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1. Viral Dynamics and Immune Correlates of Coronavirus Disease 2019 (COVID-19) Severity

Author

Young, Barnaby E, Ong, Sean W X, Ng, Lisa F P, Anderson, Danielle E, Chia, Wan Ni, Chia, Po Ying, Ang, Li Wei, Mak, Tze-Minn, Kalimuddin, Shirin, Chai, Louis Yi Ann, Pada, Surinder, Tan, Seow Yen, Sun, Louisa, Parthasarathy, Purnima, Fong, Siew-Wai, Chan, Yi-Hao, Tan, Chee Wah, Lee, Bernett, Rötzschke, Olaf, Ding, Ying, Tambyah, Paul, Low, Jenny G H, Cui, Lin, Barkham, Timothy, Lin, Raymond Tzer Pin, Leo, Yee-Sin, Renia, Laurent, Wang, Lin-Fa, Lye, David Chien, Lim, Poh Lian, Peng Ang, Brenda Sze, Lee, Cheng Chuan, U Lee, Lawrence Soon, Ling, Li Min, Ng, Oon Tek, Chan, Monica, Marimuthu, Kalisvar, Vasoo, Shawn, Wong, Chen Seong, Lee, Tau Hong, Sadarangani, Sapna, Lin, Ray Junhao, Sadasiv, Mucheli Sharavan, Ling Ng, Deborah Hee, Choy, Chiaw Yee, En Tan, Glorijoy Shi, Tan, Yu Kit, Sutjipto, Stephanie, Lee, Pei Hua, Tay, Jun Yang, Yeo, Tsin Wen, Khoo, Bo Yan, Tay, Woo Chiao, Ng, Gabrielle, Mah, Yun Yuan, Tan, Wilnard, De, Partha Pratim, Pooja, Rao, Chia, Jonathan W Z, Constance Chen, Yuan Yi, Mendis, Shehara, Toh, Boon Kiat, Choon Fong, Raymond Kok, Lin Oh, Helen May, Fong Chien, Jaime Mei, Shafi, Humaira, Cheong, Hau Yiang, Tan, Thean Yen, Tan, Thuan Tong, Tan, Ban Hock, Wijaya, Limin, Venkatachalam, Indumathi, Chua, Ying Ying, Zhi Cherng, Benjamin Pei, Zi Chan, Yvonne Fu, Wong, Hei Man, Thien, Siew Yee, Meng Goh, Kenneth Choon, Ling Tan, Shireen Yan, Ean Oon, Lynette Lin, Chan, Kian Sing, Lin, Li, Gin Chan, Douglas Su, Ooi, Say Tat, Narayana, Deepak Rama, Somani, Jyoti, Ling Oon, Jolene Ee, Yan, Gabriel Zherong, Allen, David Michael, Jureen, Roland, Yan, Benedict, Foo, Randy, Kang, Adrian, Sivalingam, Velraj, How, Wilson, Fernandez, Norman Leo, Yeo, Nicholas Kim-Wah, Chee, Rhonda Sin-Ling, Amrun, Siti Naqiah, Lee Kong Chian School of Medicine (LKCMedicine), National Centre for Infectious Diseases, Tan Tock Seng Hospital, Yong Loo Lin School of Medicine, NUS, and Saw Swee Hock School of Public Health, NUS

Subjects
0301 basic medicine, Microbiology (medical), biology, Viral culture, business.industry, 030106 microbiology, COVID-19, medicine.disease, 03 medical and health sciences, Pneumonia, 0302 clinical medicine, Infectious Diseases, Immune system, Immunoglobulin M, Viral pneumonia, Immunology, Severity of illness, medicine, biology.protein, Cytokines, Medicine [Science], 030212 general & internal medicine, Seroconversion, Antibody, business
Abstract

Background Key knowledge gaps remain in the understanding of viral dynamics and immune response of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Methods We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age, 46 years; 56% male; 38% with comorbidities). Respiratory samples (n = 74) were collected for viral culture, serum samples for measurement of IgM/IgG levels (n = 30), and plasma samples for levels of inflammatory cytokines and chemokines (n = 81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. Results Fifty-seven (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen, including 12 (12%) with invasive mechanical ventilation. Viral culture from respiratory samples was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was >30 or >14 days after symptom onset. Seroconversion occurred at a median (IQR) of 12.5 (9–18) days for IgM and 15.0 (12–20) days for IgG; 54/62 patients (87.1%) sampled at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB, and IL-1RA significantly correlated with disease severity. Conclusions We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offer targets for host-directed immunotherapy, which should be evaluated in randomized controlled trials.

