryuzo Abe, Laurent Abel, Lara Absil, Subhash Acharya, Andrew Acker, Elisabeth Adam, Diana Adrião, Saleh Al Ageel, Shakeel Ahmed, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Ait Hssain, Younes Ait Tamlihat, Takako Akimoto, Ernita Akmal, Eman Al Qasim, Razi Alalqam, Angela Alberti, Tala Al-Dabbous, Senthilkumar Alegesan, Cynthia Alegre, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman Al-Fares, Huda Alfoudri, Imran Ali, Adam Ali, Naseem Ali Shah, Kazali Enagnon Alidjnou, Jeffrey Aliudin, Qabas Alkhafajee, Clotilde Allavena, Nathalie Allou, Aneela Altaf, João Alves, Rita Alves, João Melo Alves, Maria Amaral, Nur Amira, Phoebe Ampaw, Roberto Andini, Claire Andréjak, Andrea Angheben, François Angoulvant, Séverine Ansart, Sivanesen Anthonidass, Massimo Antonelli, Carlos Alexandre Antunes de Brito, Ardiyan Apriyana, Yaseen Arabi, Irene Aragao, Francisco Arancibia, Carolline Araujo, Antonio Arcadipane, Patrick Archambault, Lukas Arenz, Jean-Benoît Arlet, Christel Arnold-Day, Lovkesh Arora, Rakesh Arora, Elise Artaud-Macari, Diptesh Aryal, Angel Asensio, Muhammad Ashraf, Namra Asif, Mohammad Asim, Jean Baptiste Assie, Amirul Asyraf, Anika Atique, A M Udara Lakshan Attanyake, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Laurène Azemar, Cecile Azoulay, Benjamin Bach, Delphine Bachelet, Claudine Badr, Nadia Baig, J Kevin Baird, Erica Bak, Agamemnon Bakakos, Nazreen Abu Bakar, Andriy Bal, Mohanaprasanth Balakrishnan, Valeria Balan, Firouzé Bani-Sadr, Renata Barbalho, Nicholas Yuri Barbosa, Wendy S Barclay, Saef Umar Barnett, Michaela Barnikel, Helena Barrasa, Audrey Barrelet, Cleide Barrigoto, Marie Bartoli, Mustehan Bashir, Romain Basmaci, Muhammad Fadhli Hassin Basri, Denise Battaglini, Jules Bauer, Diego Fernando Bautista Rincon, Denisse Bazan Dow, Alexandra Bedossa, Ker Hong Bee, Husna Begum, Sylvie Behilill, Albertus Beishuizen, Aleksandr Beljantsev, David Bellemare, Anna Beltrame, Beatriz Amorim Beltrão, Marine Beluze, Nicolas Benech, Lionel Eric Benjiman, Dehbia Benkerrou, Suzanne Bennett, Luís Bento, Jan-Erik Berdal, Delphine Bergeaud, Hazel Bergin, José Luis Bernal Sobrino, Giulia Bertoli, Lorenzo Bertolino, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Amar Bhatt, Krishna Bhavsar, Claudia Bianco, Farah Nadiah Bidin, Moirangthem Bikram Singh, Felwa Bin Humaid, Mohd Nazlin Bin Kamarudin, François Bissuel, Patrick Biston, Laurent Bitker, Jonathan Bitton, Pablo Blanco-Schweizer, Catherine Blier, Frank Bloos, Mathieu Blot, Filomena Boccia, Laetitia Bodenes, Alice Bogaarts, Debby Bogaert, Anne-Hélène Boivin, Pierre-Adrien Bolze, François Bompart, Aurelius Bonfasius, Diogo Borges, Raphaël Borie, Hans Martin Bosse, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Dounia Bouhmani, Damien Bouhour, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Anne-Sophie Boureau, John Bourke, Maude Bouscambert, Aurore Bousquet, Jason Bouziotis, Bianca Boxma, Marielle Boyer-Besseyre, Maria Boylan, Axelle Braconnier, Cynthia Braga, Timo Brandenburger, Filipa Brás Monteiro, Luca Brazzi, Patrick Breen, Dorothy Breen, Patrick Breen, Kathy Brickell, Shaunagh Browne, Alex Browne, Nicolas Brozzi, Marjolein Brusse-Keizer, Nina Buchtele, Christian Buesaquillo, Polina Bugaeva, Marielle Buisson, Danilo Buonsenso, Erlina Burhan, Ingrid G Bustos, Denis Butnaru, André Cabie, Susana Cabral, Eder Caceres, Cyril Cadoz, Mia Callahan, Kate Calligy, Jose Andres Calvache, João Camões, Valentine Campana, Paul Campbell, Josie Campisi, Cecilia Canepa, Mireia Cantero, Pauline Caraux-Paz, Sheila Cárcel, Chiara Simona Cardellino, Sofia Cardoso, Filipe Cardoso, Filipa Cardoso, Nelson Cardoso, Simone Carelli, Nicolas Carlier, Thierry Carmoi, Gayle Carney, Inês Carqueja, Marie-Christine Carret, François Martin Carrier, Ida Carroll, Maire-Laure Casanova, Mariana Cascão, Siobhan Casey, José Casimiro, Bailey Cassandra, Silvia Castañeda, Nidyanara Castanheira, Guylaine Castor-Alexandre, Henry Castrillón, Ivo Castro, Ana Catarino, François-Xavier Catherine, Paolo Cattaneo, Roberta Cavalin, Giulio Giovanni Cavalli, Alexandros Cavayas, Adrian Ceccato, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chakveatze, Adrienne Chan, Meera Chand, Christelle Chantalat Auger, Jean-Marc Chapplain, Julie Chas, Allegra Chatterjee, Mobin Chaudry, Jonathan Samuel Chávez Iñiguez, Anjellica Chen, Yih-Sharng Chen, Matthew Pellan Cheng, Antoine Cheret, Thibault Chiarabini, Julian Chica, Suresh Kumar Chidambaram, Leong Chin Tho, Catherine Chirouze, Davide Chiumello, Sung-Min Cho, Bernard Cholley, Marie-Charlotte Chopin, Ting Soo Chow, Yock Ping Chow, Hiu Jian Chua, Jonathan Chua, Jose Pedro Cidade, José Miguel Cisneros Herreros, Anna Ciullo, Jennifer Clarke, Emma Clarke, Rolando Claure-Del Granado, Sara Clohisey, Perren J Cobb, Cassidy Codan, Caitriona Cody, Alexandra Coelho, Megan Coles, Gwenhaël Colin, Michael Collins, Sebastiano Maria Colombo, Pamela Combs, Marie Connor, Anne Conrad, Sofía Contreras, Elaine Conway, Graham S Cooke, Mary Copland, Hugues Cordel, Amanda Corley, Sabine Cornelis, Alexander Daniel Cornet, Arianne Joy Corpuz, Andrea Cortegiani, Grégory Corvaisier, Emma Costigan, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Rachel Cregan, Charles Crepy D'Orleans, Cosimo Cristella, Sabine Croonen, Gloria Crowl, Jonathan Crump, Claudina Cruz, Juan Luis Cruz Berm, Jaime Cruz Rojo, Marc Csete, Ailbhe Cullen, Matthew Cummings, Gerard Curley, Elodie Curlier, Colleen Curran, Paula Custodio, Ana da Silva Filipe, Charlene Da Silveira, Al-Awwab Dabaliz, Darren Dahly, Heidi Dalton, Jo Dalton, Seamus Daly, Nick Daneman, Corinne Daniel, Jorge Dantas, Frédérick D'Aragon, Menno de Jong, Gillian de Loughry, Diego de Mendoza, Etienne De Montmollin, Rafael Freitas de Oliveira França, Ana Isabel de Pinho Oliveira, Rosanna De Rosa, Cristina De Rose, Thushan de Silva, Peter de Vries, Jillian Deacon, David Dean, Alexa Debard, Marie-Pierre Debray, Nathalie DeCastro, William Dechert, Lauren Deconninck, Romain Decours, Eve Defous, Isabelle Delacroix, Eric Delaveuve, Karen Delavigne, Nathalie M Delfos, Ionna Deligiannis, Andrea Dell'Amore, Christelle Delmas, Pierre Delobel, Corine Delsing, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Pieter Depuydt, Mehul Desai, Diane Descamps, Mathilde Desvallées, Santi Dewayanti, Pathik Dhanger, Alpha Diallo, Sylvain Diamantis, André Dias, Juan Jose Diaz, Priscila Diaz, Rodrigo Diaz, Kévin Didier, Jean-Luc Diehl, Wim Dieperink, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Yael Dishon, Félix Djossou, Annemarie B Docherty, Helen Doherty, Arjen M Dondorp, Andy Dong, Maria Donnelly, Sean Donohue, Yoann Donohue, Chloe Donohue, Peter Doran, Céline Dorival, Eric D'Ortenzio, James Joshua Douglas, Renee Douma, Nathalie Dournon, Triona Downer, Joanne Downey, Mark Downing, Tom Drake, Aoife Driscoll, Murray Dryden, Murray Dryden, Claudio Duarte Fonseca, Vincent Dubee, François Dubos, Alexandre Ducancelle, Toni Duculan, Susanne Dudman, Abhijit Duggal, Paul Dunand, Mathilde Duplaix, Emanuele Durante-Mangoni, Lucian Durham, Bertrand Dussol, Juliette Duthoit, Xavier Duval, Anne Margarita Dyrhol-Riise, Sim Choon Ean, Marco Echeverria-Villalobos, Siobhan Egan, Carla Eira, Mohammed El Sanharawi, Subbarao Elapavaluru, Brigitte Elharrar, Jacobien Ellerbroek, Philippine Eloy, Tarek Elshazly, Iqbal Elyazar, Isabelle Enderle, Tomoyuki Endo, Chan Chee Eng, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Mariano Esperatti, Hélène Esperou, Marina Esposito-Farese, João Estevão, Manuel Etienne, Nadia Ettalhaoui, Anna Greti Everding, Mirjam Evers, Marc Fabre, Isabelle Fabre, Amna Faheem, Arabella Fahy, Cameron J Fairfield, Zul Fakar, Komal Fareed, Pedro Faria, Ahmed Farooq, Hanan Fateena, Arie Zainul Fatoni, Karine Faure, Raphaël Favory, Mohamed Fayed, Niamh Feely, Laura Feeney, Jorge Fernandes, Marília Andreia Fernandes, Susana Fernandes, François-Xavier Ferrand, Eglantine Ferrand Devouge, Joana Ferrão, Mário Ferraz, Sílvia Ferreira, Isabel Ferreira, Benigno Ferreira, Ricard Ferrer-Roca, Nicolas Ferriere, Céline Ficko, Claudia Figueiredo-Mello, William Finlayson, Juan Fiorda, Thomas Flament, Clara Flateau, Tom Fletcher, Letizia Lucia Florio, Deirdre Flynn, Claire Foley, Jean Foley, Victor Fomin, Tatiana Fonseca, Patricia Fontela, Simon Forsyth, Denise Foster, Giuseppe Foti, Erwan Fourn, Robert A Fowler, Marianne Fraher, Diego Franch-Llasat, John F Fraser, Christophe Fraser, Marcela Vieira Freire, Ana Freitas Ribeiro, Caren Friedrich, Ricardo Fritz, Stéphanie Fry, Nora Fuentes, Masahiro Fukuda, G Argin, Valérie Gaborieau, Rostane Gaci, Massimo Gagliardi, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Sérgio Gaião, Linda Gail Skeie, Phil Gallagher, Carrol Gamble, Yasmin Gani, Arthur Garan, Rebekha Garcia, Julia Garcia-Diaz, Esteban Garcia-Gallo, Navya Garimella, Denis Garot, Valérie Garrait, Basanta Gauli, Nathalie Gault, Aisling Gavin, Anatoliy Gavrylov, Alexandre Gaymard, Johannes Gebauer, Eva Geraud, Louis Gerbaud Morlaes, Nuno Germano, Praveen Kumar Ghisulal, Jade Ghosn, Marco Giani, Jess Gibson, Tristan Gigante, Morgane Gilg, Elaine Gilroy, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Daniel Glikman, Petr Glybochko, Eric Gnall, Geraldine Goco, François Goehringer, Siri Goepel, Jin Yi Goh, Jonathan Golob, Rui Gomes, Kyle Gomez, Joan Gómez-Junyent, Marie Gominet, Alicia Gonzalez, Patricia Gordon, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Margarite Grable, Jeronimo Graf, Edward Wilson Grandin, Pascal Granier, Giacomo Grasselli, Christopher A Green, Courtney Greene, William Greenhalf, Segolène Greffe, Domenico Luca Grieco, Matthew Griffee, Fiona Griffiths, Ioana Grigoras, Albert Groenendijk, Anja Grosse Lordemann, Heidi Gruner, Yusing Gu, Jérémie Guedj, Martin Guego, Dewi Guellec, Anne-Marie Guerguerian, Daniela Guerreiro, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Maisa Guimarães de Castro, Thomas Guimard, Marieke Haalboom, Daniel Haber, Hannah Habraken, Ali Hachemi, Amy Hackmann, Nadir Hadri, Fakhir Haidri, Sheeba Hakak, Adam Hall, Sophie Halpin, Jawad Hameed, Ansley Hamer, Raph L Hamers, Rebecca Hamidfar, Terese Hammond, Lim Yuen Han, Rashan Haniffa, Kok Wei Hao, Hayley Hardwick, Ewen M Harrison, Janet Harrison, Samuel Bernard Ekow Harrison, Alan Hartman, Mohd Shahnaz Hasan, Junaid Hashmi, Muhammad Hayat, Ailbhe Hayes, Leanne Hays, Jan Heerman, Lars Heggelund, Ross Hendry, Martina Hennessy, Aquiles Henriquez-Trujillo, Maxime Hentzien, Jaime Hernandez-Montfort, Andrew Hershey, Liv Hesstvedt, Astarini Hidayah, Eibhilin Higgins, Dawn Higgins, Rupert Higgins, Rita Hinchion, Samuel Hinton, Hiroaki Hiraiwa, Haider Hirkani, Hikombo Hitoto, Yi Bin Ho, Alexandre Hoctin, Isabelle Hoffmann, Wei Han Hoh, Oscar Hoiting, Rebecca Holt, Jan Cato Holter, Juan Pablo Horcajada, Koji Hoshino, Ikram Houas, Catherine L Hough, Stuart Houltham, Jimmy Ming-Yang Hsu, Jean-Sébastien Hulot, Stella Huo, Abby Hurd, Iqbal Hussain, Samreen Ijaz, Hajnal-Gabriela Illes, Patrick Imbert, Mohammad Imran, Rana Imran Sikander, Aftab Imtiaz, Hugo Inácio, Carmen Infante Dominguez, Yun Sii Ing, Elias Iosifidis, Mariachiara Ippolito, Sarah Isgett, Tiago Isidoro, Nadiah Ismail, Margaux Isnard, Junji Itai, Daniel Ivulich, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Clare Jackson, Nina Jamieson, Victoria Janes, Pierre Jaquet, Coline Jaud-Fischer, Stéphane Jaureguiberry, Jeffrey Javidfar, Denise Jaworsky, Florence Jego, Anilawati Mat Jelani, Synne Jenum, Ruth Jimbo-Sotomayor, Ong Yiaw Joe, Ruth N Jorge García, Cédric Joseph, Mark Joseph, Swosti Joshi, Mercé Jourdain, Philippe Jouvet, Hanna Jung, Anna Jung, Dafsah Juzar, Ouifiya Kafif, Florentia Kaguelidou, Neerusha Kaisbain, Thavamany Kaleesvran, Sabina Kali, Alina Kalicinska, Smaragdi Kalomoiri, Muhammad Aisar Ayadi Kamaluddin, Zul Amali Che Kamaruddin, Nadiah Kamarudin, Paul Kambiya, Kavita Kamineni, Darshana Hewa Kandamby, Chris Kandel, Kong Yeow Kang, Darakhshan Kanwal, Pratap Karpayah, Todd Karsies, Daisuke Kasugai, Anant Kataria, Kevin Katz, Aasmine Kaur, Christy Kay, Hannah Keane, Seán Keating, Pulak Kedia, Claire Kelly, Yvelynne Kelly, Andrea Kelly, Niamh Kelly, Aoife Kelly, Sadie Kelly, Maeve Kelsey, Ryan Kennedy, Kalynn Kennon, Maeve Kernan, Younes Kerroumi, Sharma Keshav, Imrana Khalid, Osama Khalid, Antoine Khalil, Coralie Khan, Irfan Khan, Quratul Ain Khan, Sushil Khanal, Abid Khatak, Amin Khawaja, Krish Kherajani, Michelle E Kho, Saye Khoo, Ryan Khoo, Denisa Khoo, Nasir Khoso, Khor How Kiat, Yuri Kida, Peter Kiiza, Beathe Kiland Granerud, Anders Benjamin Kildal, Jae Burm Kim, Antoine Kimmoun, Detlef Kindgen-Milles, Alexander King, Nobuya Kitamura, Paul Klenerman, Rob Klont, Gry Kloumann Bekken, Stephen R Knight, Robin Kobbe, Chamira Kodippily, Malte Kohns Vasconcelos, Sabin Koirala, Mamoru Komatsu, Caroline Kosgei, Arsène Kpangon, Karolina Krawczyk, Vinothini Krishnan, Sudhir Krishnan, Oksana Kruglova, Deepali Kumar, Ganesh Kumar, Mukesh Kumar, Dinesh Kuriakose, Ethan Kurtzman, Demetrios Kutsogiannis, Galyna Kutsyna, Konstantinos Kyriakoulis, Marie Lachatre, Marie Lacoste, John G Laffey, Marie Lagrange, Fabrice Laine, Olivier Lairez, Sanjay Lakhey, Antonio Lalueza, Marc Lambert, François Lamontagne, Marie Langelot-Richard, Vincent Langlois, Eka Yudha Lantang, Marina Lanza, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Sakshi Lath, Naveed Latif, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Teresa Lawrence, Cassie Lawrence, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Paul Le Turnier, Ema Leal, Marta Leal Santos, Todd C Lee, James Lee, Jennifer Lee, Heng Gee Lee, Biing Horng Lee, Yi Lin Lee, Su Hwan Lee, Gary Leeming, Laurent Lefebvre, Bénédicte Lefebvre, Benjamin Lefevre, Sylvie LeGac, Jean-Daniel Lelievre, François Lellouche, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Gretchen Lemmink, Ha Sha Lene, Jenny Lennon, Rafael León, Marc Leone, Michela Leone, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Amy Lester-Grant, Bruno Levy, Yves Levy, Claire Levy-Marchal, Katarzyna Lewandowska, Erwan L'Her, Gianluigi Li Bassi, Janet Liang, Ali Liaquat, Geoffrey Liegeon, Wei Shen Lim, Kah Chuan Lim, Chantre Lima, Lim Lina, Bruno Lina, Andreas Lind, Maja Katherine Lingad, Guillaume Lingas, Sylvie Lion-Daolio, Keibun Liu, Marine Livrozet, Patricia Lizotte, Antonio Loforte, Navy Lolong, Leong Chee Loon, Diogo Lopes, Dalia Lopez-Colon, Jose W Lopez-Revilla, Anthony L Loschner, Paul Loubet, Bouchra Loufti, Guillame Louis, Silvia Lourenco, Lara Lovelace-Macon, Lee Lee Low, Marije Lowik, Jia Shyi Loy, Jean Christophe Lucet, Carlos Lumbreras Bermejo, Carlos M Luna, Olguta Lungu, Liem Luong, Nestor Luque, Dominique Luton, Nilar Lwin, Ruth Lyons, Olavi Maasikas, Oryane Mabiala, Moïse Machado, Gabriel Macheda, Hashmi Madiha, Guillermo Maestro de la Calle, Rafael Mahieu, Sophie Mahy, Ana Raquel Maia, Lars S Maier, Mylène Maillet, Thomas Maitre, Maximilian Malfertheiner, Nadia Malik, Paddy Mallon, Fernando Maltez, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Frank Manetta, Julie Mankikian, Edmund Manning, Aldric Manuel, Ceila Maria Sant Ana Malaque, Flávio Marino, Daniel Marino, Samuel Markowicz, Charbel Maroun Eid, Ana Marques, Catherine Marquis, Brian Marsh, Laura Marsh, Megan Marshal, John Marshall, Celina Turchi Martelli, Dori-Ann Martin, Emily Martin, Guillaume Martin-Blondel, Martin Martinot, Alejandro Martin-Quiros, João Martins, Ana Martins, Nuno Martins, Caroline Martins Rego, Gennaro Martucci, Olga Martynenko, Eva Miranda Marwali, Marsilla Marzukie, David Maslove, Sabina Mason, Sobia Masood, Basri Mat Nor, Moshe Matan, Meghena Mathew, Daniel Mathieu, Mathieu Mattei, Romans Matulevics, Laurence Maulin, Michael Maxwell, Javier Maynar, Thierry Mazzoni, Natalie Mc Evoy, Lisa Mc Sweeney, Colin McArthur, Colin McArthur, Anne McCarthy, Aine McCarthy, Colin McCloskey, Rachael McConnochie, Sherry McDermott, Sarah E McDonald, Aine McElroy, Samuel McElwee, Victoria McEneany, Allison McGeer, Chris McKay, Johnny McKeown, Kenneth A McLean, Paul McNally, Bairbre McNicholas, Elaine McPartlan, Edel Meaney, Cécile Mear-Passard, Maggie Mechlin, Maqsood Meher, Omar Mehkri, Ferruccio Mele, Luis Melo, Kashif Memon, Joao Joao Mendes, Ogechukwu Menkiti, Kusum Menon, Alexander J Mentzer, Emmanuelle Mercier, Noémie Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Blake Mergler, António Mesquita, Roberta Meta, Osama Metwally, Agnès Meybeck, Dan Meyer, Alison M Meynert, Vanina Meysonnier, Amina Meziane, Mehdi Mezidi, Céline Michelanglei, Isabelle Michelet, Efstathia Mihelis, Vladislav Mihnovit, Hugo Miranda-Maldonado, Nor Arisah Misnan, Tahira Jamal Mohamed, Nik Nur Eliza Mohamed, Asma Moin, David Molina, Elena Molinos, Brenda Molloy, Mary Mone, Agostinho Monteiro, Claudia Montes, Giorgia Montrucchio, Shona C Moore, Sarah Moore, Lina Morales Cely, Lucia Moro, Catherine Motherway, Ana Motos, Hugo Mouquet, Clara Mouton Perrot, Julien Moyet, Caroline Mudara, Aisha Kalsoom Mufti, Ng Yong Muh, Dzawani Muhamad, Jimmy Mullaert, Fredrik Müller, Karl Erik Müller, Syed Muneeb, Nadeem Munir, Laveena Munshi, Aisling Murphy, Lorna Murphy, Aisling Murphy, Marlène Murris, Srinivas Murthy, Himed Musaab, Himasha Muvindi, Gugapriyaa Muyandy, Dimitra Melia Myrodia, Farah Nadia Mohd-Hanafiah, Dave Nagpal, Alex Nagrebetsky, Mangala Narasimhan, Nageswaran Narayanan, Rashid Nasim Khan, Alasdair Nazerali-Maitland, Nadège Neant, Holger Neb, Erni Nelwan, Raul Neto, Emily Neumann, Pauline Yeung Ng, Wing Yiu Ng, Anthony Nghi, Duc Nguyen, Orna Ni Choileain, Niamh Ni Leathlobhair, Prompak Nitayavardhana, Stephanie Nonas, Nurul Amani Mohd Noordin, Marion Noret, Nurul Faten Izzati Norharizam, Lisa Norman, Alessandra Notari, Mahdad Noursadeghi, Karolina Nowicka, Adam Nowinski, Saad Nseir, Jose I Nunez, Nurnaningsih Nurnaningsih, Dwi Utomo Nusantara, Elsa Nyamankolly, Fionnuala O Brien, Annmarie O Callaghan, Annmarie O'Callaghan, Giovanna Occhipinti, Derbrenn OConnor, Max O'Donnell, Tawnya Ogston, Takayuki Ogura, Tak-Hyuk Oh, Sophie O'Halloran, Katie O'Hearn, Shinichiro Ohshimo, Agnieszka Oldakowska, João Oliveira, Larissa Oliveira, Jee Yan Ong, Wilna Oosthuyzen, Anne Opavsky, Peter Openshaw, Saijad Orakzai, Claudia Milena Orozco-Chamorro, Jamel Ortoleva, Javier Osatnik, Linda O'Shea, Miriam O'Sullivan, Siti Zubaidah Othman, Nadia Ouamara, Rachida Ouissa, Eric Oziol, Maïder Pagadoy, Justine Pages, Mario Palacios, Amanda Palacios, Massimo Palmarini, Giovanna Panarello, Hem Paneru, Lai Hui Pang, Mauro Panigada, Nathalie Pansu, Aurélie Papadopoulos, Rachael Parke, Melissa Parker, Briseida Parra, Taha Pasha, Jérémie Pasquier, Bruno Pastene, Fabian Patauner, Drashti Patel, Mohan Dass Pathmanathan, Luís Patrão, Patricia Patricio, Juliette Patrier, Lisa Patterson, Rajyabardhan Pattnaik, Mical Paul, Christelle Paul, Jorge Paulos, William A Paxton, Jean-François Payen, Kalaiarasu Peariasamy, Giles J Peek, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Mare Pejkovska, Paolo Pelosi, Ithan D Peltan, Rui Pereira, Daniel Perez, Luis Periel, Thomas Perpoint, Antonio Pesenti, Vincent Pestre, Lenka Petrou, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Scott Pharand, Michael Piagnerelli, Walter Picard, Olivier Picone, Maria de Piero, Carola Pierobon, Djura Piersma, Carlos Pimentel, Raquel Pinto, Catarina Pires, Isabelle Pironneau, Lionel Piroth, Ayodhia Pitaloka, Riinu Pius, Laurent Plantier, Hon Shen Png, Julien Poissy, Ryadh Pokeerbux, Maria Pokorska-Spiewak, Sergio Poli, Georgios Pollakis, Diane Ponscarme, Jolanta Popielska, Diego Bastos Porto, Andra-Maris Post, Douwe F Postma, Pedro Povoa, Diana Póvoas, Jeff Powis, Sofia Prapa, Sébastien Preau, Christian Prebensen, Jean-Charles Preiser, Anton Prinssen, Gamage Dona Dilanthi Priyadarshani, Lucia Proença, Sravya Pudota, Oriane Puéchal, Bambang Pujo Semedi, Mathew Pulicken, Gregory Purcell, Luisa Quesada, Vilmaris Quinones-Cardona, Víctor Quirós González, Else Quist-Paulsen, Mohammed Quraishi, Maia Rabaa, Christian Rabaud, Ebenezer Rabindrarajan, Aldo Rafael, Marie Rafiq, Gabrielle Ragazzo, Mutia Rahardjani, Rozanah Abd Rahman, Ahmad Kashfi Haji Ab Rahman, Arsalan Rahutullah, Fernando Rainieri, Giri Shan Rajahram, Pratheema Ramachandran, Ahmad Afiq Ramli, Blandine Rammaert, Asim Rana, Rajavardhan Rangappa, Ritika Ranjan, Christophe Rapp, Aasiyah Rashan, Thalha Rashan, Ghulam Rasheed, Menaldi Rasmin, Indrek Rätsep, Cornelius Rau, Tharmini Ravi, Ali Raza, Andre Real, Stanislas Rebaudet, Sarah Redl, Brenda Reeve, Attaur Rehman, Liadain Reid, Liadain Reid, Dag Henrik Reikvam, Renato Reis, Jordi Rello, Jonathan Remppis, Martine Remy, Hongru Ren, Hanna Renk, Anne-Sophie Resseguier, Matthieu Revest, Oleksa Rewa, Luis Felipe Reyes, Tiago Reyes, Maria Ines Ribeiro, Antonia Ricchiuto, David Richardson, Denise Richardson, Laurent Richier, Siti Nurul Atikah Ahmad Ridzuan, Jordi Riera, Ana L Rios, Asgar Rishu, Patrick Rispal, Karine Risso, Maria Angelica Rivera Nuñez, Nicholas Rizer, Chiara Robba, André Roberto, Stephanie Roberts, David L Robertson, Olivier Robineau, Ferran Roche-Campo, Paola Rodari, Simão Rodeia, Bernhard Roessler, Pierre-Marie Roger, Emmanuel Roilides, Juliette Romaru, Roberto Roncon-Albuquerque, Mélanie Roriz, Manuel Rosa-Calatrava, Michael Rose, Dorothea Rosenberger, Nurul Hidayah Mohammad Roslan, Andrea Rossanese, Matteo Rossetti, Bénédicte Rossignol, Patrick Rossignol, Stella Rousset, Carine Roy, Benoît Roze, Desy Rusmawatiningtyas, Clark D Russell, Maria Ryan, Maeve Ryan, Steffi Ryckaert, Aleksander Rygh Holten, Isabela Saba, Sairah Sadaf, Musharaf Sadat, Valla Sahraei, Maximilien Saint-Gilles, Pranya Sakiyalak, Nawal Salahuddin, Leonardo Salazar, Jodat Saleem, Gabriele Sales, Stéphane Sallaberry, Charlotte Salmon Gandonniere, Hélène Salvator, Olivier Sanchez, Angel Sanchez-Miralles, Vanessa Sancho-Shimizu, Gyan Sandhu, Zulfiqar Sandhu, Pierre-François Sandrine, Marlene Santos, Shirley Sarfo-Mensah, Bruno Sarmento Banheiro, Iam Claire E Sarmiento, Benjamine Sarton, Ankana Satya, Sree Satyapriya, Rumaisah Satyawati, Egle Saviciute, Parthena Savvidou, Yen Tsen Saw, Justin Schaffer, Tjard Schermer, Arnaud Scherpereel, Marion Schneider, Stephan Schroll, Michael Schwameis, Gary Schwartz, Brendan Scicluna, Janet T Scott, James Scott-Brown, Nicholas Sedillot, Tamara Seitz, Jaganathan Selvanayagam, Mageswari Selvarajoo, Caroline Semaille, Rasidah Bt Senian, Eric Senneville, Claudia Sepulveda, Filipa Sequeira, Tânia Sequeira, Ary Serpa Neto, Pablo Serrano Balazote, Ellen Shadowitz, Syamin Asyraf Shahidan, Mohammad Shamsah, Anuraj Shankar, Shaikh Sharjeel, Catherine A Shaw, Victoria Shaw, Ashraf Sheharyar, Rohan Shetty, Rajesh Mohan Shetty, Haixia Shi, Nisreen Shiban, Mohiuddin Shiekh, Nobuaki Shime, Hiroaki Shimizu, Keiki Shimizu, Sally Shrapnel, Pramesh Sundar Shrestha, Shubha Kalyan Shrestha, Hoi Ping Shum, Nassima Si Mohammed, Ng Yong Siang, Jeanne Sibiude, Atif Siddiqui, Piret Sillaots, Catarina Silva, Rogério Silva, Maria Joao Silva, Wai Ching Sin, Dario Sinatti, Punam Singh, Budha Charan Singh, Pompini Agustina Sitompul, Karisha Sivam, Vegard Skogen, Sue Smith, Benjamin Smood, Coilin Smyth, Michelle Smyth, Michelle Smyth, Morgane Snacken, Dominic So, Tze Vee Soh, Joshua Solomon, Tom Solomon, Agnès Sommet, Rima Song, Tae Song, Jack Song Chia, Michael Sonntagbauer, Azlan Mat Soom, Alberto Sotto, Edouard Soum, Marta Sousa, Ana Chora Sousa, Maria Sousa Uva, Vicente Souza-Dantas, Alexandra Sperry, Elisabetta Spinuzza, B P Sanka Ruwan Sri Darshana, Shiranee Sriskandan, Sarah Stabler, Thomas Staudinger, Stephanie-Susanne Stecher, Trude Steinsvik, Ymkje Stienstra, Birgitte Stiksrud, Eva Stolz, Amy Stone, Adrian Streinu-Cercel, David Stuart, Ami Stuart, Decy Subekti, Gabriel Suen, Jacky Y Suen, Asfia Sultana, Charlotte Summers, Dubravka Supic, Deepashankari Suppiah, Magdalena Surovcová, Suwarti Suwarti, Andrey Svistunov, Sarah Syahrin, Konstantinos Syrigos, Jaques Sztajnbok, Konstanty Szuldrzynski, Shirin Tabrizi, Lysa Tagherset, Shahdattul Mawarni Taib, Ewa Talarek, Sara Taleb, Jelmer Talsma, Renaud Tamisier, Maria Lawrensia Tampubolon, Kim Keat Tan, Yan Chyi Tan, Taku Tanaka, Hiroyuki Tanaka, Hayato Taniguchi, Huda Taqdees, Arshad Taqi, Coralie Tardivon, Pierre Tattevin, M Azhari Taufik, Hassan Tawfik, Richard S Tedder, Tze Yuan Tee, João Teixeira, Sofia Tejada, Marie-Capucine Tellier, Sze Kye Teoh, Vanessa Teotonio, François Téoulé, Pleun Terpstra, Olivier Terrier, Nicolas Terzi, Hubert Tessier-Grenier, Adrian Tey, Alif Adlan Mohd Thabit, Anand Thakur, Zhang Duan Tham, Suvintheran Thangavelu, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Jananee Thirumanickam, Shaun Thompson, Emma C Thomson, David Thomson, Surain Raaj Thanga Thurai, Ryan S Thwaites, Paul Tierney, Vadim Tieroshyn, Peter S Timashev, Jean-François Timsit, Noémie Tissot, Jordan Zhien Yang Toh, Maria Toki, Kristian Tonby, Sia Loong Tonnii, Margarida Torres, Antoni Torres, Rosario Maria Torres Santos-Olmo, Hernando Torres-Zevallos, Michael Towers, Tony Trapani, Théo Treoux, Cécile Tromeur, Ioannis Trontzas, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Helen Tuite, Jean-Marie Turmel, Lance C W Turtle, Anders Tveita, Pawel Twardowski, Makoto Uchiyama, P G Ishara Udayanga, Andrew Udy, Roman Ullrich, Alberto Uribe, Asad Usman, Timothy M Uyeki, Cristinava Vajdovics, Piero Valentini, Luís Val-Flores, Amélie Valran, Stijn Van de Velde, Marcel van den Berge, Machteld Van der Feltz, Job van der Palen, Paul van der Valk, Nicky Van Der Vekens, Peter Van der Voort, Sylvie Van Der Werf, Laura van Gulik, Jarne Van Hattem, Carolien van Netten, Frank van Someren Greve, Ilonka van Veen, Hugo Van Willigen, Noémie Vanel, Henk Vanoverschelde, Pooja Varghese, Michael Varrone, Shoban Raj Vasudayan, Charline Vauchy, Shaminee Veeran, Aurélie Veislinger, Sebastian Vencken, Sara Ventura, Annelies Verbon, James Vickers, José Ernesto Vidal, César Vieira, Deepak Vijayan, Joy Ann Villanueva, Judit Villar, Pierre-Marc Villeneuve, Andrea Villoldo, Gayatri Vishwanathan, Benoit Visseaux, Hannah Visser, Chiara Vitiello, Harald Vonkeman, Fanny Vuotto, Suhaila Abdul Wahab, Noor Hidayu Wahab, Nadirah Abdul Wahid, Marina Wainstein, Wan Fadzlina Wan Muhd Shukeri, Chih-Hsien Wang, Steve Webb, Katharina Weil, Tan Pei Wen, Sanne Wesselius, T Eoin West, Murray Wham, Bryan Whelan, Nicole White, Paul Henri Wicky, Aurélie Wiedemann, Surya Otto Wijaya, Keith Wille, Suzette Willems, Virginie Williams, Calvin Wong, Yew Sing Wong, Teck Fung Wong, Natalie Wright, Gan Ee Xian, Lim Saio Xian, Kuan Pei Xuan, Ioannis Xynogalas, Siti Rohani Binti Mohd Yakop, Masaki Yamazaki, Yazdan Yazdanpanah, Nicholas Yee Liang Hing, Cécile Yelnik, Chian Hui Yeoh, Stephanie Yerkovich, Toshiki Yokoyama, Hodane Yonis, Obada Yousif, Saptadi Yuliarto, Akram Zaaqoq, Marion Zabbe, Kai Zacharowski, Masliza Zahid, Maram Zahran, Nor Zaila Binti Zaidan, Maria Zambon, Miguel Zambrano, Alberto Zanella, Konrad Zawadka, Nurul Zaynah, Hiba Zayyad, Alexander Zoufaly, David Zucman, University of Oxford, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, CHU Pontchaillou [Rennes], ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was made possible by the UK Foreign, Commonwealth and Development Office, Wellcome (215091/Z/18/Z, 205228/Z/16/Z, 220757/Z/20/Z), Bill & Melinda Gates Foundation (OPP1209135), UK Medical Research Council Clinical Research Training Fellowship (MR/V001671/1), the philanthropic support of the donors to the University of Oxford’s COVID-19 Research Response Fund, CIHR Coronavirus Rapid Research Funding Opportunity (OV2170359) and the co-ordination in Canada by Sunnybrook Research Institute, endorsement of the Irish Critical Care—Clinical Trials Group, co-ordination in Ireland by the Irish Critical Care—Clinical Trials Network at University College Dublin and funding by the Health Research Board of Ireland (CTN-2014–12), the Rapid European COVID-19 Emergency Response research (RECOVER) (H2020 project 101003589) and European Clinical Research Alliance on Infectious Diseases (ECRAID) (965313), the COVID clinical management team, AIIMS, Rishikesh, India, the COVID-19 Clinical Management team, Manipal Hospital Whitefield, Bengaluru, India, Cambridge NIHR Biomedical Research Centre, the dedication and hard work of the Groote Schuur Hospital Covid ICU Team, support by the Groote Schuur nursing and University of Cape Town registrar bodies co-ordinated by the Division of Critical Care at the University of Cape Town, the Liverpool School of Tropical Medicine and the University of Oxford, the dedication and hard work of the Norwegian SARS-CoV-2 study team, the Research Council of Norway (grant no. 312780) and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner, Imperial NIHR Biomedical Research Centre, the Comprehensive Local Research Networks of which PJMO is an NIHR Senior Investigator (NIHR201385), Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115523 COMBACTE, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007– 2013) and EFPIA companies, in-kind contribution, the French COVID cohort (NCT04262921) is sponsored by INSERM and is funded by the REACTing (REsearch & ACtion emergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n 20–0424), Stiftungsfonds zur Förderung der Bekämpfung der Tuberkulose und anderer Lungenkrankheiten of the City of Vienna (project no. APCOV22BGM), Italian Ministry of Health ‘Fondi Ricerca corrente–L1P6’ to IRCCS Ospedale Sacro Cuore–Don Calabria, Australian Department of Health grant (3273191), Gender Equity Strategic Fund at University of Queensland, Artificial Intelligence for Pandemics (A14PAN) at University of Queensland, the Australian Research Council Centre of Excellence for Engineered Quantum Systems (EQUS, CE170100009), the Prince Charles Hospital Foundation, Australia, grants from Instituto de Salud Carlos III, Ministerio de Ciencia, Spain, Brazil, National Council for Scientific and Technological Development (scholarship no. 303953/2018–7), the Firland Foundation, Shoreline, Washington, USA, a grant from foundation Bevordering Onderzoek Franciscus, the South Eastern Norway Health Authority and the Research Council of Norway, and preparedness work conducted by the Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection. Data and Material provision was supported by grants from the National Institute for Health Research (NIHR, award CO-CIN-01), the Medical Research Council (MRC, and grant MC_PC_19059) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with PHE (award no. 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award no. 200927), Liverpool Experimental Cancer Medicine Centre (grant no. C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award no. IS-BRC-1215–20013) and NIHR Clinical Research Network providing infrastructure support.