Published
2020
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2. Family-focused contextual factors associated with lifestyle patterns in young children from two mother-offspring cohorts: GUSTO and EDEN

Author

Airu Chia, Alexandra Descarpentrie, Rene N. Cheong, Jia Ying Toh, Padmapriya Natarajan, Ray Sugianto, Shirong Cai, Cécilia Saldanha-Gomes, Patricia Dargent-Molina, Blandine de Lauzon-Guillain, Sabine Plancoulaine, Carla Lança, Seang Mei Saw, Keith M. Godfrey, Lynette P. Shek, Kok Hian Tan, Marie-Aline Charles, Yap Seng Chong, Barbara Heude, Johan G. Eriksson, Falk Müller-Riemenschneider, Sandrine Lioret, Mary F.-F. Chong, Jonathan Y. Bernard, Clinicum, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Saw Swee Hock School of Public Health [Singapore, Singapore], National University of Singapore (NUS), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Singapore Institute for Clinical Sciences, Agency for science, technology and research [Singapore] (A*STAR), Singapore Institute for Clinical Sciences [Singapour] (SICS), Singapore Eye Research Institute [Singapore] (SERI), NIHR Southampton Biomedical Research Centre, Yong Loo Lin School of Medicine [Singapore], KK Women's and Children's Hospital [Singapore], This research is supported by the Paris‐NUS grant (ANR‐18‐IDEX‐0001).The EDEN study is supported by Foundation for Medical Research (FRM), National Agency for Research (ANR), National Institute for Research in Public Health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO‐A), and Human Nutrition National Research Programs, Paris‐Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS.), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007–2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaborationwith the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale a complementary health insurance (MGEN), French National Agency for Food Security, French‐speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM).The GUSTO study is supported by the Singapore National Research Founda‐ tion under its Translational and Clinical Research Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council, Singapore ‐ NMRC/TCR/004‐NUS/2008, NMRC/TCR/012‐NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore. KMG is supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator (NF‐SI‐0515‐10042) and NIHR South‐ ampton Biomedical Research Centre (IS‐BRC‐1215‐20004)), the European Union (Erasmus+ Programme ImpENSA 598488‐EPP‐1‐2018‐1‐DE‐EPPKA2‐ CBHE‐JP) and the British Heart Foundation (RG/15/17/3174). The funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript., and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)

Subjects
Male, QUESTIONNAIRE, Mothers, Medicine (miscellaneous), Physical Therapy, Sports Therapy and Rehabilitation, Pregnancy, FOOD, Humans, Hierarchical analysis, VALIDITY, Child, Life Style, Nutrition and Dietetics, Physical activity, Preschool children, 1184 Genetics, developmental biology, physiology, Feeding Behavior, ADULTS, Screen time, Diet, DIETARY PATTERNS, PHYSICAL-ACTIVITY, Lifestyle patterns, Child, Preschool, OBESITY, 3121 General medicine, internal medicine and other clinical medicine, Female, Television, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Family ecological model, Snacks, 3143 Nutrition, TRANSITION
Abstract

Background Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. Purpose Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. Methods Ten behavioural variables related to child’s diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5–6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. Results Three broadly similar lifestyle patterns were identified in both cohorts: “discretionary consumption and high screen time”, “fruit, vegetables, and low screen time” and “high outdoor playtime and walking”. The latter two patterns showed small differences between cohorts and sexes. The “discretionary consumption and high screen time” pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. Conclusions Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

Published
2022
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3. Data-Driven Analysis of COVID-19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals

Author

Jackwee Lim, Kia Joo Puan, Liang Wei Wang, Karen Wei Weng Teng, Chiew Yee Loh, Kim Peng Tan, Guillaume Carissimo, Yi-Hao Chan, Chek Meng Poh, Cheryl Yi-Pin Lee, Siew-Wai Fong, Nicholas Kim-Wah Yeo, Rhonda Sin-Ling Chee, Siti Naqiah Amrun, Zi Wei Chang, Matthew Zirui Tay, Anthony Torres-Ruesta, Norman Leo Fernandez, Wilson How, Anand Kumar Andiappan, Wendy Lee, Kaibo Duan, Seow-Yen Tan, Gabriel Yan, Shirin Kalimuddin, David Chien Lye, Yee-Sin Leo, Sean W. X. Ong, Barnaby E. Young, Laurent Renia, Lisa F. P. Ng, Bernett Lee, Olaf Rötzschke, Lee Kong Chian School of Medicine (LKCMedicine), National Centre for Infectious Diseases, Tan Tock Seng Hospital, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, and Saw Swee Hock School of Public Health, National University of Singapore