Subjects
Male, Epidemiology, MESH: Hospitalization, MESH: Proportional Hazards Models, MESH: Risk Factors, Risk Factors, MESH: Child, cohort study, MESH: COVID-19, Humans, MESH: SARS-CoV-2, Child, Proportional Hazards Models, MESH: Humans, MESH: Middle Aged, SARS-CoV-2, COVID-19, risk of death, General Medicine, Middle Aged, co-morbidities, symptoms, treatments, MESH: Male, Hospitalization, Intensive Care Units, MESH: Intensive Care Units, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19/therapy
Abstract

Background We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. Methods The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death.

Published
2023

108. Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open- label, randomised, controlled adaptive platform trial

Author

Viravarn Luvira, William HK Schilling, Podjanee Jittamala, James A Watson, Simon Boyd, Tanaya Siripoon, Thundon Ngamprasertchai, Pedro J Almeida, Maneerat Ekkapongpisit, Cintia Cruz, James J Callery, Shivani Singh, Runch Tuntipaiboontana, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Srisuda Keayarsa, Wanassanan Madmanee, Renato S Aguiar, Franciele M Santos, Pongtorn Hanboonkunupakarn, Borimas Hanboonkunupakarn, Kittiyod Poovorawan, Mallika Imwong, Walter RJ Taylor, Vasin Chotivanich, Kesinee Chotivanich, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas PJ Day, Mauro M Teixeira, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, and Nicholas J White

Abstract

Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome assessed in a modified intention-to-treat population (mITT) was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial is registered at ClinicalTrials.gov (NCT05041907). Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients administered favipiravir and patients receiving no study drug -1% (95% CI: -14 to 14% change). High dose favipiravir was well tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19.

Published
2023

109. Expanding the role of village malaria workers in Cambodia: implementation and evaluation of four health education packages

Author

Mipharny Betrian, Dafne Umans, Moul Vanna, Sam Ol, Bipin Adhikari, Chan Davoeung, James J Callery, Yok Sovann, Thomas J Peto, Richard J Maude, Rob W van der Pluijm, Voeunrung Bunreth, Martin P. Grobusch, Michèle van Vugt, Yoel Lubell, Lorenz von Seidlein, Arjen M Dondorp, Siv Sovannaroth, Dysoley Lek, and Rupam Tripura

Abstract

BackgroundEarly access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant.MethodsDuring 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis.ResultsVMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities.ConclusionsThe transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs.

Published
2023

110. Falciparum malaria mortality in sub-Saharan Africa in the pretreatment era

Author

Arjen M. Dondorp, Nicholas J. White, James A Watson, and Intensive Care Medicine

Subjects
Sub saharan, Plasmodium falciparum, Balancing selection, Sickle Cell Trait, law.invention, sickle cell, law, parasitic diseases, medicine, Humans, Malaria, Falciparum, hemoglobin S, Child, Allele frequency, Africa South of the Sahara, Hemoglobin s, biology, malaria-attributable mortality, biology.organism_classification, medicine.disease, Malaria, Infectious Diseases, Transmission (mechanics), falciparum malaria, Parasitology, Demography
Abstract

Driven by the malaria-protective effect of sickle-cell trait, balancing selection results in hemoglobin S equilibrium allele frequencies of between 15% and 20% in areas of high Plasmodium falciparum transmission in sub-Saharan Africa. From this we estimate that the malaria-attributable childhood mortality in the pretreatment era was between 15% and 24%.

Published
2022

111. Author response: Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV)

Author

Podjanee Jittamala, William HK Schilling, James A Watson, Maneerat Ekkapongpisit, Tanaya Siripoon, Thundon Ngamprasertchai, Viravarn Luvira, Sasithorn Pongwilai, Cintia Cruz, James J Callery, Simon Boyd, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Nattaporn Piaraksa, Kanokon Suwannasin, Pongtorn Hanboonkunupakarn, Borimas Hanboonkunupakarn, Sakol Sookprome, Kittiyod Poovorawan, Janjira Thaipadungpanit, Stuart Blacksell, Mallika Imwong, Joel Tarning, Walter RJ Taylor, Vasin Chotivanich, Chunlanee Sangketchon, Wiroj Ruksakul, Kesinee Chotivanich, Mauro Martins Teixeira, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas PJ Day, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, and Nicholas J White

Published
2023

112. Effectiveness of community engagement among forest goers in a malaria prophylaxis trial: Implementation challenges and implications

Author

Franca Conradis-Jansen, Rupam Tripura, Thomas J Peto, James J Callery, Bipin Adhikari, Mom Eam, Monnaphat Jongdeepaisal, Christopher Pell, Panarasri Khonputsa, Riccardo Murgia, Siv Sovannaroth, Olaf Müller, Phaik Yeong Cheah, Arjen M Dondorp, Lorenz von Seidlein, and Richard James Maude

Abstract

Background: Malaria transmission in Southeast Asia is increasingly confined to forests, where marginalized groups are exposed primarily through their work. Antimalarial chemoprophylaxis may help to protect these people. This article examines the effectiveness and practical challenges of engaging forest-goers to participate in a randomized controlled clinical trial of antimalarial chemoprophylaxis. Methods: The effectiveness of engagement was assessed in terms of the proportion of people who participated during each stage of the trial: enrolment, compliance with trial procedures, and drug intake. During the trial, staff recorded the details of engagement meetings, including the views and opinions of participants and community representatives, the decision-making processes, and the challenges addressed during implementation. Results:In total, 1,613 participants were assessed for eligibility and 1480 (92%) joined the trial, 1,242 (84%) completed the trial and received prophylaxis (AL: 82% vs MV: 86%, p=0.08); 157 (11%) were lost to follow-up (AL: 11% vs MV: 11%, p=0.79); and 73 (5%) discontinued the drug (AL-7% vs MV-3%, p=0.005). The AL arm was associated with discontinuation of the study drug (AL: 48/738, 7% vs 25/742, 3%; p=0.01). Females (31/345, 9%) were more likely (42/1135, 4%) to discontinue taking drugs at some point in the trial (p= 0.005). Those (45/644, 7%) who had no previous history of malaria infection were more likely to discontinue the study drug than those (28/836, 3%) who had a history of malaria (p= 0.02). Engagement with the trial population was demanding because many types of forest work are illegal; and the involvement of an engagement team consisting of representatives from the local administration, health authorities, community leaders and community health workers played a significant role in building trust. Responsiveness to the needs and concerns of the community promoted acceptability and increased confidence in taking prophylaxis among participants. Recruitment of forest-goer volunteers to peer-supervise drug administration resulted in high compliance with drug intake. The development of locally-appropriate tools and messaging for the different linguistic and low-literacy groups was useful to ensure participants understood and adhered to the trial procedures. It was important to consider forest-goers` habits and social characteristics when planning the various trial activities. Conclusions: The comprehensive, participatory engagement strategy mobilized a wide range of stakeholders including study participants, helped build trust, and overcame potential ethical and practical challenges. This locally-adapted approach was highly effective as evidenced by high levels of trial enrolment, compliance with trial procedures and drug intake.

Published
2023

113. Short tandem repeat polymorphism in the promoter region of cyclophilin 19B drives its transcriptional upregulation and contributes to drug resistance in the malaria parasite Plasmodium falciparum

Author

Michal Kucharski, Grennady Wirjanata, Sourav Nayak, Josephine Boentoro, Jerzy Michal Dziekan, Christina Assisi, Rob W. van der Pluijm, Olivo Miotto, Sachel Mok, Arjen M. Dondorp, Zbynek Bozdech, AII - Infectious diseases, Graduate School, Infectious diseases, and School of Biological Sciences

Subjects
Plasmodium Falciparum, Antiparasitic Agent, Virology, Immunology, Genetics, Biological sciences [Science], Parasitology, Molecular Biology, Microbiology
Abstract

Resistance of the human malaria parasites, Plasmodium falciparum, to artemisinins is now fully established in Southeast Asia and is gradually emerging in Sub-Saharan Africa. Although nonsynonymous SNPs in the pfk13 Kelch-repeat propeller (KREP) domain are clearly associated with artemisinin resistance, their functional relevance requires cooperation with other genetic factors/alterations of the P. falciparum genome, collectively referred to as genetic background. Here we provide experimental evidence that P. falciparum cyclophilin 19B (PfCYP19B) may represent one putative factor in this genetic background, contributing to artemisinin resistance via its increased expression. We show that overexpression of PfCYP19B in vitro drives limited but significant resistance to not only artemisinin but also piperaquine, an important partner drug in artemisinin-based combination therapies. We showed that PfCYP19B acts as a negative regulator of the integrated stress response (ISR) pathway by modulating levels of phosphorylated eIF2α (eIF2α-P). Curiously, artemisinin and piperaquine affect eIF2α-P in an inverse direction that in both cases can be modulated by PfCYP19B towards resistance. Here we also provide evidence that the upregulation of PfCYP19B in the drug-resistant parasites appears to be maintained by a short tandem repeat (SRT) sequence polymorphism in the gene's promoter region. These results support a model that artemisinin (and other drugs) resistance mechanisms are complex genetic traits being contributed to by altered expression of multiple genes driven by genetic polymorphism at their promoter regions. Ministry of Education (MOE) National Medical Research Council (NMRC) Published version This study was supported by Singapore Ministry of Education (grant # MOE2019-T3-1- 007) and Singapore National Medical Research Council (grant # OFIRG21nov-0014) to ZB.

Published
2023

115. A framework for stakeholder engagement in the adoption of new antimalarial treatments in Africa: a case study of Nigeria

Author

Olugbenga Ayodeji Mokuolu, Oladimeji Akeem Bolarinwa, Oluwatumobi Racheal Opadiran, Hafsat Abolore Ameen, Mehul Dhorda, Phaik Yeong Cheah, Chanaki Amaratunga, Freek Haan, Paulina Tindana, and Arjen M. Dondorp

Abstract

Introduction: Recent reports of artemisinin partial resistance from Rwanda and Uganda are worrisome and suggest a future policy change to adopt new antimalarials. We conducted a case study on the evolution, adoption, and implementation of new antimalarial treatment policies in Nigeria. The main objective is providing perspectives to enhance the future uptake of new antimalarials, with an emphasis on stakeholder engagement strategies. Methods This case study is based on an analysis of policy documents and stakeholders’ perspectives drawn from an empirical study conducted in Nigeria, 2019–2020. A mixed methods approach was adopted, including historical accounts, review of programme and policy documents, and qualitative in-depth interviews and focus group discussions. Themes for the framework were developed and applied to the case study. Results Based on policy documents reviewed, the adoption of artemisinin-based combination therapies (ACTs) in Nigeria was swift due to political will, funding and support from global developmental partners. However, implementation of ACTs was met with resistance from suppliers, distributors, prescribers, and end-users, attributed to market dynamics, costs and inadequate stakeholder engagement. Deployment of ACTs in Nigeria witnessed more developmental partner support, robust data generation, ACT case-management strengthening and evidence on antimalarial use in severe malaria and antenatal care management. We propose a framework for effective stakeholder engagement for future adoption of new antimalarials or antimalarial treatment strategies. The framework covers the pathway from generating evidence to making treatment accessible and affordable to end-users. It addresses who to engage with, the content of engagement and what strategies would support effective engagement with key stakeholders at different levels of the transition process. Conclusion Early and staged engagement of stakeholders from global bodies through regulatory authorities to end-users at the community level is critical to the successful adoption and uptake of new antimalarial treatment policies. A framework for these engagements has been proposed as a unique contribution to enhancing this process.

Published
2022

116. Ten-year persistence and evolution of Plasmodium falciparum antifolate and antisulfonamide resistance markers pfdhfr and pfdhps in three Asian countries

Author

Suttipat Srisutham, Wanassanan Madmanee, Jindarat Kouhathong, Kreepol Sutawong, Rupam Tripura, Thomas J. Peto, Rob W. van der Pluijm, James J. Callery, Lek Dysoley, Mayfong Mayxay, Paul N. Newton, Tiengkham Pongvongsa, Bouasy Hongvanthong, Nicholas P. J. Day, Nicholas J. White, Arjen M. Dondorp, Mallika Imwong, Intensive Care Medicine, and AII - Infectious diseases

Subjects
Multidisciplinary
Abstract

Background The amplification of GTP cyclohydrolase 1 (pfgch1) in Plasmodium falciparum has been linked to the upregulation of the pfdhfr and pfdhps genes associated with resistance to the antimalarial drug sulfadoxine-pyrimethamine. During the 1990s and 2000s, sulfadoxine-pyrimethamine was withdrawn from use as first-line treatment in southeast Asia due to clinical drug resistance. This study assessed the temporal and geographic changes in the prevalence of pfdhfr and pfdhps gene mutations and pfgch1 amplification a decade after sulfadoxine-pyrimethamine had no longer been widely used. Methods A total of 536 P. falciparum isolates collected from clinical trials in Thailand, Cambodia, and Lao PDR between 2008 and 2018 were assayed. Single nucleotide polymorphisms of the pfdhfr and pfdhps genes were analyzed using nested PCR and Sanger sequencing. Gene copy number variations of pfgch1 were investigated using real-time polymerase chain reaction assay. Results Sequences of the pfdhfr and pfdhps genes were obtained from 96% (517/536) and 91% (486/536) of the samples, respectively. There were 59 distinct haplotypes, including single to octuple mutations. The two major haplotypes observed included IRNI-AGEAA (25%) and IRNL-SGKGA (19%). The sextuple mutation IRNL-SGKGA increased markedly over time in several study sites, including Pailin, Preah Vihear, Ratanakiri, and Ubon Ratchathani, whereas IRNI-AGEAA decreased over time in Preah Vihear, Champasak, and Ubon Ratchathani. Octuple mutations were first observed in west Cambodia in 2011 and subsequently in northeast Cambodia, as well as in southern Laos by 2018. Amplification of the pfgch1 gene increased over time across the region, particularly in northeast Thailand close to the border with Laos and Cambodia. Conclusion Despite the fact that SP therapy was discontinued in Thailand, Cambodia, and Laos decades ago, parasites retained the pfdhfr and pfdhps mutations. Numerous haplotypes were found to be prevalent among the parasites. Frequent monitoring of pfdhfr and pfdhps in these areas is required due to the relatively rapid evolution of mutation patterns.

Published
2022

117. Cooperation in Countering Artemisinin Resistance in Africa

Author

Philip J. Rosenthal, Anders Björkman, Mehul Dhorda, Abdoulaye Djimde, Arjen M. Dondorp, Oumar Gaye, Philippe J. Guerin, Elizabeth Juma, Dominic P. Kwiatkowski, Laura Merson, Francine Ntoumi, Ric N. Price, Jaishree Raman, David S. Roos, Feiko ter Kuile, Halidou Tinto, Sheena S. Tomko, Nicholas J. White, and Karen I. Barnes

Subjects
wa_30, Infectious Diseases, Virology, qx_600, wc_506, Parasitology, wa_20_5
Published
2022

118. Plasma Plasmodium falciparum Histidine-rich Protein 2 Concentrations in Children With Malaria Infections of Differing Severity in Kilifi, Kenya

Author

Gideon Nyutu, Jesse C Rop, Perpetual Wanjiku, Johnstone Makale, Alexander Macharia, Kennedy A Awuondo, Sophie Uyoga, Arjen M. Dondorp, Charles J. Woodrow, Kathryn Maitland, Mohammed Shebe, Neema Mturi, Thomas N. Williams, Wellcome Trust, and Intensive Care Medicine

Subjects
Microbiology (medical), medicine.medical_specialty, Vector-Borne Diseases Collection, Plasmodium falciparum, Protozoan Proteins, malaria, Antigens, Protozoan, Parasitemia, Asymptomatic, Gastroenterology, Parasite load, Microbiology, Parasite Load, PfHRP2, Internal medicine, parasite biomass, parasitic diseases, medicine, Humans, Malaria, Falciparum, Child, Online Only Articles, 11 Medical and Health Sciences, biology, business.industry, sequestration, 06 Biological Sciences, medicine.disease, biology.organism_classification, Kenya, Confidence interval, Plasmodium falciparum histidine-rich protein-2, AcademicSubjects/MED00290, Infectious Diseases, Concomitant, Asymptomatic malaria, medicine.symptom, business, Malaria
Abstract

Background Most previous studies support a direct link between total parasite load and the clinical severity of Plasmodium falciparum malaria infections. Methods We estimated P. falciparum parasite loads in 3 groups of children with malaria infections of differing severity: (1) children with World Health Organization–defined severe malaria (n = 1544), (2) children admitted with malaria but without features of severity (n = 200), and (3) children in the community with asymptomatic parasitemia (n = 33). Results Peripheral parasitemias were highest in those with uncomplicated malaria (geometric mean [GM] parasite count, 111 064/μL; 95% confidence interval, CI, 86 798–141 819/μL), almost 3 times higher than in those with severe malaria (39 588/μL; 34 990–44 791/μL) and >100 times higher than in those with asymptomatic malaria (1092/μL; 523–2280/μL). However, the GM P. falciparum histidine-rich protein 2 (PfHRP2) values (95% CI) increased with severity, being 7 (4–12) ng/mL in asymptomatic malaria, 843 (655–1084) ng/mL in uncomplicated malaria, and 1369 (1244–1506) ng/mL in severe malaria. PfHRP2 concentrations were markedly lower in the subgroup of patients with severe malaria and concomitant invasive bacterial infections of blood or cerebrospinal fluid (GM concentration, 312 ng/mL; 95% CI, 175–557 ng/mL; P < .001) than in those without such infections (1439 ng/mL; 1307–1584; P < .001). Conclusions The clinical severity of malaria infections related strongly to the total burden of P. falciparum parasites. A quantitative test for plasma concentrations of PfHRP2 could be useful in identifying children at the greatest clinical risk and identifying critically ill children in whom malaria is not the primary cause., Through a clinical surveillance study, we show that plasma levels of Plasmodium falciparum histidine-rich protein 2, a marker of total body parasite load, are strongly correlated with the severity of P. falciparum infections among children in Kilifi, Kenya.

Published
2021

119. Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-2 Delta and Omicron variants

Author

Podjanee Jittamala, William HK Schilling, James A Watson, Viravarn Luvira, Tanaya Siripoon, Thundon Ngamprasertchai, Pedro J Almeida, Maneerat Ekkapongpisit, Cintia Cruz, James J Callery, Simon Boyd, Orawan Anunsittichai, Maliwan Hongsuwan, Yutatirat Singhaboot, Watcharee Pagornrat, Runch Tuntipaiboontana, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Srisuda Keayarsa, Wanassanan Madmanee, Renato S Aguiar, Franciele M Santos, Elizabeth M Batty, Pongtorn Hanboonkunupakarn, Borimas Hanboonkunupakarn, Sakol Sookprome, Kittiyod Poovorawan, Mallika Imwong, Walter RJ Taylor, Vasin Chotivanich, Chunlanee Sangketchon, Wiroj Ruksakul, Kesinee Chotivanich, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas PJ Day, Mauro M Teixeira, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, and Nicholas J White

Abstract

BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absentin vitroactivity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended.MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered atClinicalTrials.gov(NCT05041907).ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In apost hocsubgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: −21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants.ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reducedin vitroactivities, casirivimab/imdevimab retainsin vivoantiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants.Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.

Published
2022

120. A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa

Author

Anita Ghansah, Kevin Wamae, Jaishree Raman, Deus S. Ishengoma, Ben Andagalu, Nancy O Duah-Quashie, Stephen Tukwasibwe, Lynette Isabella Ochola-Oyier, Leonard Ndwiga, Arjen M. Dondorp, Kelvin M. Kimenyi, Abdoulaye Djimde, Sofonias K. Tessema, Mercy Akinyi, Corine Karema, Philip Bejon, Victor Osoti, Irene Omedo, Alfred Amambua-Ngwa, and Robert W. Snow

Subjects
0301 basic medicine, Plasmodium falciparum, 030231 tropical medicine, Drug Resistance, Protozoan Proteins, Infectious and parasitic diseases, RC109-216, Molecular marker, Pfk13, medicine.disease_cause, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, parasitic diseases, medicine, Humans, Pharmacology (medical), South east asia, Malaria, Falciparum, Artemisinin, Pharmacology, Mutation, biology, Artemisinin resistance, biology.organism_classification, medicine.disease, Virology, ACT, Artemisinins, Special issue articles on 'Drug Resistance - Mechanisms, Surveillance and Parasite Populations', 030104 developmental biology, Infectious Diseases, Tanzania, chemistry, Africa, Parasitology, Malaria, medicine.drug
Abstract

Artemisinin resistance (AR) emerged in South East Asia 13 years ago and the identification of the resistance conferring molecular marker, Plasmodium falciparum Kelch 13 (Pfk13), 7 years ago has provided an invaluable tool for monitoring AR in malaria endemic countries. Molecular Pfk13 surveillance revealed the resistance foci in the Greater Mekong Subregion, an independent emergence in Guyana, South America, and a low frequency of mutations in Africa. The recent identification of the R561H Pfk13 AR associated mutation in Tanzania, Uganda and in Rwanda, where it has been associated with delayed parasite clearance, should be a concern for the continent. In this review, we provide a summary of Pfk13 resistance associated propeller domain mutation frequencies across Africa from 2012 to 2020, to examine how many other countries have identified these mutations. Only four African countries reported a recent identification of the M476I, P553L, R561H, P574L, C580Y and A675V Pfk13 mutations at low frequencies and with no reports of clinical treatment failure, except for Rwanda. These mutations present a threat to malaria control across the continent, since the greatest burden of malaria remains in Africa. A rise in the frequency of these mutations and their spread would reverse the gains made in the reduction of malaria over the last 20 years, given the lack of new antimalarial treatments in the event artemisinin-based combination therapies fail. The review highlights the frequency of Pfk13 propeller domain mutations across Africa, providing an up-to-date perspective of Pfk13 mutations, and appeals for an urgent and concerted effort to monitoring antimalarial resistance markers in Africa and the efficacy of antimalarials by re-establishing sentinel surveillance systems., Graphical abstract Image 1, Highlights • Indigenous Pfk13 resistance associated mutations have been identified in Africa • Currently, only 4 African countries have reported 6 (M476I, P553L, R561H, P574L, C580Y and A675V) of the 10 validated artemisinin resistance associated mutations • The 6 mutations though identified at low frequencies are an early warning signal for Africa, since a rise in frequency and their spread to other countries could be catastrophic for malaria control • Africa needs a concerted and systematic approach to monitoring Pfk13 mutations (beyond the few research studies published across Africa) and antimalarial efficacy through a re-establishment of sentinel surveillance platforms

Published
2021

121. Artemisinin and multidrug-resistant Plasmodium falciparum – a threat for malaria control and elimination

Author

Mehul Dhorda, Arjen M. Dondorp, and Chanaki Amaratunga

Subjects
Microbiology (medical), medicine.medical_specialty, Plasmodium. falciparum, Plasmodium falciparum, Drug Resistance, Drug resistance, resistance, Antimalarials, Malaria elimination, parasitic diseases, Humans, Medicine, Malaria, Falciparum, Artemisinin, Intensive care medicine, treatment, biology, business.industry, Artemisinin resistance, biology.organism_classification, medicine.disease, Artemisinins, Multiple drug resistance, Infectious Diseases, artemisinin, Mutation, TROPICAL AND TRAVEL-ASSOCIATED DISEASES: Edited by Christina M. Coyle, epidemiology, business, Malaria control, Malaria, medicine.drug
Abstract

Purpose of review Artemisinin-based combination therapies (ACTs) are globally the first-line treatment for uncomplicated falciparum malaria and new compounds will not be available within the next few years. Artemisinin-resistant Plasmodium falciparum emerged over a decade ago in the Greater Mekong Subregion (GMS) and, compounded by ACT partner drug resistance, has caused significant ACT treatment failure. This review provides an update on the epidemiology, and mechanisms of artemisinin resistance and approaches to counter multidrug-resistant falciparum malaria. Recent findings An aggressive malaria elimination programme in the GMS has helped prevent the spread of drug resistance to neighbouring countries. However, parasites carrying artemisinin resistance-associated mutations in the P. falciparum Kelch13 gene (pfk13) have now emerged independently in multiple locations elsewhere in Asia, Africa and South America. Notably, artemisinin-resistant infections with parasites carrying the pfk13 R561H mutation have emerged and spread in Rwanda. Summary Enhancing the geographic coverage of surveillance for resistance will be key to ensure prompt detection of emerging resistance in order to implement effective countermeasures without delay. Treatment strategies designed to prevent the emergence and spread of multidrug resistance must be considered, including deployment of triple drug combination therapies and multiple first-line therapies.