Subjects
Adult, Male, Immunology, Cytokine Profile, severity, Inflammation, cytokine profile, CD38, active infection, Cohort Studies, Post-Acute COVID-19 Syndrome, Immune system, immunophenotyping, medicine, Humans, Immunology and Allergy, Medicine [Science], Aged, Original Research, CD86, SARS-CoV-2, business.industry, COVID-19, Convalescence, Middle Aged, immune recovery, RC581-607, Vascular endothelial growth factor A, inflammation, SARS – CoV – 2, Female, Hepatocyte growth factor, Interleukin-3 receptor, Immunologic diseases. Allergy, medicine.symptom, business, CD8, medicine.drug
Abstract

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of "long COVID-19", and defines key cells and cytokines that delineate true and quasi-convalescent states. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by A*STAR Infectious Diseases Labs and Singapore Immunology Network (SIgN) core research grants, and the A*STAR COVID-19 Research funding (H/20/04/g1/006) provided to SIgN by the Biomedical Research Council (BMRC). Subject recruitment, sample collection and analyses were funded by the National Medical Research Council (NMRC) COVID-19 Research Fund (COVID19RF-001, COVID19-RF007, COVID190RF-060). The SIgN Immunomonitoring Platform is supported by a BMRC IAF 311006 grant and BMRC transition funds #H16/99/b0/011. The SIgN Flow Cytometry and the Multiple Analyte Platforms were supported by a grant from the National Research Foundation, Immunomonitoring Service Platform ISP) (#NRF2017_SISFP09) and the National Research Foundation Singapore (NRF).

Published
2021
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4. Analysis of COVID-19 Incidence and Severity Among Adults Vaccinated With 2-Dose mRNA COVID-19 or Inactivated SARS-CoV-2 Vaccines With and Without Boosters in Singapore

Author

Oon Tek Ng, Kalisvar Marimuthu, Nigel Lim, Ze Qin Lim, Natascha May Thevasagayam, Vanessa Koh, Calvin J. Chiew, Stefan Ma, Mingshi Koh, Pin Yan Low, Say Beng Tan, Joses Ho, Sebastian Maurer-Stroh, Vernon J. M. Lee, Yee-Sin Leo, Kelvin Bryan Tan, Alex R. Cook, Chorh Chuan Tan, Lee Kong Chian School of Medicine (LKCMedicine), National Centre for Infectious Diseases, Singapore, Tan Tock Seng Hospital, Yong Loo Lin School of Medicine, NUS, National University Health System, Singapore, and Saw Swee Hock School of Public Health

Subjects
Male, Singapore, Vaccines, Synthetic, COVID-19 Vaccines, SARS-CoV-2, Messenger RNA, Incidence, COVID-19, Viral Vaccines, General Medicine, Middle Aged, Cohort Studies, Coronavac, Humans, Medicine [Science], Female, RNA, Messenger, mRNA Vaccines, BNT162 Vaccine, Aged
Abstract

ImportanceAssessing booster effectiveness of COVID-19 mRNA vaccine and inactivated SARS-CoV-2 vaccine over longer time intervals and in response to any further SARS-CoV-2 variants is crucial in determining optimal COVID-19 vaccination strategies.ObjectiveTo determine levels of protection against severe COVID-19 and confirmed SARS-CoV-2 infection by types and combinations of vaccine boosters in Singapore during the Omicron wave.Design, Setting, and ParticipantsThis cohort study included Singapore residents aged 30 years or more vaccinated with either at least 2 doses of mRNA COVID-19 vaccines (ie, Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273) or inactivated SARS-CoV-2 vaccines (Sinovac CoronaVac or Sinopharm BBIBP-CorV) as of March 10, 2022. Individuals with a known SARS-CoV-2 infection prior to December 27, 2021, an infection on or before the date of their second vaccine dose, or with reinfection cases were excluded.ExposuresTwo or 3 doses of Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Sinovac CoronaVac, or Sinopharm BBIBP-CorV.Main Outcomes and MeasuresNotified infections from December 27, 2021, to March 10, 2022, adjusted for age, sex, race, housing status, and calendar days. Estimated booster effectiveness, defined as the relative incidence-rate reduction of severe disease (supplemental oxygen, intensive care, or death) or confirmed infection following 3-dose vaccination compared with 5 months after second mRNA dose, was determined using binomial regression.ResultsAmong 2 441 581 eligible individuals (1 279 047 [52.4%] women, 846 110 (34.7%) aged 60 years and older), there were 319 943 (13.1%) confirmed SARS-CoV-2 infections, of which 1513 (0.4%) were severe COVID-19 cases. mRNA booster effectiveness against confirmed infection 15 to 60 days after boosting was estimated to range from 31.7% to 41.3% for the 4 boosting combinations (homologous BNT162b2, homologous mRNA-1273, 2-dose BNT162b2/mRNA-1273 booster, and 2-dose mRNA-1273/BNT162b2 booster). Five months and more after boosting, estimated booster effectiveness against confirmed infection waned, ranging from –2.8% to 14.6%. Against severe COVID-19, estimated mRNA booster effectiveness was 87.4% (95% CI, 83.3%-90.5%) 15 to 60 days after boosting and 87.2% (95% CI, 84.2%-89.7%) 5 to 6 months after boosting, with no significant difference comparing vaccine combinations. Booster effectiveness against severe COVID-19 15 days to 330 days after 3-dose inactivated COVID-19 vaccination, regardless of combination, was estimated to be 69.6% (95% CI, 48.7%-81.9%).Conclusions and RelevanceBooster mRNA vaccine protection against severe COVID-19 was estimated to be durable over 6 months. Three-dose inactivated SARS-CoV-2 vaccination provided greater protection than 2-dose but weaker protection compared with 3-dose mRNA.

Published
2022
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5. Reflexiones sobre cómo evaluar y mejorar la respuesta a la pandemia de COVID-19

Author

Martín Moreno, José M., Arenas, Alex, Bengoa, Rafael, Borrell, Carme, Franco, Manuel, García-Basteiro, Alberto L., Gestal Otero, Juan Jesús, González López Valcárcel, Beatriz, Hernández Aguado, Ildefonso, Legido-Quigley, Helena, March, Joan Carles, Minué, Sergio, Muntaner, Carles, Vives-Cases, Carmen, Universidad de Alicante. Departamento de Enfermería Comunitaria, Medicina Preventiva y Salud Pública e Historia de la Ciencia, Salud Pública, Investigación en Género (IG), [Martín-Moreno,JM] Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina e INCLIVA, Universitat de València, Valencia, España. [Arenas,A] Departament d’Enginyeria Informàtica i Matemàtiques, Universitat Rovira i Virgili, Tarragona, España. [Bengoa,R] Instituto de Salud y Estrategia, Bilbao, España. [Borrell,C] Agència de Salut Pública de Barcelona, Barcelona, España. [Borrell,C, Hernández Aguado,I, Vives-Cases,C] CIBER de Epidemiología y Salud Pública (CIBERESP), España. [Franco,M] Grupo de Investigación en Epidemiología y Salud Pública, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, España. [Franco,M] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [García-Basteiro.AL] ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, España. [García-Basteiro.AL] Centro de Investigac¸ ão em Saúde de Manhic¸ a (CISM), Maputo, Mozambique. [Gestal,J] Universidad de Santiago de Compostela, España. [González López-Valcárcel,B] Universidad de Las Palmas de Gran Canaria, España. [Hernández Aguado,I] Universidad Miguel Hernández, Elche, España. [Legido-Quigley,H] London School of Hygiene and Tropical Medicine and Saw Swee Hock School of Public Health, University of Singapore. [March,JC, and Minué,S] Escuela Andaluza de Salud Pública, Granada, España. [Muntaner,C] University of Toronto y Center for Urban Health Solucions, Li Ka Shing Knowledge Institute, Canadá. [Vives-Cases,C] Universidad de Alicante, España.