Published
2021

122. Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial

Author

Mavuto Mukaka, Stije Stije Leopold, Arjen M. Dondorp, Grace Wezi Mzumara, Eric O Ohuma, and Kevin Marsh

Subjects
Male, RC955-962, Infectious and parasitic diseases, RC109-216, Logistic regression, Ghana, Tanzania, 0302 clinical medicine, Arctic medicine. Tropical medicine, Medicine, Uganda, 030212 general & internal medicine, Malaria, Falciparum, Child, Mozambique, Acidosis, Respiratory distress, Metabolic acidosis, Acute kidney injury, Prognosis, Infectious Diseases, Child, Preschool, Democratic Republic of the Congo, Female, Gambia, medicine.symptom, medicine.medical_specialty, 030231 tropical medicine, Plasmodium falciparum, Nigeria, 03 medical and health sciences, Severe malaria, Internal medicine, Humans, Africa South of the Sahara, Retrospective Studies, Uremia, Coma, business.industry, Research, Rwanda, Infant, Retrospective cohort study, medicine.disease, Kenya, Africa, Parasitology, business
Abstract

Background Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. Methods A retrospective analysis of the ‘Artesunate versus quinine in the treatment of severe falciparum malaria in African children’ (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. Results There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51–6.2), hypoglycaemia (OR: 5.16, CI 2.74–9.75), coma (OR: 1.72 CI 1.17–2.51), respiratory distress (OR: 1.46, CI 1.02–2.1) and prostration (OR: 1.88 CI 1.35–2.59). Features associated with uraemia were coma (3.18, CI 2.36–4.27), Prostration (OR: 1.78 CI 1.37–2.30), decompensated shock (OR: 1.89, CI 1.31–2.74), black water fever (CI 1.58. CI 1.09–2.27), jaundice (OR: 3.46 CI 2.21–5.43), severe anaemia (OR: 1.77, CI 1.36–2.29) and hypoglycaemia (OR: 2.77, CI 2.22–3.46) Conclusion Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

Published
2021

123. Genetic analysis of a malaria outbreak in Laos driven by a selective sweep for Plasmodium falciparum kelch13 R539T mutants

Author

Varanya Wasakul, Areeya Disratthakit, Mayfong Mayxay, Keobouphaphone Chindavongsa, Viengphone Sengsavath, Nguyen Thuy-Nhien, Richard D Pearson, Sonexay Phalivong, Saiamphone Xayvanghang, Sonia Gonçalves, Nicholas P Day, Paul N Newton, Elizabeth A Ashley, Dominic P Kwiatkowski, Arjen M Dondorp, and Olivo Miotto

Abstract

Malaria outbreaks are an important public health concern in endemic regions approaching elimination. Genetic surveillance of malaria parasites can elucidate the population dynamics of an outbreak, and help identify its causes. We investigated the epidemiology of a Plasmodium falciparum outbreak in Attapeu Province, Laos, during the 2020-2021 season. An analysis of 249 samples, collected by routine genetic surveillance during the outbreak, revealed a massive loss of genetic diversity in the parasite population, primarily caused by the rapid expansion of a multidrug resistant strain, named LAA1. This strain carried the kelch13 R539T mutation and expanded clonally, replacing the previously dominant kelch13 C580Y mutants (KEL1/PLA1) resistant to dihydroartemisinin-piperaquine. Identity by descent (IBD) patterns showed that LAA1 was a recombinant that inherited 60% of its genome from a strain first sampled in Cambodia over a decade ago. A less common outbreak strain (LAA2) carried the kelch13 C580Y allele, but was distinct from KEL1/PLA1, its genome essentially identical to that of a Cambodian parasite from 2009. A third, low-frequency strain (LAA7) was a recombinant of KEL1/PLA1 with a R539T mutant, the latter providing the kelch13 variant. These results strongly suggest that the outbreak was driven by a selective sweep, possibly associated with drug-resistant phenotypes of the outbreak strains. The observation that new variants of established multidrug resistant populations can overwhelm previously dominant strains so rapidly has implications for elimination of malaria. Genetic surveillance provides the tools for characterizing outbreaks, and for monitoring the evolution and spread of the populations involved.

Published
2022

124. Author response for 'Symptom‐based case definitions for COVID‐19: Time and geographical variations for detection at hospital admission among 260,000 patients'

Author

null Joaquin Baruch, null Amanda Rojek, null Christiana Kartsonaki, null Bharath K. T. Vijayaraghavan, null Bronner P. Gonçalves, null Mark G. Pritchard, null Laura Merson, null Jake Dunning, null Matthew Hall, null Louise Sigfrid, null Barbara W. Citarella, null Srinivas Murthy, null Trokon O. Yeabah, null Piero Olliaro, null Ali Abbas, null Sheryl Ann Abdukahil, null Nurul Najmee Abdulkadir, null Ryuzo Abe, null Laurent Abel, null Lara Absil, null Subhash Acharya, null Andrew Acker, null Elisabeth Adam, null Diana Adrião, null Saleh Al Ageel, null Shakeel Ahmed, null Kate Ainscough, null Eka Airlangga, null Tharwat Aisa, null Ali Ait Hssain, null Younes Ait Tamlihat, null Takako Akimoto, null Ernita Akmal, null Eman Al Qasim, null Razi Alalqam, null Angela Alberti, null Tala Al‐dabbous, null Senthilkumar Alegesan, null Cynthia Alegre, null Marta Alessi, null Beatrice Alex, null Kévin Alexandre, null Abdulrahman Al‐Fares, null Huda Alfoudri, null Imran Ali, null Adam Ali, null Naseem Ali Shah, null Kazali Enagnon Alidjnou, null Jeffrey Aliudin, null Qabas Alkhafajee, null Clotilde Allavena, null Nathalie Allou, null Aneela Altaf, null João Alves, null Rita Alves, null João Melo Alves, null Maria Amaral, null Nur Amira, null Phoebe Ampaw, null Roberto Andini, null Claire Andréjak, null Andrea Angheben, null François Angoulvant, null Séverine Ansart, null Sivanesen Anthonidass, null Massimo Antonelli, null Carlos Alexandre Antunes de Brito, null Ardiyan Apriyana, null Yaseen Arabi, null Irene Aragao, null Carolline Araujo, null Antonio Arcadipane, null Patrick Archambault, null Lukas Arenz, null Jean‐Benoît Arlet, null Lovkesh Arora, null Rakesh Arora, null Elise Artaud‐Macari, null Diptesh Aryal, null Angel Asensio, null Muhammad Ashraf, null Namra Asif, null Mohammad Asim, null Jean Baptiste Assie, null Amirul Asyraf, null Anika Atique, null A. M. Udara Lakshan Attanyake, null Johann Auchabie, null Hugues Aumaitre, null Adrien Auvet, null Eyvind W. Axelsen, null Laurène Azemar, null Cecile Azoulay, null Benjamin Bach, null Delphine Bachelet, null Claudine Badr, null Roar Bævre‐Jensen, null Nadia Baig, null J. Kenneth Baillie, null J. Kevin Baird, null Erica Bak, null Agamemnon Bakakos, null Nazreen Abu Bakar, null Andriy Bal, null Mohanaprasanth Balakrishnan, null Valeria Balan, null Firouzé Bani‐Sadr, null Renata Barbalho, null Nicholas Yuri Barbosa, null Wendy S. Barclay, null Saef Umar Barnett, null Michaela Barnikel, null Helena Barrasa, null Audrey Barrelet, null Cleide Barrigoto, null Marie Bartoli, null Joaquín Baruch, null Mustehan Bashir, null Romain Basmaci, null Muhammad Fadhli Hassin Basri, null Denise Battaglini, null Jules Bauer, null Diego Fernando Bautista Rincon, null Denisse Bazan Dow, null Abigail Beane, null Alexandra Bedossa, null Ker Hong Bee, null Husna Begum, null Sylvie Behilill, null Albertus Beishuizen, null Aleksandr Beljantsev, null David Bellemare, null Anna Beltrame, null Beatriz Amorim Beltrão, null Marine Beluze, null Nicolas Benech, null Lionel Eric Benjiman, null Dehbia Benkerrou, null Suzanne Bennett, null Luís Bento, null Jan‐Erik Berdal, null Delphine Bergeaud, null Hazel Bergin, null José Luis Bernal Sobrino, null Giulia Bertoli, null Lorenzo Bertolino, null Simon Bessis, null Sybille Bevilcaqua, null Karine Bezulier, null Amar Bhatt, null Krishna Bhavsar, null Claudia Bianco, null Farah Nadiah Bidin, null Moirangthem Bikram Singh, null Felwa Bin Humaid, null Mohd Nazlin Bin Kamarudin, null François Bissuel, null Laurent Bitker, null Jonathan Bitton, null Pablo Blanco‐Schweizer, null Catherine Blier, null Frank Bloos, null Mathieu Blot, null Filomena Boccia, null Laetitia Bodenes, null Alice Bogaarts, null Debby Bogaert, null Anne‐Hélène Boivin, null Pierre‐Adrien Bolze, null François Bompart, null Aurelius Bonfasius, null Diogo Borges, null Raphaël Borie, null Hans Martin Bosse, null Elisabeth Botelho‐Nevers, null Lila Bouadma, null Olivier Bouchaud, null Sabelline Bouchez, null Dounia Bouhmani, null Damien Bouhour, null Kévin Bouiller, null Laurence Bouillet, null Camile Bouisse, null Anne‐Sophie Boureau, null John Bourke, null Maude Bouscambert, null Aurore Bousquet, null Jason Bouziotis, null Bianca Boxma, null Marielle Boyer‐Besseyre, null Maria Boylan, null Fernando Augusto Bozza, null Axelle Braconnier, null Cynthia Braga, null Timo Brandenburger, null Filipa Brás Monteiro, null Luca Brazzi, null Patrick Breen, null Dorothy Breen, null Kathy Brickell, null Shaunagh Browne, null Alex Browne, null Nicolas Brozzi, null Sonja Hjellegjerde Brunvoll, null Marjolein Brusse‐Keizer, null Nina Buchtele, null Christian Buesaquillo, null Polina Bugaeva, null Marielle Buisson, null Danilo Buonsenso, null Erlina Burhan, null Aidan Burrell, null Ingrid G. Bustos, null Denis Butnaru, null André Cabie, null Susana Cabral, null Eder Caceres, null Cyril Cadoz, null Kate Calligy, null Jose Andres Calvache, null João Camões, null Valentine Campana, null Paul Campbell, null Josie Campisi, null Cecilia Canepa, null Mireia Cantero, null Pauline Caraux‐Paz, null Sheila Cárcel, null Chiara Simona Cardellino, null Sofia Cardoso, null Filipe Cardoso, null Filipa Cardoso, null Nelson Cardoso, null Simone Carelli, null Nicolas Carlier, null Thierry Carmoi, null Gayle Carney, null Inês Carqueja, null Marie‐Christine Carret, null François Martin Carrier, null Ida Carroll, null Gail Carson, null Maire‐Laure Casanova, null Mariana Cascão, null Siobhan Casey, null José Casimiro, null Bailey Cassandra, null Silvia Castañeda, null Nidyanara Castanheira, null Guylaine Castor‐Alexandre, null Henry Castrillón, null Ivo Castro, null Ana Catarino, null François‐Xavier Catherine, null Paolo Cattaneo, null Roberta Cavalin, null Giulio Giovanni Cavalli, null Alexandros Cavayas, null Adrian Ceccato, null Minerva Cervantes‐Gonzalez, null Anissa Chair, null Catherine Chakveatze, null Adrienne Chan, null Meera Chand, null Christelle Chantalat Auger, null Jean‐Marc Chapplain, null Julie Chas, null Allegra Chatterjee, null Mobin Chaudry, null Jonathan Samuel Chávez Iñiguez, null Anjellica Chen, null Yih‐Sharng Chen, null Matthew Pellan Cheng, null Antoine Cheret, null Thibault Chiarabini, null Julian Chica, null Suresh Kumar Chidambaram, null Leong Chin Tho, null Catherine Chirouze, null Davide Chiumello, null Sung‐Min Cho, null Bernard Cholley, null Marie‐Charlotte Chopin, null Ting Soo Chow, null Yock Ping Chow, null Jonathan Chua, null Hiu Jian Chua, null Jose Pedro Cidade, null José Miguel Cisneros Herreros, null Barbara Wanjiru Citarella, null Anna Ciullo, null Jennifer Clarke, null Emma Clarke, null Rolando Claure‐Del Granado, null Sara Clohisey, null Perren J. Cobb, null Cassidy Codan, null Caitriona Cody, null Alexandra Coelho, null Megan Coles, null Gwenhaël Colin, null Michael Collins, null Sebastiano Maria Colombo, null Pamela Combs, null Marie Connor, null Anne Conrad, null Sofía Contreras, null Elaine Conway, null Graham S. Cooke, null Mary Copland, null Hugues Cordel, null Amanda Corley, null Sabine Cornelis, null Alexander Daniel Cornet, null Arianne Joy Corpuz, null Andrea Cortegiani, null Grégory Corvaisier, null Emma Costigan, null Camille Couffignal, null Sandrine Couffin‐Cadiergues, null Roxane Courtois, null Stéphanie Cousse, null Rachel Cregan, null Sabine Croonen, null Gloria Crowl, null Jonathan Crump, null Claudina Cruz, null Juan Luis Cruz Bermúdez, null Jaime Cruz Rojo, null Marc Csete, null Ailbhe Cullen, null Matthew Cummings, null Gerard Curley, null Elodie Curlier, null Colleen Curran, null Paula Custodio, null Ana da Silva Filipe, null Charlene Da Silveira, null Al‐Awwab Dabaliz, null Andrew Dagens, null John Arne Dahl, null Darren Dahly, null Heidi Dalton, null Jo Dalton, null Seamus Daly, null Nick Daneman, null Corinne Daniel, null Emmanuelle A. Dankwa, null Jorge Dantas, null Frédérick D'Aragon, null Gillian de Loughry, null Diego de Mendoza, null Etienne De Montmollin, null Rafael Freitas de Oliveira França, null Ana Isabel de Pinho Oliveira, null Rosanna De Rosa, null Cristina De Rose, null Thushan de Silva, null Peter de Vries, null Jillian Deacon, null David Dean, null Alexa Debard, null Marie‐Pierre Debray, null Nathalie DeCastro, null William Dechert, null Lauren Deconninck, null Romain Decours, null Eve Defous, null Isabelle Delacroix, null Eric Delaveuve, null Karen Delavigne, null Nathalie M. Delfos, null Ionna Deligiannis, null Andrea Dell'Amore, null Christelle Delmas, null Pierre Delobel, null Corine Delsing, null Elisa Demonchy, null Emmanuelle Denis, null Dominique Deplanque, null Pieter Depuydt, null Mehul Desai, null Diane Descamps, null Mathilde Desvallées, null Santi Dewayanti, null Pathik Dhanger, null Alpha Diallo, null Sylvain Diamantis, null André Dias, null Juan Jose Diaz, null Priscila Diaz, null Rodrigo Diaz, null Kévin Didier, null Jean‐Luc Diehl, null Wim Dieperink, null Jérôme Dimet, null Vincent Dinot, null Fara Diop, null Alphonsine Diouf, null Yael Dishon, null Félix Djossou, null Annemarie B. Docherty, null Helen Doherty, null Arjen M. Dondorp, null Maria Donnelly, null Christl A. Donnelly, null Sean Donohue, null Yoann Donohue, null Chloe Donohue, null Peter Doran, null Céline Dorival, null Eric D'Ortenzio, null James Joshua Douglas, null Renee Douma, null Nathalie Dournon, null Triona Downer, null Joanne Downey, null Mark Downing, null Tom Drake, null Aoife Driscoll, null Murray Dryden, null Claudio Duarte Fonseca, null Vincent Dubee, null François Dubos, null Alexandre Ducancelle, null Toni Duculan, null Susanne Dudman, null Abhijit Duggal, null Paul Dunand, null Mathilde Duplaix, null Emanuele Durante‐Mangoni, null Lucian Durham, null Bertrand Dussol, null Juliette Duthoit, null Xavier Duval, null Anne Margarita Dyrhol‐Riise, null Sim Choon Ean, null Marco Echeverria‐Villalobos, null Siobhan Egan, null Linn Margrete Eggesbø, null Carla Eira, null Mohammed El Sanharawi, null Subbarao Elapavaluru, null Brigitte Elharrar, null Jacobien Ellerbroek, null Merete Ellingjord‐Dale, null Philippine Eloy, null Tarek Elshazly, null Iqbal Elyazar, null Isabelle Enderle, null Tomoyuki Endo, null Chan Chee Eng, null Ilka Engelmann, null Vincent Enouf, null Olivier Epaulard, null Martina Escher, null Mariano Esperatti, null Hélène Esperou, null Marina Esposito‐Farese, null João Estevão, null Manuel Etienne, null Nadia Ettalhaoui, null Anna Greti Everding, null Mirjam Evers, null Marc Fabre, null Isabelle Fabre, null Amna Faheem, null Arabella Fahy, null Cameron J. Fairfield, null Zul Fakar, null Komal Fareed, null Pedro Faria, null Ahmed Farooq, null Hanan Fateena, null Arie Zainul Fatoni, null Karine Faure, null Raphaël Favory, null Mohamed Fayed, null Niamh Feely, null Laura Feeney, null Jorge Fernandes, null Marília Andreia Fernandes, null Susana Fernandes, null François‐Xavier Ferrand, null Eglantine Ferrand Devouge, null Joana Ferrão, null Mário Ferraz, null Sílvia Ferreira, null Isabel Ferreira, null Benigno Ferreira, null Ricard Ferrer‐Roca, null Nicolas Ferriere, null Céline Ficko, null Claudia Figueiredo‐Mello, null William Finlayson, null Juan Fiorda, null Thomas Flament, null Clara Flateau, null Tom Fletcher, null Letizia Lucia Florio, null Deirdre Flynn, null Claire Foley, null Jean Foley, null Victor Fomin, null Tatiana Fonseca, null Patricia Fontela, null Simon Forsyth, null Denise Foster, null Giuseppe Foti, null Erwan Fourn, null Robert A. Fowler, null Marianne Fraher, null Diego Franch‐Llasat, null John F. Fraser, null Christophe Fraser, null Marcela Vieira Freire, null Ana Freitas Ribeiro, null Caren Friedrich, null Stéphanie Fry, null Nora Fuentes, null Masahiro Fukuda, null G. Argin, null Valérie Gaborieau, null Rostane Gaci, null Massimo Gagliardi, null Jean‐Charles Gagnard, null Amandine Gagneux‐Brunon, null Sérgio Gaião, null Linda Gail Skeie, null Phil Gallagher, null Carrol Gamble, null Yasmin Gani, null Arthur Garan, null Rebekha Garcia, null Noelia García Barrio, null Julia Garcia‐Diaz, null Esteban Garcia‐Gallo, null Navya Garimella, null Denis Garot, null Valérie Garrait, null Basanta Gauli, null Nathalie Gault, null Aisling Gavin, null Anatoliy Gavrylov, null Alexandre Gaymard, null Johannes Gebauer, null Eva Geraud, null Louis Gerbaud Morlaes, null Nuno Germano, null Praveen Kumar Ghisulal, null Jade Ghosn, null Marco Giani, null Jess Gibson, null Tristan Gigante, null Morgane Gilg, null Elaine Gilroy, null Guillermo Giordano, null Michelle Girvan, null Valérie Gissot, null Daniel Glikman, null Petr Glybochko, null Eric Gnall, null Geraldine Goco, null François Goehringer, null Siri Goepel, null Jean‐Christophe Goffard, null Jin Yi Goh, null Jonathan Golob, null Kyle Gomez, null Joan Gómez‐Junyent, null Marie Gominet, null Alicia Gonzalez, null Patricia Gordon, null Isabelle Gorenne, null Laure Goubert, null Cécile Goujard, null Tiphaine Goulenok, null Margarite Grable, null Jeronimo Graf, null Edward Wilson Grandin, null Pascal Granier, null Giacomo Grasselli, null Christopher A. Green, null Courtney Greene, null William Greenhalf, null Segolène Greffe, null Domenico Luca Grieco, null Matthew Griffee, null Fiona Griffiths, null Ioana Grigoras, null Albert Groenendijk, null Anja Grosse Lordemann, null Heidi Gruner, null Yusing Gu, null Jérémie Guedj, null Martin Guego, null Dewi Guellec, null Anne‐Marie Guerguerian, null Daniela Guerreiro, null Romain Guery, null Anne Guillaumot, null Laurent Guilleminault, null Maisa Guimarães de Castro, null Thomas Guimard, null Marieke Haalboom, null Daniel Haber, null Hannah Habraken, null Ali Hachemi, null Amy Hackmann, null Nadir Hadri, null Fakhir Haidri, null Sheeba Hakak, null Adam Hall, null Sophie Halpin, null Jawad Hameed, null Ansley Hamer, null Raph L. Hamers, null Rebecca Hamidfar, null Bato Hammarström, null Terese Hammond, null Lim Yuen Han, null Rashan Haniffa, null Kok Wei Hao, null Hayley Hardwick, null Ewen M. Harrison, null Janet Harrison, null Samuel Bernard Ekow Harrison, null Alan Hartman, null Mohd Shahnaz Hasan, null Junaid Hashmi, null Muhammad Hayat, null Ailbhe Hayes, null Leanne Hays, null Jan Heerman, null Lars Heggelund, null Ross Hendry, null Martina Hennessy, null Aquiles Henriquez‐Trujillo, null Maxime Hentzien, null Jaime Hernandez‐Montfort, null Andrew Hershey, null Liv Hesstvedt, null Astarini Hidayah, null Eibhilin Higgins, null Dawn Higgins, null Rupert Higgins, null Rita Hinchion, null Samuel Hinton, null Hiroaki Hiraiwa, null Haider Hirkani, null Hikombo Hitoto, null Yi Bin Ho, null Antonia Ho, null Alexandre Hoctin, null Isabelle Hoffmann, null Wei Han Hoh, null Oscar Hoiting, null Rebecca Holt, null Jan Cato Holter, null Peter Horby, null Juan Pablo Horcajada, null Koji Hoshino, null Ikram Houas, null Catherine L. Hough, null Stuart Houltham, null Jimmy Ming‐Yang Hsu, null Jean‐Sébastien Hulot, null Stella Huo, null Abby Hurd, null Iqbal Hussain, null Samreen Ijaz, null Hajnal‐Gabriela Illes, null Patrick Imbert, null Mohammad Imran, null Rana Imran Sikander, null Aftab Imtiaz, null Hugo Inácio, null Carmen Infante Dominguez, null Yun Sii Ing, null Elias Iosifidis, null Mariachiara Ippolito, null Sarah Isgett, null Tiago Isidoro, null Nadiah Ismail, null Margaux Isnard, null Mette Stausland Istre, null Junji Itai, null Daniel Ivulich, null Danielle Jaafar, null Salma Jaafoura, null Julien Jabot, null Clare Jackson, null Nina Jamieson, null Pierre Jaquet, null Coline Jaud‐Fischer, null Stéphane Jaureguiberry, null Denise Jaworsky, null Florence Jego, null Anilawati Mat Jelani, null Synne Jenum, null Ruth Jimbo‐Sotomayor, null Ong Yiaw Joe, null Ruth N. Jorge García, null Silje Bakken Jørgensen, null Cédric Joseph, null Mark Joseph, null Swosti Joshi, null Mercé Jourdain, null Philippe Jouvet, null Hanna Jung, null Anna Jung, null Dafsah Juzar, null Ouifiya Kafif, null Florentia Kaguelidou, null Neerusha Kaisbain, null Thavamany Kaleesvran, null Sabina Kali, null Alina Kalicinska, null Karl Trygve Kalleberg, null Smaragdi Kalomoiri, null Muhammad Aisar Ayadi Kamaluddin, null Zul Amali Che Kamaruddin, null Nadiah Kamarudin, null Kavita Kamineni, null Darshana Hewa Kandamby, null Chris Kandel, null Kong Yeow Kang, null Darakhshan Kanwal, null Pratap Karpayah, null Daisuke Kasugai, null Anant Kataria, null Kevin Katz, null Aasmine Kaur, null Christy Kay, null Hannah Keane, null Seán Keating, null Pulak Kedia, null Claire Kelly, null Yvelynne Kelly, null Andrea Kelly, null Niamh Kelly, null Aoife Kelly, null Sadie Kelly, null Maeve Kelsey, null Ryan Kennedy, null Kalynn Kennon, null Maeve Kernan, null Younes Kerroumi, null Sharma Keshav, null Imrana Khalid, null Osama Khalid, null Antoine Khalil, null Coralie Khan, null Irfan Khan, null Quratul Ain Khan, null Sushil Khanal, null Abid Khatak, null Amin Khawaja, null Krish Kherajani, null Michelle E. Kho, null Ryan Khoo, null Denisa Khoo, null Saye Khoo, null Nasir Khoso, null Khor How Kiat, null Yuri Kida, null Peter Kiiza, null Beathe Kiland Granerud, null Anders Benjamin Kildal, null Jae Burm Kim, null Antoine Kimmoun, null Detlef Kindgen‐Milles, null Alexander King, null Nobuya Kitamura, null Eyrun Floerecke Kjetland Kjetland, null Paul Klenerman, null Rob Klont, null Gry Kloumann Bekken, null Stephen R. Knight, null Robin Kobbe, null Chamira Kodippily, null Malte Kohns Vasconcelos, null Sabin Koirala, null Mamoru Komatsu, null Caroline Kosgei, null Arsène Kpangon, null Karolina Krawczyk, null Vinothini Krishnan, null Sudhir Krishnan, null Oksana Kruglova, null Ganesh Kumar, null Deepali Kumar, null Mukesh Kumar, null Pavan Kumar Vecham, null Dinesh Kuriakose, null Ethan Kurtzman, null Demetrios Kutsogiannis, null Galyna Kutsyna, null Konstantinos Kyriakoulis, null Marie Lachatre, null Marie Lacoste, null John G. Laffey, null Marie Lagrange, null Fabrice Laine, null Olivier Lairez, null Sanjay Lakhey, null Antonio Lalueza, null Marc Lambert, null François Lamontagne, null Marie Langelot‐Richard, null Vincent Langlois, null Eka Yudha Lantang, null Marina Lanza, null Cédric Laouénan, null Samira Laribi, null Delphine Lariviere, null Stéphane Lasry, null Sakshi Lath, null Naveed Latif, null Odile Launay, null Didier Laureillard, null Yoan Lavie‐Badie, null Andy Law, null Teresa Lawrence, null Cassie Lawrence, null Minh Le, null Clément Le Bihan, null Cyril Le Bris, null Georges Le Falher, null Lucie Le Fevre, null Quentin Le Hingrat, null Marion Le Maréchal, null Soizic Le Mestre, null Gwenaël Le Moal, null Vincent Le Moing, null Hervé Le Nagard, null Paul Le Turnier, null Ema Leal, null Marta Leal Santos, null Heng Gee Lee, null Biing Horng Lee, null Yi Lin Lee, null Todd C. Lee, null James Lee, null Jennifer Lee, null Su Hwan Lee, null Gary Leeming, null Laurent Lefebvre, null Bénédicte Lefebvre, null Benjamin Lefèvre, null Sylvie LeGac, null Jean‐Daniel Lelievre, null François Lellouche, null Adrien Lemaignen, null Véronique Lemee, null Anthony Lemeur, null Gretchen Lemmink, null Ha Sha Lene, null Jenny Lennon, null Rafael León, null Marc Leone, null Michela Leone, null Quentin Lepiller, null François‐Xavier Lescure, null Olivier Lesens, null Mathieu Lesouhaitier, null Amy Lester‐Grant, null Yves Levy, null Bruno Levy, null Claire Levy‐Marchal, null Katarzyna Lewandowska, null Erwan L'Her, null Gianluigi Li Bassi, null Janet Liang, null Ali Liaquat, null Geoffrey Liegeon, null Kah Chuan Lim, null Wei Shen Lim, null Chantre Lima, null Lim Lina, null Bruno Lina, null Andreas Lind, null Maja Katherine Lingad, null Guillaume Lingas, null Sylvie Lion‐Daolio, null Samantha Lissauer, null Keibun Liu, null Marine Livrozet, null Patricia Lizotte, null Antonio Loforte, null Navy Lolong, null Leong Chee Loon, null Diogo Lopes, null Dalia Lopez‐Colon, null Jose W. Lopez‐Revilla, null Anthony L. Loschner, null Paul Loubet, null Bouchra Loufti, null Guillame Louis, null Silvia Lourenco, null Lara Lovelace‐Macon, null Lee Lee Low, null Marije Lowik, null Jia Shyi Loy, null Jean Christophe Lucet, null Carlos Lumbreras Bermejo, null Carlos M. Luna, null Olguta Lungu, null Liem Luong, null Nestor Luque, null Dominique Luton, null Nilar Lwin, null Ruth Lyons, null Olavi Maasikas, null Oryane Mabiala, null Moïse Machado, null Gabriel Macheda, null Hashmi Madiha, null Guillermo Maestro de la Calle, null Rafael Mahieu, null Sophie Mahy, null Ana Raquel Maia, null Lars S. Maier, null Mylène Maillet, null Thomas Maitre, null Maximilian Malfertheiner, null Nadia Malik, null Paddy Mallon, null Fernando Maltez, null Denis Malvy, null Victoria Manda, null Laurent Mandelbrot, null Frank Manetta, null Julie Mankikian, null Edmund Manning, null Aldric Manuel, null Ceila Maria Sant'Ana Malaque, null Flávio Marino, null Daniel Marino, null Samuel Markowicz, null Charbel Maroun Eid, null Ana Marques, null Catherine Marquis, null Brian Marsh, null Laura Marsh, null Megan Marshal, null John Marshall, null Celina Turchi Martelli, null Dori‐Ann Martin, null Emily Martin, null Guillaume Martin‐Blondel, null Ignacio Martin‐Loeches, null Martin Martinot, null Alejandro Martin‐Quiros, null João Martins, null Ana Martins, null Nuno Martins, null Caroline Martins Rego, null Gennaro Martucci, null Olga Martynenko, null Eva Miranda Marwali, null Marsilla Marzukie, null David Maslove, null Sabina Mason, null Sobia Masood, null Basri Mat Nor, null Moshe Matan, null Meghena Mathew, null Daniel Mathieu, null Mathieu Mattei, null Romans Matulevics, null Laurence Maulin, null Michael Maxwell, null Javier Maynar, null Thierry Mazzoni, null Natalie Mc Evoy, null Lisa Mc Sweeney, null Colin McArthur, null Anne McCarthy, null Aine McCarthy, null Colin McCloskey, null Rachael McConnochie, null Sherry McDermott, null Sarah E. McDonald, null Aine McElroy, null Samuel McElwee, null Victoria McEneany, null Allison McGeer, null Chris McKay, null Johnny McKeown, null Kenneth A. McLean, null Paul McNally, null Bairbre McNicholas, null Elaine McPartlan, null Edel Meaney, null Cécile Mear‐Passard, null Maggie Mechlin, null Maqsood Meher, null Omar Mehkri, null Ferruccio Mele, null Luis Melo, null Kashif Memon, null Joao Joao Mendes, null Ogechukwu Menkiti, null Kusum Menon, null France Mentré, null Alexander J. Mentzer, null Noémie Mercier, null Emmanuelle Mercier, null Antoine Merckx, null Mayka Mergeay‐Fabre, null Blake Mergler, null António Mesquita, null Roberta Meta, null Osama Metwally, null Agnès Meybeck, null Dan Meyer, null Alison M. Meynert, null Vanina Meysonnier, null Amina Meziane, null Mehdi Mezidi, null Céline Michelanglei, null Isabelle Michelet, null Efstathia Mihelis, null Vladislav Mihnovit, null Hugo Miranda‐Maldonado, null Nor Arisah Misnan, null Tahira Jamal Mohamed, null Nik Nur Eliza Mohamed, null Asma Moin, null David Molina, null Elena Molinos, null Brenda Molloy, null Mary Mone, null Agostinho Monteiro, null Claudia Montes, null Giorgia Montrucchio, null Shona C. Moore, null Sarah Moore, null Lina Morales Cely, null Lucia Moro, null Ben Morton, null Catherine Motherway, null Ana Motos, null Hugo Mouquet, null Clara Mouton Perrot, null Julien Moyet, null Caroline Mudara, null Aisha Kalsoom Mufti, null Ng Yong Muh, null Dzawani Muhamad, null Jimmy Mullaert, null Fredrik Müller, null Karl Erik Müller, null Daniel Munblit, null Syed Muneeb, null Nadeem Munir, null Laveena Munshi, null Aisling Murphy, null Lorna Murphy, null Marlène Murris, null Himed Musaab, null Himasha Muvindi, null Gugapriyaa Muyandy, null Dimitra Melia Myrodia, null Farah Nadia Mohd‐Hanafiah, null Dave Nagpal, null Alex Nagrebetsky, null Mangala Narasimhan, null Nageswaran Narayanan, null Rashid Nasim Khan, null Alasdair Nazerali‐Maitland, null Nadège Neant, null Holger Neb, null Nikita Nekliudov, null Erni Nelwan, null Raul Neto, null Emily Neumann, null Pauline Yeung Ng, null Wing Yiu Ng, null Anthony Nghi, null Duc Nguyen, null Orna Ni Choileain, null Niamh Ni Leathlobhair, null Alistair Nichol, null Prompak Nitayavardhana, null Stephanie Nonas, null Nurul Amani Mohd Noordin, null Marion Noret, null Nurul Faten Izzati Norharizam, null Lisa Norman, null Alessandra Notari, null Mahdad Noursadeghi, null Karolina Nowicka, null Adam Nowinski, null Saad Nseir, null Jose I. Nunez, null Nurnaningsih Nurnaningsih, null Dwi Utomo Nusantara, null Elsa Nyamankolly, null Anders Benteson Nygaard, null Fionnuala O. Brien, null Annmarie O. Callaghan, null Annmarie O'Callaghan, null Giovanna Occhipinti, null Derbrenn OConnor, null Max O'Donnell, null Tawnya Ogston, null Takayuki Ogura, null Tak‐Hyuk Oh, null Sophie O'Halloran, null Katie O'Hearn, null Shinichiro Ohshimo, null Agnieszka Oldakowska, null João Oliveira, null Larissa Oliveira, null Piero L. Olliaro, null Jee Yan Ong, null David S. Y. Ong, null Wilna Oosthuyzen, null Anne Opavsky, null Peter Openshaw, null Saijad Orakzai, null Claudia Milena Orozco‐Chamorro, null Jamel Ortoleva, null Javier Osatnik, null Linda O'Shea, null Miriam O'Sullivan, null Siti Zubaidah Othman, null Nadia Ouamara, null Rachida Ouissa, null Eric Oziol, null Maïder Pagadoy, null Justine Pages, null Mario Palacios, null Amanda Palacios, null Massimo Palmarini, null Giovanna Panarello, null Prasan Kumar Panda, null Hem Paneru, null Lai Hui Pang, null Mauro Panigada, null Nathalie Pansu, null Aurélie Papadopoulos, null Rachael Parke, null Melissa Parker, null Briseida Parra, null Taha Pasha, null Jérémie Pasquier, null Bruno Pastene, null Fabian Patauner, null Drashti Patel, null Mohan Dass Pathmanathan, null Luís Patrão, null Patricia Patricio, null Juliette Patrier, null Lisa Patterson, null Rajyabardhan Pattnaik, null Mical Paul, null Christelle Paul, null Jorge Paulos, null William A. Paxton, null Jean‐François Payen, null Kalaiarasu Peariasamy, null Miguel Pedrera Jiménez, null Giles J. Peek, null Florent Peelman, null Nathan Peiffer‐Smadja, null Vincent Peigne, null Mare Pejkovska, null Paolo Pelosi, null Ithan D. Peltan, null Rui Pereira, null Daniel Perez, null Luis Periel, null Thomas Perpoint, null Antonio Pesenti, null Vincent Pestre, null Lenka Petrou, null Michele Petrovic, null Ventzislava Petrov‐Sanchez, null Frank Olav Pettersen, null Gilles Peytavin, null Scott Pharand, null Walter Picard, null Olivier Picone, null Maria de Piero, null Carola Pierobon, null Djura Piersma, null Carlos Pimentel, null Raquel Pinto, null Catarina Pires, null Isabelle Pironneau, null Lionel Piroth, null Ayodhia Pitaloka, null Riinu Pius, null Laurent Plantier, null Hon Shen Png, null Julien Poissy, null Ryadh Pokeerbux, null Maria Pokorska‐Spiewak, null Sergio Poli, null Georgios Pollakis, null Diane Ponscarme, null Jolanta Popielska, null Diego Bastos Porto, null Andra‐Maris Post, null Douwe F. Postma, null Pedro Povoa, null Diana Póvoas, null Jeff Powis, null Sofia Prapa, null Sébastien Preau, null Christian Prebensen, null Jean‐Charles Preiser, null Anton Prinssen, null Gamage Dona Dilanthi Priyadarshani, null Lucia Proença, null Sravya Pudota, null Oriane Puéchal, null Bambang Pujo Semedi, null Mathew Pulicken, null Gregory Purcell, null Luisa Quesada, null Vilmaris Quinones‐Cardona, null Víctor Quirós González, null Else Quist‐Paulsen, null Mohammed Quraishi, null Maia Rabaa, null Christian Rabaud, null Ebenezer Rabindrarajan, null Aldo Rafael, null Marie Rafiq, null Mutia Rahardjani, null Rozanah Abd Rahman, null Ahmad Kashfi Haji Ab Rahman, null Arsalan Rahutullah, null Fernando Rainieri, null Giri Shan Rajahram, null Pratheema Ramachandran, null Nagarajan Ramakrishnan, null Ahmad Afiq Ramli, null Blandine Rammaert, null Grazielle Viana Ramos, null Asim Rana, null Rajavardhan Rangappa, null Ritika Ranjan, null Christophe Rapp, null Aasiyah Rashan, null Thalha Rashan, null Ghulam Rasheed, null Menaldi Rasmin, null Indrek Rätsep, null Cornelius Rau, null Tharmini Ravi, null Ali Raza, null Andre Real, null Stanislas Rebaudet, null Sarah Redl, null Brenda Reeve, null Attaur Rehman, null Liadain Reid, null Dag Henrik Reikvam, null Renato Reis, null Jordi Rello, null Jonathan Remppis, null Martine Remy, null Hongru Ren, null Hanna Renk, null Anne‐Sophie Resseguier, null Matthieu Revest, null Oleksa Rewa, null Luis Felipe Reyes, null Tiago Reyes, null Maria Ines Ribeiro, null Antonia Ricchiuto, null David Richardson, null Denise Richardson, null Laurent Richier, null Siti Nurul Atikah Ahmad Ridzuan, null Jordi Riera, null Ana L. Rios, null Asgar Rishu, null Patrick Rispal, null Karine Risso, null Maria Angelica Rivera Nuñez, null Nicholas Rizer, null Chiara Robba, null André Roberto, null Stephanie Roberts, null David L. Robertson, null Olivier Robineau, null Ferran Roche‐Campo, null Paola Rodari, null Simão Rodeia, null Julia Rodriguez Abreu, null Bernhard Roessler, null Pierre‐Marie Roger, null Claire Roger, null Emmanuel Roilides, null Juliette Romaru, null Roberto Roncon‐Albuquerque, null Mélanie Roriz, null Manuel Rosa‐Calatrava, null Michael Rose, null Dorothea Rosenberger, null Nurul Hidayah Mohammad Roslan, null Andrea Rossanese, null Matteo Rossetti, null Bénédicte Rossignol, null Patrick Rossignol, null Stella Rousset, null Carine Roy, null Benoît Roze, null Desy Rusmawatiningtyas, null Clark D. Russell, null Maria Ryan, null Maeve Ryan, null Steffi Ryckaert, null Aleksander Rygh Holten, null Isabela Saba, null Sairah Sadaf, null Musharaf Sadat, null Valla Sahraei, null Maximilien Saint‐Gilles, null Pranya Sakiyalak, null Nawal Salahuddin, null Leonardo Salazar, null Jodat Saleem, null Gabriele Sales, null Stéphane Sallaberry, null Charlotte Salmon Gandonniere, null Hélène Salvator, null Olivier Sanchez, null Angel Sanchez‐Miralles, null Vanessa Sancho‐Shimizu, null Gyan Sandhu, null Zulfiqar Sandhu, null Pierre‐François Sandrine, null Oana Sandulescu, null Marlene Santos, null Shirley Sarfo‐Mensah, null Bruno Sarmento Banheiro, null Iam Claire E. Sarmiento, null Benjamine Sarton, null Ankana Satya, null Sree Satyapriya, null Rumaisah Satyawati, null Egle Saviciute, null Parthena Savvidou, null Yen Tsen Saw, null Justin Schaffer, null Tjard Schermer, null Arnaud Scherpereel, null Marion Schneider, null Stephan Schroll, null Michael Schwameis, null Gary Schwartz, null Janet T. Scott, null James Scott‐Brown, null Nicholas Sedillot, null Tamara Seitz, null Jaganathan Selvanayagam, null Mageswari Selvarajoo, null Caroline Semaille, null Malcolm G. Semple, null Rasidah Bt Senian, null Eric Senneville, null Filipa Sequeira, null Tânia Sequeira, null Ary Serpa Neto, null Pablo Serrano Balazote, null Ellen Shadowitz, null Syamin Asyraf Shahidan, null Mohammad Shamsah, null Anuraj Shankar, null Shaikh Sharjeel, null Pratima Sharma, null Catherine A. Shaw, null Victoria Shaw, null Ashraf Sheharyar, null Rohan Shetty, null Rajesh Mohan Shetty, null Haixia Shi, null Mohiuddin Shiekh, null Nobuaki Shime, null Keiki Shimizu, null Sally Shrapnel, null Pramesh Sundar Shrestha, null Shubha Kalyan Shrestha, null Hoi Ping Shum, null Nassima Si Mohammed, null Ng Yong Siang, null Jeanne Sibiude, null Atif Siddiqui, null Piret Sillaots, null Catarina Silva, null Rogério Silva, null Maria Joao Silva, null Benedict Sim Lim Heng, null Wai Ching Sin, null Dario Sinatti, null Punam Singh, null Budha Charan Singh, null Pompini Agustina Sitompul, null Karisha Sivam, null Vegard Skogen, null Sue Smith, null Benjamin Smood, null Coilin Smyth, null Michelle Smyth, null Morgane Snacken, null Dominic So, null Tze Vee Soh, null Lene Bergendal Solberg, null Joshua Solomon, null Tom Solomon, null Emily Somers, null Agnès Sommet, null Rima Song, null Myung Jin Song, null Tae Song, null Jack Song Chia, null Michael Sonntagbauer, null Azlan Mat Soom, null Arne Søraas, null Camilla Lund Søraas, null Alberto Sotto, null Edouard Soum, null Marta Sousa, null Ana Chora Sousa, null Maria Sousa Uva, null Vicente Souza‐Dantas, null Alexandra Sperry, null Elisabetta Spinuzza, null B. P. Sanka Ruwan Sri Darshana, null Shiranee Sriskandan, null Sarah Stabler, null Thomas Staudinger, null Stephanie‐Susanne Stecher, null Trude Steinsvik, null Ymkje Stienstra, null Birgitte Stiksrud, null Eva Stolz, null Amy Stone, null Adrian Streinu‐Cercel, null Anca Streinu‐Cercel, null David Stuart, null Ami Stuart, null Decy Subekti, null Gabriel Suen, null Jacky Y. Suen, null Asfia Sultana, null Charlotte Summers, null Dubravka Supic, null Deepashankari Suppiah, null Magdalena Surovcová, null Suwarti Suwarti, null Andrey Svistunov, null Sarah Syahrin, null Konstantinos Syrigos, null Jaques Sztajnbok, null Konstanty Szuldrzynski, null Shirin Tabrizi, null Fabio S. Taccone, null Lysa Tagherset, null Shahdattul Mawarni Taib, null Ewa Talarek, null Sara Taleb, null Jelmer Talsma, null Renaud Tamisier, null Maria Lawrensia Tampubolon, null Kim Keat Tan, null Yan Chyi Tan, null Taku Tanaka, null Hiroyuki Tanaka, null Hayato Taniguchi, null Huda Taqdees, null Arshad Taqi, null Coralie Tardivon, null Pierre Tattevin, null M. Azhari Taufik, null Hassan Tawfik, null Richard S. Tedder, null Tze Yuan Tee, null João Teixeira, null Sofia Tejada, null Marie‐Capucine Tellier, null Sze Kye Teoh, null Vanessa Teotonio, null François Téoulé, null Pleun Terpstra, null Olivier Terrier, null Nicolas Terzi, null Hubert Tessier‐Grenier, null Adrian Tey, null Alif Adlan Mohd Thabit, null Anand Thakur, null Zhang Duan Tham, null Suvintheran Thangavelu, null Vincent Thibault, null Simon‐Djamel Thiberville, null Benoît Thill, null Jananee Thirumanickam, null Shaun Thompson, null Emma C. Thomson, null Surain Raaj Thanga Thurai, null Ryan S. Thwaites, null Paul Tierney, null Vadim Tieroshyn, null Peter S. Timashev, null Jean‐François Timsit, null Bharath Kumar Tirupakuzhi Vijayaraghavan, null Noémie Tissot, null Jordan Zhien Yang Toh, null Maria Toki, null Kristian Tonby, null Sia Loong Tonnii, null Margarida Torres, null Antoni Torres, null Rosario Maria Torres Santos‐Olmo, null Hernando Torres‐Zevallos, null Michael Towers, null Tony Trapani, null Théo Treoux, null Cécile Tromeur, null Ioannis Trontzas, null Tiffany Trouillon, null Jeanne Truong, null Christelle Tual, null Sarah Tubiana, null Helen Tuite, null Jean‐Marie Turmel, null Lance C. W. Turtle, null Anders Tveita, null Pawel Twardowski, null Makoto Uchiyama, null P. G. Ishara Udayanga, null Andrew Udy, null Roman Ullrich, null Alberto Uribe, null Asad Usman, null Timothy M. Uyeki, null Cristinava Vajdovics, null Piero Valentini, null Luís Val‐Flores, null Amélie Valran, null Stijn Van de Velde, null Marcel van den Berge, null Machteld Van der Feltz, null Job van der Palen, null Paul van der Valk, null Nicky Van Der Vekens, null Peter Van der Voort, null Sylvie Van Der Werf, null Laura van Gulik, null Jarne Van Hattem, null Carolien van Netten, null Ilonka van Veen, null Noémie Vanel, null Henk Vanoverschelde, null Pooja Varghese, null Michael Varrone, null Shoban Raj Vasudayan, null Charline Vauchy, null Shaminee Veeran, null Aurélie Veislinger, null Sebastian Vencken, null Sara Ventura, null Annelies Verbon, null James Vickers, null José Ernesto Vidal, null César Vieira, null Deepak Vijayan, null Joy Ann Villanueva, null Judit Villar, null Pierre‐Marc Villeneuve, null Andrea Villoldo, null Gayatri Vishwanathan, null Benoit Visseaux, null Hannah Visser, null Chiara Vitiello, null Harald Vonkeman, null Fanny Vuotto, null Noor Hidayu Wahab, null Suhaila Abdul Wahab, null Nadirah Abdul Wahid, null Marina Wainstein, null Wan Fadzlina Wan Muhd Shukeri, null Chih‐Hsien Wang, null Steve Webb, null Jia Wei, null Katharina Weil, null Tan Pei Wen, null Sanne Wesselius, null T. Eoin West, null Murray Wham, null Bryan Whelan, null Nicole White, null Paul Henri Wicky, null Aurélie Wiedemann, null Surya Otto Wijaya, null Keith Wille, null Suzette Willems, null Virginie Williams, null Evert‐Jan Wils, null Xin Ci Wong, null Calvin Wong, null Yew Sing Wong, null Teck Fung Wong, null Natalie Wright, null Gan Ee Xian, null Lim Saio Xian, null Kuan Pei Xuan, null Ioannis Xynogalas, null Siti Rohani Binti Mohd Yakop, null Masaki Yamazaki, null Yazdan Yazdanpanah, null Nicholas Yee Liang Hing, null Cécile Yelnik, null Chian Hui Yeoh, null Stephanie Yerkovich, null Toshiki Yokoyama, null Hodane Yonis, null Obada Yousif, null Saptadi Yuliarto, null Akram Zaaqoq, null Marion Zabbe, null Kai Zacharowski, null Masliza Zahid, null Maram Zahran, null Nor Zaila Binti Zaidan, null Maria Zambon, null Alberto Zanella, null Konrad Zawadka, null Nurul Zaynah, null Hiba Zayyad, null Alexander Zoufaly, null David Zucman, and null ISARIC Clinical Characterisation Group