Subjects
Determinantes sociales de salud, Policy responses, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Social determinants of health, Respuestas políticas, Prevención y control, Health Care::Environment and Public Health::Public Health [Medical Subject Headings], Health services research, Evaluation, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Health Care::Health Care Economics and Organizations::Organizations::International Agencies::United Nations::World Health Organization [Medical Subject Headings], Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospitals [Medical Subject Headings], Pandemia, Health Care::Health Care Economics and Organizations::Policy::Social Control Policies::Public Policy [Medical Subject Headings], Evaluación, Pandemic, Prevención y control Investigación sobre servicios de salud, Health Care::Environment and Public Health::Public Health::Disease Outbreaks::Epidemics::Pandemics [Medical Subject Headings], COVID-19, Health Care::Health Services Administration::Quality of Health Care::Outcome and Process Assessment (Health Care) [Medical Subject Headings], Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [Medical Subject Headings], Health Care::Health Services Administration::Patient Care Management::Comprehensive Health Care::Primary Health Care [Medical Subject Headings], Investigación sobre servicios de salud, Prevention and control, Medicina Preventiva y Salud Pública, Health Care::Health Care Facilities, Manpower, and Services::Health Services::Community Health Services::Preventive Health Services::Health Education [Medical Subject Headings]
Abstract

La pandemia de COVID-19 ha afectado de manera particularmente intensa a España, pese a su nivel de desarrollo y la elogiada solidez de su Sistema Nacional de Salud. Para comprender qué ha pasado e identificar cómo mejorar la respuesta creemos imprescindible una evaluación independiente multidisciplinaria de la esfera sanitaria, política y socioeconómica. En este trabajo proponemos objetivos, principios, metodología y dimensiones a evaluar, además de esbozar el tipo de resultados y conclusiones esperadas. Nos inspiramos en los requerimientos formulados por el panel independiente de la Organización Mundial de la Salud y en las experiencias evaluativas en otros países, y detallamos la propuesta de aspectos multidimensionales que deben valorarse. La idea es comprender aspectos clave en los ámbitos estudiados y su margen de mejora en lo relativo a preparación, gobernanza, marco normativo, estructuras del Sistema Nacional de Salud (atención primaria, hospitalaria y de salud pública), sector de educación, esquemas de protección social, minimización del impacto económico, y marco y reformas en el ámbito laboral para una sociedad más resiliente. En definitiva, buscamos que este ejercicio sirva no solo para el presente, sino también para que en el futuro estemos mejor preparados y con más ágil capacidad de recuperación ante las amenazas pandémicas que puedan surgir. The COVID-19 pandemic has hit Spain particularly hard, despite being a country with a developed economy and being praised for the robustness of its national health system. In order to understand what happened and to identify how to improve the response, we believe that an independent multi-disciplinary evaluation of the health, political and socio-economic spheres is essential. In this piece we propose objectives, principles, methodology and dimensions to be evaluated, as well as outlining the type of results and conclusions expected. Inspired by the requirements formulated by the WHO Independent Panel for Pandemic Preparedness and Response and by experiences in other countries, we detail the multidimensional aspects to be evaluated. The goal is to understand key aspects in the studied areas and their scope for improvement in terms of preparedness, governance, regulatory framework, national health system structures (primary care, hospital, and public health), education sector, social protection schemes, minimization of economic impact, and labour framework and reforms for a more resilient society. We seek to ensure that this exercise serves not only at present, but also that in the future we are better prepared and more agile in terms of our ability to recover from any pandemic threats that may arise. Ayuda referencia: PI 18/01937 del Fondo de Investigación Sanitaria- Instituto de Salud Carlos III, España, con cofinanciación de Fondos FEDER.