Published
2022

125. Improving the diagnosis of severe malaria in African children using platelet counts and plasma

Author

James A, Watson, Sophie, Uyoga, Perpetual, Wanjiku, Johnstone, Makale, Gideon M, Nyutu, Neema, Mturi, Elizabeth C, George, Charles J, Woodrow, Nicholas P J, Day, Philip, Bejon, Robert O, Opoka, Arjen M, Dondorp, Chandy C, John, Kathryn, Maitland, Thomas N, Williams, and Nicholas J, White

Subjects
Adult, Platelet Count, Plasmodium falciparum, Protozoan Proteins, Humans, Antigens, Protozoan, Bayes Theorem, Uganda, Malaria, Falciparum, Child, Malaria
Abstract

Severe malaria caused by

Published
2022

126. Pharmacometric assessment of the in vivo antiviral activity of ivermectin in early symptomatic COVID-19

Author

William HK Schilling, Podjanee Jittamala, James A Watson, Maneerat Ekkapongpisit, Tanaya Siripoon, Thundon Ngamprasertchai, Viravarn Luvira, Sasithon Pongwilai, Cintia Cruz, James J Callery, Simon Boyd, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Nattaporn Piaraksa, Kanokon Suwannasin, Pongtorn Hanboonkunupakarn, Borimas Hanboonkunupakarn, Sakol Sookprome, Kittiyod Poovorawan, Janjira Thaipadungpanit, Stuart Blacksell, Mallika Imwong, Joel Tarning, Walter RJ Taylor, Vasin Chotivanich, Chunlanee Sangketchon, Wiroj Ruksakul, Kesinee Chotivanich, Mauro M Teixeira, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas PJ Day, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, and Nicholas J White

Abstract

BackgroundThere is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain.MethodsIn a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).ResultsRandomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41].ConclusionsHigh dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 therapeutics in vivo.Funding“Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)” is funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z).ImpactRate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection.High dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection.

Published
2022

127. Are national treatment guidelines for falciparum malaria in line with WHO recommendations and is antimalarial resistance taken into consideration? – A review of guidelines in non-endemic countries

Author

Marc T. Visser, Rens Zonneveld, Thomas J. Peto, Michele Vugt, Arjen M. Dondorp, and Rob W. Pluijm

Subjects
treatment, Artemether, Lumefantrine Drug Combination, malaria, review, Public Health, Environmental and Occupational Health, Drug Resistance, Artesunate, Guidelines as Topic, World Health Organization, WHO, Antimalarials, Infectious Diseases, parasitic diseases, Humans, Parasitology, guidelines, Malaria, Falciparum
Abstract

Objective Plasmodium falciparum infections are a relatively rare but potentially deadly disease found in returning travellers. We compare the national treatment guidelines of non-endemic countries with the WHO guidelines for the treatment of Plasmodium falciparum infections. Methods Review. We identified non-endemic countries with an incidence rate of imported malaria of at least one per 100,000 population and at least 50 cases annually. Using PubMed and Google Search, we reviewed national guidelines published before 1 March 2021. Results Thirteen guidelines were identified. For uncomplicated falciparum malaria, 11 of 13 countries (85%) recommend an artemisinin-based combination therapy as first-line regimen in adults, of which artemether–lumefantrine was the most common. For severe malaria, all guidelines recommend the use of intravenous artesunate. Only three countries adjust treatment recommendations based on expected artemisinin resistance. Conclusion Treatment guidelines for uncomplicated falciparum malaria in non-endemic countries generally adhere to WHO recommendations but often fail to mention the risk of drug resistance in returning travellers. Artemisinin-based Combination Therapies (ACTs) should be the first choice for all uncomplicated malaria cases. Furthermore, the choice between ACTs should be based on regional resistance patterns.

Published
2022

129. Epidemiological characteristics, ventilator management, and clinical outcome in patients receiving invasive ventilation in intensive care units from 10 Asian middle-income countries (PRoVENT-iMiC): An international, multicenter, prospective study

Author

Sriram Sampath, Luigi Pisani, Marcelo Gama de Abreu, Kanishka Indraratna, Seyed Mohammadreza Hashemian, Gyan Kayastha, Rajyabardhan Pattnaik, Nicholas P. J. Day, Nor’azim Mohd Yunos, Arjen M. Dondorp, Frederique Paulus, Kaweesak Chittawatanarat, Louise Thwaites, Rashan Haniffa, Nicholas J. White, Bhuvana Krishna, Hassan Moosa, Paolo Pelosi, Abi Beane, Shivakumar Iyer, Ary Serpa Neto, Areef Ahsan, Salvatore Grasso, Marcus J. Schultz, Tai Li Ling, Anna Geke Algera, Behzad Nadjm, Hisham Ahmed Imad, Abul Faiz, Ni Ni Tun, Madiha Hashmi, Graduate School, Intensive Care Medicine, Nursing, AII - Inflammatory diseases, ACS - Pulmonary hypertension & thrombosis, ACS - Diabetes & metabolism, and ACS - Microcirculation

Subjects
Adult, Male, medicine.medical_specialty, ARDS, Asia, 030231 tropical medicine, Lung injury, 03 medical and health sciences, 0302 clinical medicine, Virology, Internal medicine, Intensive care, Epidemiology, medicine, Humans, Prospective Studies, Prospective cohort study, Developing Countries, Tidal volume, Aged, Respiratory Distress Syndrome, business.industry, Incidence (epidemiology), Area under the curve, Articles, Middle Aged, medicine.disease, Respiration, Artificial, Intensive Care Units, Treatment Outcome, Infectious Diseases, Epidemiological Monitoring, Female, Parasitology, business
Abstract

Epidemiology, ventilator management, and outcome in patients receiving invasive ventilation in intensive care units (ICUs) in middle-income countries are largely unknown. PRactice of VENTilation in Middle-income Countries is an international multicenter 4-week observational study of invasively ventilated adult patients in 54 ICUs from 10 Asian countries conducted in 2017/18. Study outcomes included major ventilator settings (including tidal volume [VT] and positive end-expiratory pressure [PEEP]); the proportion of patients at risk for acute respiratory distress syndrome (ARDS), according to the lung injury prediction score (LIPS), or with ARDS; the incidence of pulmonary complications; and ICU mortality. In 1,315 patients included, median VT was similar in patients with LIPS < 4 and patients with LIPS ≥ 4, but lower in patients with ARDS (7.90 [6.8–8.9], 8.0 [6.8–9.2], and 7.0 [5.8–8.4] mL/kg Predicted body weight; P = 0.0001). Median PEEP was similar in patients with LIPS < 4 and LIPS ≥ 4, but higher in patients with ARDS (five [5–7], five [5–8], and 10 [5–12] cmH2O; P < 0.0001). The proportions of patients with LIPS ≥ 4 or with ARDS were 68% (95% CI: 66–71) and 7% (95% CI: 6–8), respectively. Pulmonary complications increased stepwise from patients with LIPS < 4 to patients with LIPS ≥ 4 and patients with ARDS (19%, 21%, and 38% respectively; P = 0.0002), with a similar trend in ICU mortality (17%, 34%, and 45% respectively; P < 0.0001). The capacity of the LIPS to predict development of ARDS was poor (receiver operating characteristic [ROC] area under the curve [AUC] of 0.62, 95% CI: 0.54–0.70). In Asian middle-income countries, where two-thirds of ventilated patients are at risk for ARDS according to the LIPS and pulmonary complications are frequent, setting of VT is globally in line with current recommendations.

Published
2021

130. Measurement of gene amplifications related to drug resistance in Plasmodium falciparum using droplet digital PCR

Author

Mallika Imwong, Arjen M. Dondorp, Kanokon Suwannasin, Rungniran Sug-aram, Suttipat Srisutham, and Intensive Care Medicine

Subjects
lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Plasmodium falciparum, Drug Resistance, ddPCR, Drug resistance, Polymerase Chain Reaction, lcsh:Infectious and parasitic diseases, Antimalarials, 03 medical and health sciences, 0302 clinical medicine, pfmdr1, parasitic diseases, Digital polymerase chain reaction, Multiplex, lcsh:RC109-216, Copy-number variation, pfplasmepsin2, Gene, 030304 developmental biology, 0303 health sciences, biology, Methodology, Gene Amplification, pfgch1, Thailand, biology.organism_classification, Molecular biology, 3. Good health, Infectious Diseases, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Parasitology, Human genome, Multiplex Polymerase Chain Reaction
Abstract

Background Copy number variations (CNVs) of the Plasmodium falciparum multidrug resistance 1 (pfmdr1), P. falciparum plasmepsin2 (pfplasmepsin2) and P. falciparum GTP cyclohydrolase 1 (pfgch1) genes are associated with anti-malarial drug resistance in P. falciparum malaria. Droplet digital PCR (ddPCR) assays have been developed for accurate assessment of CNVs in several human genes. The aim of the present study was to develop and validate ddPCR assays for detection of the CNVs of P. falciparum genes associated with resistance to anti-malarial drugs. Methods A multiplex ddPCR assay was developed to detect the CNVs in the pfmdr1 and pfplasmepsin2 genes, while a duplex ddPCR assay was developed to detect CNV in the pfgch1 gene. The gene copy number (GCN) quantification limit, as well as the accuracy and precision of the ddPCR assays were determined and compared to conventional quantitative PCR (qPCR). In order to reduce the cost of testing, a multiplex ddPCR assay of two target genes, pfmdr1 and pfplasmepsin2, was validated. In addition, the CNVs of genes of field samples collected from Thailand from 2015 to 2019 (n = 84) were assessed by ddPCR and results were compared to qPCR as the reference assay. Results There were no significant differences between the GCN results obtained from uniplex and multiplex ddPCR assays for detection of CNVs in the pfmdr1 and pfplasmepsin2 genes (p = 0.363 and 0.330, respectively). Based on the obtained gene copy number quantification limit, the accuracy and percent relative standard deviation (%RSD) value of the multiplex ddPCR assay were 95% and 5%, respectively, for detection of the CNV of the pfmdr1 gene, and 91% and 5% for detection of the CNV of the pfplasmepsin2 gene. There was no significant difference in gene copy numbers assessed by uniplex or duplex ddPCR assays regarding CNV in the pfgch1 gene (p = 0.276). The accuracy and %RSD value of the duplex ddPCR assay were 95% and 4%, respectively, regarding pfgch1 GCN. In the P. falciparum field samples, pfmdr1 and pfplasmepsin2 GCNs were amplified in 15% and 27% of samples from Ubon Ratchathani, Thailand, while pfgch1 GCN was amplified in 50% of samples from Yala, Thailand. There was 100% agreement between the GCN results obtained from the ddPCR and qPCR assays (κ = 1.00). The results suggested that multiplex ddPCR assay is the optional assay for the accurate detection of gene copy number without requiring calibration standards, while the cost and required time are reduced. Based on the results of this study, criteria for GCN detection by ddPCR analysis were generated. Conclusions The developed ddPCR assays are simple, accurate, precise and cost-effective tools for detection of the CNVs in the pfmdr1, pfplasmepsin2 and pfgch1 genes of P. falciparum. The ddPCR assay is a useful additional tool for the surveillance of anti-malarial drug resistance.