Published
2020

6. GenomegaMap: within-species genome-widedN/dSestimation from over 10,000 genomes

Author

Wilson, DJ, Crook, DW, Peto, TEA, Walker, AS, Hoosdally, SJ, Gibertoni Cruz, AL, Carter, J, Grazian, C, Earle, SG, Kouchaki, S, Lachapelle, A, Yang, Y, Clifton, DA, Fowler, PW, Iqbal, Z, Hunt, M, Knaggs, J, Smith, EG, Rathod, P, Jarrett, L, Matias, D, Cirillo, DM, Borroni, E, Battaglia, S, Ghodousi, A, Spitaleri, A, Cabibbe, A, Tahseen, S, Nilgiriwala, K, Shah, S, Rodrigues, C, Kambli, P, Surve, U, Khot, R, Niemann, S, Kohl, TA, Merker, M, Hoffmann, H, Todt, K, Plesnik, S, Ismail, N, Omar, SV, Joseph, L, Thwaites, G, Thuong, TNT, Ngoc, NH, Srinivasan, V, Walker, TM, Moore, D, Coronel, J, Solano, W, Gao, GF, He, G, Zhao, Y, Liu, C, Ma, A, Zhu, B, Laurenson, I, Claxton, P, Koch, A, Wilkinson, R, Lalvani, A, Posey, J, Gardy, J, Werngren, J, Paton, N, Jou, R, Wu, M-H, Lin, W-H, Ferrazoli, L, De Oliveira, RS, Arandjelovic, I, Chaiprasert, A, Comas, I, Roig, CJ, Drobniewski, FA, Farhat, MR, Gao, Q, Hee, ROT, Sintchenko, V, Supply, P, Van Soolingen, D, University of Oxford, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), D.J.W. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant no. 101237/Z/13/B) and is a Big Data Institute Robertson Fellow. The CRyPTIC Consortium was supported by grants from the Bill and Melinda Gates Foundation (OPP1133541) and a Wellcome Trust/Newton Fund-MRC Collaborative Award (200205/Z/15/Z). F.A.D. was supported by the Imperial Biomedical Research Centre., Members of the CRyPTIC Consortium : Derrick W. Crook, Timothy E.A. Peto, A. Sarah Walker, Sarah J. Hoosdally, Ana L. Gibertoni Cruz, Joshua Carter, Clara Grazian, Sarah G. Earle, Samaneh Kouchaki, Alexander Lachapelle, Yang Yang, David A. Clifton, and Philip W. Fowler, University of Oxford, Zamin Iqbal, Martin Hunt, and Jeffrey Knaggs, European Bioinformatics Institute, E. Grace Smith, Priti Rathod, Lisa Jarrett, and Daniela Matias, Public Health England, Birmingham, Daniela M. Cirillo, Emanuele Borroni, Simone Battaglia, Arash Ghodousi, Andrea Spitaleri, and Andrea Cabibbe, Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, Milan, Sabira Tahseen, National Tuberculosis Control Program Pakistan, Islamabad, Kayzad Nilgiriwala and Sanchi Shah, The Foundation for Medical Research, Mumbai, Camilla Rodrigues, Priti Kambli, Utkarsha Surve, and Rukhsar Khot, P.D. Hinduja National Hospital and Medical Research Centre, Mumbai, Stefan Niemann, Thomas A. Kohl, and Matthias Merker, Research Center Borstel, Harald Hoffmann, Katharina Todt, and Sara Plesnik, Institute of Microbiology & Laboratory Medicine, IML Red, Gauting, Nazir Ismail, Shaheed Vally Omar, and Lavania Joseph, National Institute for Communicable Diseases, Johannesburg, Guy Thwaites, Thuong Nguyen Thuy Thuong, Nhung Hoang Ngoc, Vijay Srinivasan, and Timothy M. Walker, Oxford University Clinical Research Unit, Ho Chi Minh City, David Moore, Jorge Coronel and Walter Solano, London School of Hygiene and Tropical Medicine and Universidad Peruana Cayetano Heredá, Lima, George F. Gao, Guangxue He, Yanlin Zhao, and Chunfa Liu, China CDC, Beijing, Aijing Ma, Shenzhen Third People’s Hospital, Shenzhen, Baoli Zhu, Institute of Microbiology, CAS, Beijing, Ian Laurenson and Pauline Claxton, Scottish Mycobacteria Reference Laboratory, Edinburgh, Anastasia Koch, Robert Wilkinson, University of Cape Town, Ajit Lalvani, Imperial College London, James Posey, CDC Atlanta, Jennifer Gardy, University of British Columbia, Jim Werngren, Public Health Agency of Sweden, Nicholas Paton, National University of Singapore, Ruwen Jou, Mei-Hua Wu, Wan-Hsuan Lin, CDC Taiwan, Lucilaine Ferrazoli, Rosangela Siqueira de Oliveira, Institute Adolfo Lutz, São Paulo. Authors contributing to the CRyPTIC Consortium are (in alphabetical order): Irena Arandjelovic (Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia), Angkana Chaiprasert (Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand), Iñaki Comas (Instituto de Biomedicina de Valencia [IBV-CSIC], Calle Jaime Roig, Valencia, Spain, FISABIO Public Health, Valencia, Spain, CIBER in Epidemiology and Public Health, Madrid, Spain), Francis A. Drobniewski (Imperial College, London, UK), Maha R. Farhat (Harvard Medical School, Boston, USA), Qian Gao (Shanghai Medical College, Fudan University, Shanghai, China), Rick Ong Twee Hee (Saw Swee Hock School of Public Health, National University of Singapore, Singapore), Vitali Sintchenko (Centre for Infectious Diseases and Microbiology—Public Health, University of Sydney, Sydney, Australia), Philip Supply (Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019—UMR 8204—CIIL—Centre d’Infection et d’Immunité de Lille, F-59000 Lille, France), and Dick van Soolingen (National Institute for Public Health and the Environment [RIVM], Bilthoven, The Netherlands)., Supply, Philip, Consortium, CRyPTIC, University of Oxford [Oxford], Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Royal Society (UK), Bill & Melinda Gates Foundation, Newton Fund, Comas, Iñaki [0000-0001-5504-9408], and Comas, Iñaki

Subjects
Natural selection, [SDV]Life Sciences [q-bio], Population genetics, adaptation, Computational biology, Biology, AcademicSubjects/SCI01180, 0601 Biochemistry and Cell Biology, Genome, Coalescent theory, DEAD-box RNA Helicases, Big data, 03 medical and health sciences, 0603 Evolutionary Biology, big data, Parent-dependent mutation, Genetics, dN/dS, Adaptation, Selection, Genetic, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, Silent Mutation, Selection (genetic algorithm), 030304 developmental biology, Evolutionary Biology, 0604 Genetics, 0303 health sciences, Models, Genetic, Phylogenetic tree, 030306 microbiology, AcademicSubjects/SCI01130, natural selection, Mycobacterium tuberculosis, Recombination, Resources, recombination, 3. Good health, [SDV] Life Sciences [q-bio], Genetic Techniques, Mutation (genetic algorithm), parent-dependent mutation, Genome, Bacterial
Abstract

11 págs, 4 figuras y fórmulas matemáticas. Material suplementario en: http://dx.doi.org/10.1093/molbev/msaa069, The dN/dS ratio provides evidence of adaptation or functional constraint in protein-coding genes by quantifying the relative excess or deficit of amino acid-replacing versus silent nucleotide variation. Inexpensive sequencing promises a better understanding of parameters, such as dN/dS, but analyzing very large data sets poses a major statistical challenge. Here, I introduce genomegaMap for estimating within-species genome-wide variation in dN/dS, and I apply it to 3,979 genes across 10,209 tuberculosis genomes to characterize the selection pressures shaping this global pathogen. GenomegaMap is a phylogeny-free method that addresses two major problems with existing approaches: 1) It is fast no matter how large the sample size and 2) it is robust to recombination, which causes phylogenetic methods to report artefactual signals of adaptation. GenomegaMap uses population genetics theory to approximate the distribution of allele frequencies under general, parent-dependent mutation models. Coalescent simulations show that substitution parameters are well estimated even when genomegaMap's simplifying assumption of independence among sites is violated. I demonstrate the ability of genomegaMap to detect genuine signatures of selection at antimicrobial resistance-conferring substitutions in Mycobacterium tuberculosis and describe a novel signature of selection in the cold-shock DEAD-box protein A gene deaD/csdA. The genomegaMap approach helps accelerate the exploitation of big data for gaining new insights into evolution within species., D.J.W. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant no. 101237/Z/13/B) and is a Big Data Institute Robertson Fellow. The CRyPTIC Consortium was supported by grants from the Bill and Melinda Gates Foundation (OPP1133541) and a Wellcome Trust/Newton Fund-MRC Collaborative Award (200205/Z/15/Z). F.A.D. was supported by the Imperial Biomedical Research Centre

Published
2019
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7. Maternal Lutein and Zeaxanthin Concentrations in Relation to Offspring Visual Acuity at 3 Years of Age: The GUSTO Study

Author

Jun Shi Lai, Mary Foong-Fong Chong, Vaishnavi O Veetil, Lynette Pei-Chi Shek, Choon Nam Ong, Seang-Mei Saw, Cheryl Ngo, Keith M. Godfrey, Carla Costa Lança, Fabian Yap, Bee Lan Lee, Yap Seng Chong, Peter D. Gluckman, Kok Hian Tan, Lee Kong Chian School of Medicine (LKCMedicine), Duke-NUS Graduate Medical School, Saw Swee Hock School of Public Health, and Singapore Eye Research Institute