Published
2021

131. Lung ultrasound for detection of pulmonary complications in critically ill obstetric patients in a resource-limited setting

Author

Giovanni Putoto, Francesco Di Gennaro, Arjen M. Dondorp, Claudia Marotta, Alimamy P. Koroma, Anna De Nicolo, Michael M. Koroma, Salvatore Grasso, James Russel, Adetunji O. Adeniji, Marcella Schiavone, Angela De Palma, Marcus J. Schultz, Eva Hanciles, Stije J. Leopold, Edward E. Emuveyan, Giuseppe Marulli, Luigi Pisani, Patricia C. Henwood, Ary Serpa Neto, Enzo Pisani, Intensive Care Medicine, ACS - Pulmonary hypertension & thrombosis, AII - Inflammatory diseases, ACS - Diabetes & metabolism, and ACS - Microcirculation

Subjects
Adult, medicine.medical_specialty, Pleural effusion, Critical Illness, Pulmonary Edema, Atelectasis, Sierra Leone, Sierra leone, Young Adult, Pregnancy, Virology, medicine, Humans, Prospective Studies, Respiratory system, Lung, Ultrasonography, Respiratory Distress Syndrome, Respiratory distress, business.industry, Pneumonia, Articles, Odds ratio, Pulmonary edema, medicine.disease, Pregnancy Complications, Infectious Diseases, Emergency medicine, Female, Parasitology, business
Abstract

Critically ill parturients have an increased risk of developing pulmonary complications. Lung ultrasound (LUS) could be effective in addressing the cause of respiratory distress in resource-limited settings with high maternal mortality. We aimed to determine the frequency, timing of appearance, and type of pulmonary complications in critically ill parturients in an obstetric unit in Sierra Leone. In this prospective observational study, LUS examinations were performed on admission, after 24 and 48 hours, and in case of respiratory deterioration. Primary endpoint was the proportion of parturients with one or more pulmonary complications, stratified for the presence of respiratory distress. Secondary endpoints included timing and types of complications, and their association with “poor outcome,” defined as a composite of transfer for escalation of care or death. Of 166 patients enrolled, 35 patients (21% [95% CI: 15–28]) had one or more pulmonary complications, the majority diagnosed on admission. Acute respiratory distress syndrome (period prevalence 4%) and hydrostatic pulmonary edema (4%) were only observed in patients with respiratory distress. Pneumonia (2%), atelectasis (10%), and pleural effusion (7%) were present, irrespective of respiratory distress. When ultrasound excluded pulmonary complications, respiratory distress was related to anemia or metabolic acidosis. Pulmonary complications were associated with an increased risk of poor outcome (odds ratio: 5.0; 95% CI: 1.7–14.6; P = 0.003). In critically ill parturients in a resource-limited obstetric unit, LUS contributed to address the cause of respiratory distress by identifying or excluding pulmonary complications. These were associated with a poor outcome.

Published
2021

132. Arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial

Author

Patricia Njuguna, Peter Kalume, Mwanajuma Ngama, Gabriel Mwambingu, Arjen M. Dondorp, Neema Mturi, Nicholas P. J. Day, Mwanamvua Boga, Nicholas J. White, Mallika Imwong, Sónia Gonçalves, Joseph Weya, Brian Mutinda, Altaf A. Lal, Olivo Miotto, Juliana Wambua, Philip Bejon, Joel Tarning, Arshad Khuroo, Mainga Hamaluba, Mavuto Mukaka, Rob W. van der Pluijm, Mehul Dhorda, Naomi Waithira, Richard M. Hoglund, Walter R. J. Taylor, Caroline Ngetsa, and Intensive Care Medicine

Subjects
0301 basic medicine, education.field_of_study, medicine.medical_specialty, Artemether/lumefantrine, business.industry, Mefloquine, 030231 tropical medicine, 030106 microbiology, Population, Articles, Lumefantrine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Infectious Diseases, Tolerability, chemistry, Internal medicine, Piperaquine, Medicine, Artemether, Arterolane, business, education, medicine.drug
Abstract

Summary Background Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children. Methods In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov , NCT03452475 , and is completed. Findings Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths. Interpretation This study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance. Funding UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries

Published
2021

133. Triple Artemisinin-Based Combination Therapies for Malaria – A New Paradigm?

Author

Mehul Dhorda, Chanaki Amaratunga, Rob W. van der Pluijm, and Arjen M. Dondorp

Subjects
0301 basic medicine, Drug, Artemisinins, medicine.medical_specialty, media_common.quotation_subject, Plasmodium falciparum, 030231 tropical medicine, malaria, Drug Resistance, Drug resistance, P. falciparum, resistance, Antimalarials, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, medicine, Humans, Malaria, Falciparum, Available drugs, Artemisinin, Intensive care medicine, TACT, Asia, Southeastern, media_common, biology, business.industry, biology.organism_classification, medicine.disease, ACT, 030104 developmental biology, Infectious Diseases, artemisinin, Drug Therapy, Combination, Parasitology, business, Malaria, medicine.drug
Abstract

Recent gains in the fight against malaria are threatened by the emergence and spread of artemisinin and partner drug resistance in Plasmodium falciparum in the Greater Mekong Subregion (GMS). When artemisinins are combined with a single partner drug, all recommended artemisinin-based combination therapies have shown reduced efficacy in some countries in the GMS at some point. Novel drugs are not available for the near future. Triple artemisinin-based combination therapies, combining artemisinins with two currently available partner drugs, will provide one of the last remaining safe and effective treatments for falciparum malaria that can be deployed rapidly in the GMS, whereas their deployment beyond the GMS could delay or prevent the global emergence and spread of resistance to currently available drugs.

Published
2021

134. Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection

Author

Arjen M. Dondorp, Chaisith Sivakorn, Srivicha Krudsood, Khanittha Kheawsawaung, Tachpon Techarang, Polrat Wilairatana, Marcus J. Schultz, Intensive Care Medicine, ACS - Atherosclerosis & ischemic syndromes, AII - Infectious diseases, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation

Subjects
Adult, Resuscitation, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Plasmodium vivax, Orthostatic intolerance, Case Report, 030204 cardiovascular system & hematology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, chemistry.chemical_compound, Orthostatic vital signs, Antimalarials, Hypotension, Orthostatic, 0302 clinical medicine, Chloroquine, parasitic diseases, Malaria, Vivax, Medicine, Humans, lcsh:RC109-216, 030212 general & internal medicine, biology, Orthostatic hypotension, business.industry, Shock, biology.organism_classification, medicine.disease, Thailand, Infectious Diseases, chemistry, Artesunate, Anesthesia, Shock (circulatory), Parasitology, Female, medicine.symptom, business, Malaria, medicine.drug
Abstract

Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has not been previously reported. We describe a non-immune previously healthy Thai woman presenting with Plasmodium vivax infection with well-documented orthostatic hypotension. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her hemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.

Published
2021

135. An open dataset of

Author

Ishag, Adam, Mohammad Shafiul, Alam, Sisay, Alemu, Chanaki, Amaratunga, Roberto, Amato, Voahangy, Andrianaranjaka, Nicholas M, Anstey, Abraham, Aseffa, Elizabeth, Ashley, Ashenafi, Assefa, Sarah, Auburn, Bridget E, Barber, Alyssa, Barry, Dhelio, Batista Pereira, Jun, Cao, Nguyen Hoang, Chau, Kesinee, Chotivanich, Cindy, Chu, Arjen M, Dondorp, Eleanor, Drury, Diego F, Echeverry, Berhanu, Erko, Fe, Espino, Rick, Fairhurst, Abdul, Faiz, María, Fernanda Villegas, Qi, Gao, Lemu, Golassa, Sonia, Goncalves, Matthew J, Grigg, Yaghoob, Hamedi, Tran Tinh, Hien, Ye, Htut, Kimberly J, Johnson, Nadira, Karunaweera, Wasif, Khan, Srivicha, Krudsood, Dominic P, Kwiatkowski, Marcus, Lacerda, Benedikt, Ley, Pharath, Lim, Yaobao, Liu, Alejandro, Llanos-Cuentas, Chanthap, Lon, Tatiana, Lopera-Mesa, Jutta, Marfurt, Pascal, Michon, Olivo, Miotto, Rezika, Mohammed, Ivo, Mueller, Chayadol, Namaik-Larp, Paul N, Newton, Thuy-Nhien, Nguyen, Francois, Nosten, Rintis, Noviyanti, Zuleima, Pava, Richard D, Pearson, Beyene, Petros, Aung P, Phyo, Ric N, Price, Sasithon, Pukrittayakamee, Awab Ghulam, Rahim, Milijaona, Randrianarivelojosia, Julian C, Rayner, Angela, Rumaseb, Sasha V, Siegel, Victoria J, Simpson, Kamala, Thriemer, Alberto, Tobon-Castano, Hidayat, Trimarsanto, Marcelo, Urbano Ferreira, Ivan D, Vélez, Sonam, Wangchuk, Thomas E, Wellems, Nicholas J, White, Timothy, William, Maria F, Yasnot, and Daniel, Yilma

Abstract

This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 samples of

Published
2022

136. Assessment In Vitro of the Antimalarial and Transmission-Blocking Activities of Cipargamin and Ganaplacide in Artemisinin-Resistant Plasmodium falciparum

Author

Achaporn Yipsirimetee, Pornpawee Chiewpoo, Rupam Tripura, Dysoley Lek, Nicholas P. J. Day, Arjen M. Dondorp, Sasithon Pukrittayakamee, Nicholas J. White, and Kesinee Chotivanich

Subjects
Pharmacology, Infectious Diseases, parasitic diseases, Pharmacology (medical)
Abstract

Artemisinin resistance in Plasmodium falciparum has emerged and spread widely in the Greater Mekong Subregion, threatening current first-line artemisinin combination treatments. New antimalarial drugs are needed urgently.

Published
2022

138. Genetic analysis of the orthologous crt and mdr1 genes in Plasmodium malariae from Thailand and Myanmar

Author

Mallika Imwong, Arjen M. Dondorp, François Nosten, Usa Boonyuen, Frank Smithuis, Naowarat Saralamba, Nicholas P. J. Day, Yupawadee Pimpat, Sasithon Pukrittayakamee, and Intensive Care Medicine

Subjects
Insecticides, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, 030231 tropical medicine, Plasmodium vivax, Population, Chloroquine resistant transporter, Drug Resistance, Protozoan Proteins, Plasmodium malariae, Myanmar, Genetic analysis, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, lcsh:RC109-216, 030212 general & internal medicine, education, Gene, Genetics, education.field_of_study, Polymorphism, Genetic, biology, Research, Haplotype, Multidrug resistance proteins 1, Membrane Transport Proteins, Plasmodium falciparum, Chloroquine, biology.organism_classification, Thailand, Malaria, Mefloquine, Infectious Diseases, Parasitology, Multidrug Resistance-Associated Proteins, Synonymous substitution
Abstract

Background Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. Studies on genetic polymorphisms of anti-malarial drug target genes in P. malariae are limited. Previous reports have shown polymorphisms in the P. malariae dihydrofolate reductase gene associated with pyrimethamine resistance and linked to pyrimethamine drug pressure. This study investigated polymorphisms of the P. malariae homologous genes, chloroquine resistant transporter and multidrug resistant 1, associated with chloroquine and mefloquine resistance in Plasmodium falciparum. Methods The orthologous P. malariae crt and mdr1 genes were studied in 95 patients with P. malariae infection between 2002 and 2016 from Thailand (N = 51) and Myanmar (N = 44). Gene sequences were analysed using BioEdit, MEGA7, and DnaSP programs. Mutations and gene amplifications were compared with P. falciparum and Plasmodium vivax orthologous genes. Protein topology models derived from the observed pmcrt and pmmdr1 haplotypes were constructed and analysed using Phyre2, SWISS MODEL and Discovery Studio Visualization V 17.2. Results Two non-synonymous mutations were observed in exon 2 (H53P, 40%) and exon 8 (E278D, 44%) of pmcrt. The topology model indicated that H53P and E278D were located outside of the transmembrane domain and were unlikely to affect protein function. Pmmdr1 was more diverse than pmcrt, with 10 non-synonymous and 3 synonymous mutations observed. Non-synonymous mutations were located in the parasite cytoplasmic site, transmembrane 11 and nucleotide binding domains 1 and 2. Polymorphisms conferring amino acid changes in the transmembrane and nucleotide binding domains were predicted to have some effect on PmMDR1 conformation, but were unlikely to affect protein function. All P. malariae parasites in this study contained a single copy of the mdr1 gene. Conclusions The observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.

Published
2020

139. Respiratory Support in COVID-19 Patients, with a Focus on Resource-Limited Settings

Author

Marcus J. Schultz, Muhammad Hayat, Diptesh Aryal, Arjen M. Dondorp, and Abi Beane

Subjects
medicine.medical_specialty, medicine.medical_treatment, Pneumonia, Viral, 030231 tropical medicine, Population, Review Article, Disease, Lopinavir, Hypoxemia, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Virology, Case fatality rate, medicine, Humans, Intubation, education, Intensive care medicine, Developing Countries, Lung, Pandemics, education.field_of_study, Alanine, Ritonavir, Continuous Positive Airway Pressure, Respiratory distress, SARS-CoV-2, business.industry, COVID-19, Disease Management, Chloroquine, medicine.disease, Respiration, Artificial, Adenosine Monophosphate, Oxygen, Pneumonia, Infectious Diseases, Breathing, Parasitology, medicine.symptom, Coronavirus Infections, Tomography, X-Ray Computed, business, Hydroxychloroquine
Abstract

The ongoing novel coronavirus disease (COVID-19) pandemic is threatening the global human population, including in countries with resource-limited health facilities. Severe bilateral pneumonia is the main feature of severe COVID-19, and adequate ventilatory support is crucial for patient survival. Although our knowledge of the disease is still rapidly increasing, this review summarizes current guidance on the best provision of ventilatory support, with a focus on resource-limited settings. Key messages include that supplemental oxygen is a first essential step for the treatment of severe COVID-19 patients with hypoxemia and should be a primary focus in resource-limited settings where capacity for invasive ventilation is limited. Oxygen delivery can be increased by using a non-rebreathing mask and prone positioning. The presence of only hypoxemia should in general not trigger intubation because hypoxemia is often remarkably well tolerated. Patients with fatigue and at risk for exhaustion, because of respiratory distress, will require invasive ventilation. In these patients, lung protective ventilation is essential. Severe pneumonia in COVID-19 differs in some important aspects from other causes of severe pneumonia or acute respiratory distress syndrome, and limiting the positive end-expiratory pressure level on the ventilator may be important. This ventilation strategy might reduce the currently very high case fatality rate of more than 50% in invasively ventilated COVID-19 patients.

Published
2020

140. Severe malaria. Current concepts and practical overview: What every intensivist should know

Author

Martin W. Dünser, Regina Giera, Mervyn Mer, and Arjen M. Dondorp

Subjects
Gynecology, medicine.medical_specialty, Critical Care, biology, business.industry, Intensivist, Plasmodium falciparum, Critical Care and Intensive Care Medicine, medicine.disease, biology.organism_classification, Disease control, World health, Malaria, Intensive Care Units, Cerebral Malaria, Intensive care, medicine, Humans, Severe Malaria, business
Abstract

White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM (2014) Malaria. Lancet 383:723–735 Tangpukdee N, Duangdee C, Wilairatana P, Krudsood S (2009) Malaria diagnosis: a brief review. Korean J Parasitol 47(2):93–102 World Malaria Report 2018 (2018) World Health Organization, Geneva. https://www.who.int/malaria/publications/world-malaria-report-2018/en/ Karnad DR, Nor MBM, Richards GA, Baker T, Amin P, on behalf of the Council of the World Federation of Societies of Intensive and Critical Care Medicine (2018) Intensive care in severe malaria: report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. J Crit Care 43:356–360 Dondorp AM, Hoang MNT, Mer M, Sepsis in Resource-Limited Settings-Expert Consensus Recommendations Group of the European Society of Intensive Care Medicine (ESICM) and the Mahidol-Oxford Research Unit (MORU) in Bangkok, Thailand (2017) Recommendations for the management of severe malaria and severe dengue in resource-limited settings. Intensive Care Med 43(11):1683–1685 Odilini S, Parola P, Gkrania-Klotsas E, Caumes E, Schlagenhauf P, Lopez-Velez R, Burchard GD, Santos-O’Connor F, Weld L, von Sonnenburg F, Field V, de Vries P, Jensenius M, Loutan L, Castelli F (2012) Travel-related important infections in Europe, EuroTravNet 2009. Clin Microbiol Infect 18:468 Leder K, Torresi J, Libman MD, Cramer JP, Castelli F, Schlagenhauf P, Wilder-Smith A, Wilson ME, Keystone JS, Schwartz E, Barnett ED, von Sonnenburg F, Browstein JS, Cheng AC, Sotir MJ, Esposito DH, Freedman DO, GeoSentinel Surveillance Network (2013) Geosentinel surveillance of illness of returned travellers, 2007-2011. Ann Intern Med 158:456–468 Jensenius M, Han PY, Schagenhauf P, Schwartz E, Parola P, Castelli F, von Sonnenburg Loutau L, Leder K, Freedman DO (2013) Acute and potentially life-threatening diseases in western travellers—a GeoSentinel multicentre study 1996–2011. Am J Trop Med Hyg 88(2):397–404 Marks M, Gupta-Wright A, Doherty JF, Singer M, Walker D (2014) Managing malaria in the intensive care unit. Brit J Anaesth 113(6):910–921 Trivedi T, Bajaj P, Moulick N, Padwal N (2014) Mortality in malaria: Intensive care (MIMIC). J Assoc Phys India 66:16–20 World Health Organization (2014) Severe malaria. Trop Med Int Health 19 (Suppl 1): 7–131. Guidelines for the treatment of malaria (2015). 3rd edn. World Health Organization World Health Organization (2015) Guidelines for the treatment of malaria, 3rd edn. World Health Organization, Geneva World Health Organization. Global Health Observatory (GHO) data. www.int/gho/malaria/en. Accessed 11 Aug 2019 Gething PW, Patil AP, Smith DL, Guerra CA, Elyazar IRF, Johnston GL, Tatem AJ, Hay SI (2011) A new world malaria map: plasmodium endemicity in 2010. Malar J 10:378 Centres for Disease Control and Prevention. Where malaria occurs. https://www.cdc.gov/malaria/about/distribution.html. Accessed 11 Aug 2019 Pasvol G (2005) Management of severe malaria: interventions and controversies. Infect Dis Clin N Am 19:211–240 Dondorp AM, Lee SJ, Faiz MA, Mishra S, Price R, Tjitra E, Than M, Htut Y, Mohanty S, Yunus ER, Rahman R, Nosten F, Anstey NM, Day NP, White NJ (2008) The relationship between age and the manifestations of mortality associated with severe malaria. Clin Infect Dis 47(2):151–157 Von Seidlein L, Olaosebikan R, Hendriksen IC, Lee SJ, Adedoyin OT, Agbenyega T, Nguah SB, Bojang K, Deen JL, Evans J, Fanello CI, Gomes E, Pedro AJ, Kahabuka C, Karema C, Kivaya E, Maitland K, Mokuolu OA, Mtove G, Mwanga-Amumpaire J, Nadim B, Nansumba M, Ngum WP, Onyamboko MA, Reyburn H, Sakulthaew T, Silamut K, Tshefu AK, Umulisa N, Gesase S, Day NP, Dondorp AM, Dondorp AM (2012) Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial. Clin Infect Dis 54(8):1080–1090 Day NP, Phu NH, Mai NT, Chau TT, Loc PP, Chuong LV, Sinh DX, Holloway P, Hien TT, White NJ (2000) The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med 28:1833–1840 Plewes K, Turner GDH, Dondorp AM (2018) Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria. Curr Opin Infect Dis 31:69–77 Enomoto M, Kawazu S-I, Kawai S, Furuyama W, Ikegami T, Wantanabe J, Mikoshiba K (2012) Blockage of spontaneous Ca2+ oscillation causes cell death in intraerythrocytic Plasmodium falciparum. PLoS ONE 7(7):e39499 Centres for Disease Control and Prevention. Biology: Lifecycle. https://www.cdc.gov/malaria/about/biology/index.html. Accessed 11 Aug 2019 MacKintosh CL, Beeson JG, Marsh K (2004) Clinical features and pathogenesis of severe malaria. Trends Parasitol 20(12):597–603 Miller LH, Good MF, Milon G (1994) Malaria pathogenesis. Science 264(5167):1878–1883 Milner DA Jr (2018) Malaria pathogenesis. Cold Spring Harb Perspec Med 8(1):pii: a025569 Dondorp AM (2008) Clinical significance of sequestration in adults with severe malaria. Transfus Clin Biol 15(1–2):56 Ponsford MJ, Medana IM, Prapanslip P, Hien TT, Lee SJ, Dondorp AM, Esiri MM, Day NP, White NJ, Turner GD (2012) Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis 205(4):663–671 Newbold C, Craig A, Kyes S, Rowe A, Fernandez-Reyes D, Fagan T (1999) Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum. Int J Parasitol 29(6):927 Wassmer SC, Taylor TE, Rathod PK, Mishra SK, Mohanty S, Arevalo-Herrera M, Duraisingh MT, Smith JD (2015) Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am J Trop Med Hyg 93(3 Suppl):42 Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J, Craddock CFC, Nosten F, Chapman D, Brewster D, Holloway PA, White NJ (1994) Lactic acidosis...