Subjects
Male, Lutein, Visual acuity, genetic structures, visual acuity, Physiology, chemistry.chemical_compound, 0302 clinical medicine, Outcome Assessment, Health Care, Medicine, 10. No inequality, Singapore, child, Nutrition and Dietetics, Confounding, food and beverages, Zeaxanthin, zeaxanthin, Child, Preschool, Prenatal Exposure Delayed Effects, Cohort, symbols, Female, pregnancy, medicine.symptom, lcsh:Nutrition. Foods and food supply, Adult, endocrine system, Offspring, Vision Disorders, lcsh:TX341-641, Article, 03 medical and health sciences, symbols.namesake, Zeaxanthins, Humans, Medicine [Science], Poisson regression, lutein, Pregnancy, business.industry, Maternal Nutritional Physiological Phenomena, medicine.disease, eye diseases, Pregnancy Complications, chemistry, 030221 ophthalmology & optometry, sense organs, business, Maternal Serum Screening Tests, 030217 neurology & neurosurgery, Food Science
Abstract

Lutein and zeaxanthin play important roles in visual functions, but their influence on early visual development is unclear. We related maternal lutein and zeaxanthin concentrations during pregnancy to offspring visual acuity (VA) in 471 mother&ndash, child pairs from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Maternal concentrations of plasma lutein and zeaxanthin were determined at delivery. We measured uncorrected distance of VA in 3-year old children using a LEA Symbols chart, readings were converted to the logarithm of Minimum Angle of Resolution (logMAR), with &gt, 0.3 logMAR indicating poor VA. Associations were examined using linear or Poisson regression adjusted for confounders. The median (inter-quartile range) of maternal lutein and zeaxanthin concentrations were 0.13 (0.09, 0.18) and 0.09 (0.07, 0.12) &micro, mol/L, respectively. A total of 126 children had poor VA. The highest tertile of maternal zeaxanthin concentration was associated with 38% lower likelihood of poor VA in children (95% CI: 0.42, 0.93, p-Trends = 0.02). Higher maternal lutein concentrations were associated with a lower likelihood of poor VA in children (RR 0.60 (95% CI: 0.40, 0.88) for middle tertile, RR 0.78 (95% CI: 0.51, 1.19) for highest tertile (p-Quadratic = 0.02)). In conclusion, lutein and zeaxanthin status during pregnancy may influence offspring early visual development, but the results require confirmation with further studies, including more comprehensive measurements of macular functions.

Published
2020
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8. Body mass index and lung cancer risk: a pooled analysis based on nested case-control studies from four cohort studies

Author

Gary E. Goodman, Lesley M. Butler, Paolo Vineis, Woon-Puay Koh, Mattias Johansson, Isabelle Stücker, Harinakshi Sanikini, Jian-Min Yuan, Chu Chen, Annika Steffen, Rayjean J. Hung, Matt J. Barnett, Yu-Tang Gao, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Duke-NUS Medical School [Singapore], Saw Swee Hock School of Public Health, National University of Singapore (NUS), Department of Epidemiology, Shanghai Cancer Institute, School of Medicine [Shanghai Jiaotong University], Shanghai Jiaotong University, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Department of Epidemiology and Biostatistics [Imperial College London], Imperial College London, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], This work was supported by the Fondation de France and Ecole doctarale de Sante Publique (ED420). The EPIC study has been supported by the Europe Against Cancer Program of the European Commission. The SCHS and SCS were supported by NCI, NIH grants U01-CA63673, UM1-CA167462 and R01-CA111703. The CARET was supported by the National Institute of Health (U01 CA63673) and the Fred Hutchinson Cancer Research Center, Seattle, WA., BMC, BMC, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Overweight, Body Mass Index, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, 2. Zero hunger, Smoking, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, MENDELIAN RANDOMIZATION, Female, Lung cancer, medicine.symptom, Underweight, Life Sciences & Biomedicine, Research Article, Cohort study, Adult, medicine.medical_specialty, HYPOXIA-INDUCIBLE FACTOR, [SDV.CAN]Life Sciences [q-bio]/Cancer, SECULAR TRENDS, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetics, medicine, Humans, Oncology & Carcinogenesis, Obesity, METAANALYSIS, Aged, Science & Technology, HISTOLOGIC TYPE, business.industry, MORTALITY, Case-control study, Odds ratio, medicine.disease, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Nested case-control study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, WEIGHT, SINGAPORE CHINESE HEALTH, business, 1112 Oncology And Carcinogenesis, Body mass index
Abstract

Background Obesity has been proposed as a potential protective factor against lung cancer. We examined the association between BMI and lung cancer risk in a pooled analysis based on nested case-control studies from four cohort studies. Methods A case-control study was nested within four cohorts in USA, Europe, China and Singapore that included 4172 cases and 8471 control subjects. BMI at baseline was calculated as weight in kilograms divided by height in meters squared (kg/m2), and classified into 4 categories: underweight (BMI

Published
2018
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