Published
2020

141. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial

Author

Rob W van der Pluijm, Rupam Tripura, Richard M Hoglund, Aung Pyae Phyo, Dysoley Lek, Akhter ul Islam, Anupkumar R Anvikar, Parthasarathi Satpathi, Sanghamitra Satpathi, Prativa Kumari Behera, Amar Tripura, Subrata Baidya, Marie Onyamboko, Nguyen Hoang Chau, Yok Sovann, Seila Suon, Sokunthea Sreng, Sivanna Mao, Savuth Oun, Sovannary Yen, Chanaki Amaratunga, Kitipumi Chutasmit, Chalermpon Saelow, Ratchadaporn Runcharern, Weerayuth Kaewmok, Nhu Thi Hoa, Ngo Viet Thanh, Borimas Hanboonkunupakarn, James J Callery, Akshaya Kumar Mohanty, James Heaton, Myo Thant, Kripasindhu Gantait, Tarapada Ghosh, Roberto Amato, Richard D Pearson, Christopher G Jacob, Sónia Gonçalves, Mavuto Mukaka, Naomi Waithira, Charles J Woodrow, Martin P Grobusch, Michele van Vugt, Rick M Fairhurst, Phaik Yeong Cheah, Thomas J Peto, Lorenz von Seidlein, Mehul Dhorda, Richard J Maude, Markus Winterberg, Nguyen Thanh Thuy-Nhien, Dominic P Kwiatkowski, Mallika Imwong, Podjanee Jittamala, Khin Lin, Tin Maung Hlaing, Kesinee Chotivanich, Rekol Huy, Caterina Fanello, Elizabeth Ashley, Mayfong Mayxay, Paul N Newton, Tran Tinh Hien, Neena Valecha, Frank Smithuis, Sasithon Pukrittayakamee, Abul Faiz, Olivo Miotto, Joel Tarning, Nicholas P J Day, Nicholas J White, Arjen M Dondorp, Nguyen T Thuy-Nhien, Neena Valeche, Nicholas PJ Day, Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, APH - Global Health, APH - Quality of Care, and Intensive Care Medicine

Subjects
medicine.medical_specialty, Amodiaquine, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, parasitic diseases, medicine, Humans, 030212 general & internal medicine, Artemether, Artemisinin, Malaria, Falciparum, Intention-to-treat analysis, biology, business.industry, Mefloquine, Plasmodium falciparum, General Medicine, Articles, medicine.disease, biology.organism_classification, Artemisinins, Malaria, Tolerability, business, medicine.drug
Abstract

Summary Background Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. Methods In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin–piperaquine or dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. Findings Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin–piperaquine (183 [17%]), dihydroartemisinin–piperaquine plus mefloquine (269 [24%]), artesunate–mefloquine (73 [7%]), artemether–lumefantrine (289 [26%]), or artemether–lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p

Published
2020

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

Author

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

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

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

Published
2020

143. Comparison of Antibody Responses and Parasite Clearance in Artemisinin Therapeutic Efficacy Studies in the Democratic Republic of Congo and Asia

Author

Julia C Cutts, Katherine O’Flaherty, Sophie G Zaloumis, Elizabeth A Ashley, Jo Anne Chan, Marie A Onyamboko, Caterina Fanello, Arjen M Dondorp, Nicholas P Day, Aung Pyae Phyo, Mehul Dhorda, Mallika Imwong, Rick M Fairhurst, Pharath Lim, Chanaki Amaratunga, Sasithon Pukrittayakamee, Tran Tinh Hien, Ye Htut, Mayfong Mayxay, M Abdul Faiz, Eizo Takashima, Takafumi Tsuboi, James G Beeson, Francois Nosten, Julie A Simpson, Nicholas J White, Freya J I Fowkes, AII - Infectious diseases, and Intensive Care Medicine

Subjects
Plasmodium falciparum, malaria, Drug Resistance, Artemisinins, resistance, Antimalarials, Infectious Diseases, artemisinin, parasite, Antibody Formation, Democratic Republic of the Congo, antibodies, Immunology and Allergy, Animals, Humans, Parasites, Malaria, Falciparum, Child
Abstract

Background Understanding the effect of immunity on Plasmodium falciparum clearance is essential for interpreting therapeutic efficacy studies designed to monitor emergence of artemisinin drug resistance. In low-transmission areas of Southeast Asia, where resistance has emerged, P. falciparum antibodies confound parasite clearance measures. However, variation in naturally acquired antibodies across Asian and sub-Saharan African epidemiological contexts and their impact on parasite clearance re yet to be quantified. Methods In an artemisinin therapeutic efficacy study, antibodies to 12 pre-erythrocytic and erythrocytic P. falciparum antigens were measured in 118 children with uncomplicated P. falciparum malaria in the Democratic Republic of Congo (DRC) and compared with responses in patients from Asian sites, described elsewhere. Results Parasite clearance half-life was shorter in DRC patients (median, 2 hours) compared with most Asian sites (median, 2–7 hours), but P. falciparum antibody levels and seroprevalences were similar. There was no evidence for an association between antibody seropositivity and parasite clearance half-life (mean difference between seronegative and seropositive, −0.14 to +0.40 hour) in DRC patients. Conclusions In DRC, where artemisinin remains highly effective, the substantially shorter parasite clearance time compared with Asia was not explained by differences in the P. falciparum antibody responses studied.

Published
2022

144. An improved pharmacometric model for artesunate treatment of falciparum malaria

Author

Sompob Saralamba, Julie A Simpson, Noppon Choosri, Lisa White, Wirichada Pan-Ngum, Arjen M Dondorp, and Nicholas J White

Abstract

Previous mathematical models characterising the pharmacokinetic and pharmacodynamic properties of artemisinins in-vivo have not accounted satisfactorily for observed dose-response relationships. We present a new mathematical model of antimalarial pharmacodynamics which incorporates the hypothesis that parasites enter a transitional unresponsive state after contact with artemisinins, followed either by delayed death or reactivation. The model predictions are consistent with both in vitro and in vivo study results.

Published
2022

145. PRICE COVID19 Data Report December 2021 Pakistan Registry of Intensive Care

Author

Ahmed farooq, Rahatullah Arsalan, Mufti Kulsoom Aisha, Asim Muhammad, Muhammad Hayat, Aneela Altaf, Arshad Taqi, Ashok Kumar, Attaur Rehman, Fakhir Raza Haidri, Iqbal Hussain, Mobin Chaudhry, Safdar Rehman, Irfan Malik, Jodat Saleem, Liaquat Ali, Muhammad Ashraf Zia, Maria Ali Khan, Mohiuddin Sheikh, Muhammad Sheharyar Ashraf, Muhammad Asim Rana, Muhammad Nasir Khoso, Saadiya Rizvi, Naseem Ali Shaikh, Nawal Salahuddin, Qurat-ul-Ain Khan, Rana Imran Sikander, Syed Muneeb Ali, Rashid Nasim Khan, Sairah Babar, Abigail Beane, Arjen M Dondorp, Chamira Kodippily, Dilanthi Priyadarshani, Ishara Udayanga, Pramodya Ishani, Sri Darshana, Thalha Rashan, Rashan Haniffa, Srinivas Murthy, and Madiha Hashmi

Abstract

Pakistan Registry of Intensive Care (PRICE) is a platform that has enabled standardized COVID-19 clinical data collection based on ISARIC/WHO Clinical Characterization Protocol. The near real-time data platform includes epidemiology, severity of illness, microbiology, treatment and outcomes of patients admitted with suspected or laboratory confirmed COVID19 infection to 67 intensive care and high dependency units across the country. Data has been extracted and analysed at regular intervals to inform stakeholders and improve care practices. This is our 28th report including all patients with suspected or confirmed COVID-19 from 26th March 2020 to 26th December 2021. Key findings from 8624 patients who met eligibility criteria, are as follows: ● Median age of 60 years (IQR 50-70). ● The most common symptoms were shortness of breath (n = 6428, 77.8%), fever (n = 6091, 73.8%), and Cough (n = 3354, 38.9%) ● The most common comorbidity was hypertension followed by diabetes. ● During the course of illness 2804 (32.6%) patients received non-invasive ventilation, whereas 2474 (28.8%) patients had mechanical ventilation as their highest organ support. In addition, 2246 (26.1%) patients needed haemodynamic support and 1249 (14.7%) patients required renal replacement therapy as their highest organ support. ● Median APACHE II score was 18 ● Overall mortality at ICU discharge was 39.2% ● Increasing age and requirement for invasive mechanical ventilation were independent risk factors for mortality increased the risk of death

Published
2022

146. Assessment

Author

Achaporn, Yipsirimetee, Pornpawee, Chiewpoo, Rupam, Tripura, Dysoley, Lek, Nicholas P J, Day, Arjen M, Dondorp, Sasithon, Pukrittayakamee, Nicholas J, White, and Kesinee, Chotivanich

Subjects
Male, Antimalarials, Indoles, Susceptibility, Plasmodium falciparum, Imidazoles, Animals, Female, Spiro Compounds, Malaria, Falciparum, Artemisinins, Piperazines
Abstract

Artemisinin resistance in Plasmodium falciparum has emerged and spread widely in the Greater Mekong Subregion, threatening current first-line artemisinin combination treatments. New antimalarial drugs are needed urgently. Cipargamin (KAE609) and ganaplacide (KAF156) are promising novel antimalarial compounds in advanced stages of development. Both compounds have potent asexual blood stage activities, inhibit P. falciparum gametocytogenesis, and reduce oocyst development in anopheline mosquitoes. In this study, we compared the asexual and sexual stage activities of cipargamin, ganaplacide, and artesunate in artemisinin-resistant P. falciparum isolates (n = 6; K13 mutations C580Y, G449A, and R539T) from Thailand and Cambodia. Asexual blood stage antimalarial activity was evaluated in a SYBR-green I-based 72-h in vitro assay, and the effects on male and female mature stage V gametocytes were assessed in the P. falciparum dual gamete formation assay. Ganaplacide had higher activities than cipargamin and artesunate, with mean (standard deviation [SD]) 50% inhibitory concentrations (IC(50)s) against asexual stages of 5.6 (1.2) nM and 6.9 (3.8) nM for male gametocytes and 47.5 (54.7) nM for female gametocytes. Cipargamin had a similar potency against male and female gametocytes, with mean (SD) IC(50)s of 115.6 (66.9) nM for male gametocytes, 104.9 (84.3) nM for female gametocytes, and 2.4 (0.7) nM for asexual stages. Both cipargamin and ganaplacide showed significant transmission-blocking activities against artemisinin-resistant P. falciparum in vitro.

Published
2022

147. Age-Dosed Single Low Dose Primaquine in Falciparum-Infected African Children with G6pd Deficiency is Well Tolerated and Safe

Author

Walter Taylor, Peter Olupot Oluput, Marie Onyamboko, Pimnara Peerawaranun, Winifred Were, Cate Namayanja, Peter Onyas, Harriet Titin, Joy Baseke, Rita Muhindo, Daddy K. Kayembe, Pauline Ndjowo, Charles Okalebo, Grace Abongo, Sophie Ugoya, Thomas N. Williams, Chiraporn Taya, Mehul Dhorda, Joel Tarning, Arjen M. Dondorp, Caterina Fanello, Kathryn Maitland, Mavuto Mukaka, and Nicholas P. J. Day

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2022

148. Mixed methods study protocol for combining stakeholder-led rapid evaluation with near real-time continuous registry data to facilitate evaluations of quality of care in intensive care units

Author

Aasiyah Rashan, Wangari Waweru-Siika, Swagata Tripathy, Catherine Thwaites, Arjen M Dondorp, Mohd Basri Mat Nor, David Thomson, Luigi Pisani, Timo Tolppa, Rashan Haniffa, Hem Raj Paneru, Madiha Hashmi, Jorge Salluh, Tiffany Gooden, Snehal Pinto Pereira, Ishara Udayanga, Dilanthi Priyadarshani Gamage Dona, Maryam Shamal Ghalib, Diptesh Aryal, Aniruddha Ghose, Abigail Beane, and Bharath Kumar Tirupakuzhi Vijayaraghavan

Subjects
Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology
Abstract

Background: Improved access to healthcare in low- and middle-income countries (LMICs) has not equated to improved health outcomes. Absence or unsustained quality of care is partly to blame. Improving outcomes in intensive care units (ICUs) requires delivery of complex interventions by multiple specialties working in concert, and the simultaneous prevention of avoidable harms associated with the illness and the treatment interventions. Therefore, successful design and implementation of improvement interventions requires understanding of the behavioural, organisational, and external factors that determine care delivery and the likelihood of achieving sustained improvement. We aim to identify care processes that contribute to suboptimal clinical outcomes in ICUs located in LMICs and to establish barriers and enablers for improving the care processes. Methods: Using rapid evaluation methods, we will use four data collection methods: 1) registry embedded indicators to assess quality of care processes and their associated outcomes; 2) process mapping to provide a preliminary framework to understand gaps between current and desired care practices; 3) structured observations of processes of interest identified from the process mapping and; 4) focus group discussions with stakeholders to identify barriers and enablers influencing the gap between current and desired care practices. We will also collect self-assessments of readiness for quality improvement. Data collection and analysis will be performed in parallel and through an iterative process across eight countries: Kenya, India, Malaysia, Nepal, Pakistan, South Africa, Uganda and Vietnam. Conclusions: The results of our study will provide essential information on where and how care processes can be improved to facilitate better quality of care to critically ill patients in LMICs; thus, reduce preventable mortality and morbidity in ICUs. Furthermore, understanding the rapid evaluation methods that will be used for this study will allow other researchers and healthcare professionals to carry out similar research in ICUs and other health services.

Published
2023

149. Genetic population of Plasmodium knowlesi during pre-malaria elimination in Thailand

Author

Usa Boonyuen, Watcharee Pagornrat, Suttipat Srisutham, Mallika Imwong, Patcharida Boondej, Prayuth Sudathip, Aungkana Saejeng, Chanon Kunasol, Rungniran Sug-aram, Arjen M. Dondorp, and Intensive Care Medicine

Subjects
Genetic Markers, Lineage (genetic), RC955-962, Genes, Protozoan, 030231 tropical medicine, Protozoan Proteins, Infectious and parasitic diseases, RC109-216, Drug resistance, 03 medical and health sciences, 0302 clinical medicine, Arctic medicine. Tropical medicine, parasitic diseases, medicine, Humans, Plasmodium knowlesi, Disease Eradication, pkdhfr, Genotyping, 030304 developmental biology, 0303 health sciences, biology, Incidence, Research, pkmsp1, Thailand, medicine.disease, biology.organism_classification, Virology, Malaria, 3. Good health, Infectious Diseases, Pyrimethamine, Microsatellite, Parasitology, Nested polymerase chain reaction, medicine.drug
Abstract

Background Thailand is committed to eliminating malaria by 2024. From 2013 to 2020, the total number of malaria cases have decreased, from 37,741 to 4474 (an 88.1% reduction). However, infections with Plasmodium knowlesi, a monkey malarial pathogen that can also infect humans, have been increasingly observed. This study focused on the molecular analysis of P. knowlesi parasites causing malaria in Thailand. Methods Under Thailand’s integrated Drug Efficacy Surveillance (iDES), which includes drug-resistance monitoring as part of routine case-based surveillance and responses, specimens were collected from malaria patients (n = 966) between 2018 and 2020. Thirty-one mono P. knowlesi infections (3.1%), most of which were from eastern and southern Thailand, were observed and confirmed by nested PCR assay and DNA sequencing. To evaluate whether these pathogens were from different lineages, cluster analysis based on seven microsatellite genotyping markers and the merozoite surface protein 1 (pkmsp1) gene was carried out. The P. knowlesi pyrimethamine resistance gene dihydrofolate reductase (pkdhfr) was sequenced and homology modelling was constructed. Results The results of analysing the seven microsatellite markers and pkmsp1 sequence demonstrated that P. knowlesi parasites from eastern Thailand were of the same lineage as those isolated in Cambodia, while the parasites causing malaria in southern Thailand were the same lineage as those isolated from Malaysia. The sequencing results for the pkdhfr genes indicated the presence of two mutations, Arg34Leu and a deletion at position 105. On analysis with homology modelling, the two mutations were not associated with anti-malarial drug resistance. Conclusions This report compared the genetic populations of P. knowlesi parasites in Thailand from 2018 to 2020 and have shown similar lineages as those isolated in Cambodia and Malaysia of P. knowlesi infection in Thailand and demonstrated that the P. knowlesi parasites were of the same lineages as those isolated in Cambodia and Malaysia. The parasites were also shown to be sensitive to pyrimethamine.

Published
2021

150. A scoping review of registry captured indicators for evaluating quality of critical care in ICU

Author

Abi Beane, Sumayyah Rashan, Issrah Jawad, Chathurani Sigera, Arjen M. Dondorp, Jorge I. F. Salluh, Rashan Haniffa, and Intensive Care Medicine

Subjects
MEDLINE, Psychological intervention, Quality indicators, CINAHL, Critical Care and Intensive Care Medicine, 03 medical and health sciences, Patient safety, 0302 clinical medicine, Intensive care, Medicine, 030212 general & internal medicine, business.industry, RC86-88.9, Health system improvement, Research, 030208 emergency & critical care medicine, Medical emergencies. Critical care. Intensive care. First aid, Benchmarking, medicine.disease, 3. Good health, ICU, Patient-reported outcome, Medical emergency, business, Critical illness, Health care quality
Abstract

Background Excess morbidity and mortality following critical illness is increasingly attributed to potentially avoidable complications occurring as a result of complex ICU management (Berenholtz et al., J Crit Care 17:1-2, 2002; De Vos et al., J Crit Care 22:267-74, 2007; Zimmerman J Crit Care 1:12-5, 2002). Routine measurement of quality indicators (QIs) through an Electronic Health Record (EHR) or registries are increasingly used to benchmark care and evaluate improvement interventions. However, existing indicators of quality for intensive care are derived almost exclusively from relatively narrow subsets of ICU patients from high-income healthcare systems. The aim of this scoping review is to systematically review the literature on QIs for evaluating critical care, identify QIs, map their definitions, evidence base, and describe the variances in measurement, and both the reported advantages and challenges of implementation. Method We searched MEDLINE, EMBASE, CINAHL, and the Cochrane libraries from the earliest available date through to January 2019. To increase the sensitivity of the search, grey literature and reference lists were reviewed. Minimum inclusion criteria were a description of one or more QIs designed to evaluate care for patients in ICU captured through a registry platform or EHR adapted for quality of care surveillance. Results The search identified 4780 citations. Review of abstracts led to retrieval of 276 full-text articles, of which 123 articles were accepted. Fifty-one unique QIs in ICU were classified using the three components of health care quality proposed by the High Quality Health Systems (HQSS) framework. Adverse events including hospital acquired infections (13.7%), hospital processes (54.9%), and outcomes (31.4%) were the most common QIs identified. Patient reported outcome QIs accounted for less than 6%. Barriers to the implementation of QIs were described in 35.7% of articles and divided into operational barriers (51%) and acceptability barriers (49%). Conclusions Despite the complexity and risk associated with ICU care, there are only a small number of operational indicators used. Future selection of QIs would benefit from a stakeholder-driven approach, whereby the values of patients and communities and the priorities for actionable improvement as perceived by healthcare providers are prioritized and include greater focus on measuring discriminable processes of care.

Published
2021

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