SOX9 Maintains Reserve Stem Cells and Preserves Radioresistance in Mouse Small Intestine

Reserve intestinal stem cells (rISCs) are quiescent/slowly cycling under homeostatic conditions, allowing for their identification with label-retention assays. rISCs mediate epithelial regeneration after tissue damage by converting to actively proliferating stem cells (aISCs) that self renew and demonstrate multipotency, which are defining properties of stem cells. Little is known about the genetic mechanisms that regulate the production and maintenance of rISCs. High expression levels of the transcription factor Sox9 (Sox9high) are associated with rISCs. This study investigates the role of SOX9 in regulating the rISC state

Functional and Psychosocial Outcomes of Hand Transplantation Compared with Prosthetic Fitting in Below-Elbow Amputees:A Multicenter Cohort Study

BACKGROUND:Hand-transplantation and improvements in the field of prostheses opened new frontiers in restoring hand function in below-elbow amputees. Both concepts aim at restoring reliable hand function, however, the indications, advantages and limitations for each treatment must be carefully considered depending on level and extent of amputation. Here we report our findings of a multi-center cohort study comparing hand function and quality-of-life of people with transplanted versus prosthetic hands. METHODS:Hand function in amputees with either transplant or prostheses was tested with Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP) and the Disabilities of the Arm, Shoulder and Hand measure (DASH). Quality-of-life was compared with the Short-Form 36 (SF-36). RESULTS:Transplanted patients (n = 5) achieved a mean ARAT score of 40.86 ± 8.07 and an average SHAP score of 75.00 ± 11.06. Prosthetic patients (n = 7) achieved a mean ARAT score of 39.00 ± 3.61 and an average SHAP score of 75.43 ± 10.81. There was no significant difference between transplanted and prosthetic hands in ARAT, SHAP or DASH. While quality-of-life metrics were equivocal for four scales of the SF-36, transplanted patients reported significantly higher scores in "role-physical" (p = 0.006), "vitality" (p = 0.008), "role-emotional" (p = 0.035) and "mental-health" (p = 0.003). CONCLUSIONS:The indications for hand transplantation or prosthetic fitting in below-elbow amputees require careful consideration. As functional outcomes were not significantly different between groups, patient's best interests and the route of least harm should guide treatment. Due to the immunosuppressive side-effects, the indication for allotransplantation must still be restrictive, the best being bilateral amputees

Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline—A Multinational Registry Analysis

Rationale: Intravenous plasma-purified alpha-1 antitrypsin (IV-AAT) has been used as therapy for alpha-1 antitrypsin deficiency (AATD) since 1987. Previous trials (RAPID and RAPID-OLE) demonstrated efficacy in preserving computed tomography of lung density but no effect on FEV1. This observational study evaluated 615 people with severe AATD from three countries with socialized health care (Ireland, Switzerland, and Austria), where access to standard medical care was equal but access to IV-AAT was not. Objectives: To assess the real-world longitudinal effects of IV-AAT. Methods: Pulmonary function and mortality data were utilized to perform longitudinal analyses on registry participants with severe AATD. Measurements and Main Results: IV-AAT confers a survival benefit in severe AATD (P < 0.001). We uncovered two distinct AATD phenotypes based on an initial respiratory diagnosis: lung index and non-lung index. Lung indexes demonstrated a more rapid FEV1 decline between the ages of 20 and 50 and subsequently entered a plateau phase of minimal decline from 50 onward. Consequentially, IV-AAT had no effect on FEV1 decline, except in patients with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 lung index. Conclusions: This real-world study demonstrates a survival advantage from IV-AAT. This improved survival is largely decoupled from FEV1 decline. The observation that patients with severe AATD fall into two major phenotypes has implications for clinical trial design where FEV1 is a primary endpoint. Recruits into trials are typically older lung indexes entering the plateau phase and, therefore, unlikely to show spirometric benefits. IV-AAT attenuates spirometric decline in lung indexes in GOLD stage 2, a spirometric group commonly outside current IV-AAT commencement recommendations

Intermittent preventive treatment for malaria in pregnancy in Africa: What's new, what's needed?

Falciparum malaria is an important cause of maternal, perinatal and neonatal morbidity in high transmission settings in Sub-Saharan Africa. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPT) has proven efficacious in reducing the burden of pregnancy-associated malaria but increasing levels of parasite resistance mean that the benefits of national SP-IPT programmes may soon be seriously undermined in much of the region. Hence, there is an urgent need to develop alternative drug regimens for IPT in pregnancy. This paper reviews published safety and efficacy data on various antimalarials and proposes several candidate combination regimens for assessment in phase II/III clinical trials

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Human Nasal Challenge with Streptococcus pneumoniae Is Immunising in the Absence of Carriage

Infectious challenge of the human nasal mucosa elicits immune responses that determine the fate of the host-bacterial interaction; leading either to clearance, colonisation and/or disease. Persistent antigenic exposure from pneumococcal colonisation can induce both humoral and cellular defences that are protective against carriage and disease. We challenged healthy adults intra-nasally with live 23F or 6B Streptococcus pneumoniae in two sequential cohorts and collected nasal wash, bronchoalveolar lavage (BAL) and blood before and 6 weeks after challenge. We hypothesised that both cohorts would successfully become colonised but this did not occur except for one volunteer. The effect of bacterial challenge without colonisation in healthy adults has not been previously assessed. We measured the antigen-specific humoral and cellular immune responses in challenged but not colonised volunteers by ELISA and Flow Cytometry. Antigen-specific responses were seen in each compartment both before and after bacterial challenge for both cohorts. Antigen-specific IgG and IgA levels were significantly elevated in nasal wash 6 weeks after challenge compared to baseline. Immunoglobulin responses to pneumococci were directed towards various protein targets but not capsular polysaccharide. 23F but not 6B challenge elevated IgG anti-PspA in BAL. Serum immunoglobulins did not increase in response to challenge. In neither challenge cohort was there any alteration in the frequencies of TNF, IL-17 or IFNγ producing CD4 T cells before or after challenge in BAL or blood. We show that simple, low dose mucosal exposure with pneumococci may immunise mucosal surfaces by augmenting anti-protein immunoglobulin responses; but not capsular or cellular responses. We hypothesise that mucosal exposure alone may not replicate the systemic immunising effect of experimental or natural carriage in humans

«La relation de limitation et d’exception dans le français d’aujourd’hui : excepté, sauf et hormis comme pivots d’une relation algébrique »

L’analyse des emplois prépositionnels et des emplois conjonctifs d’ “excepté”, de “sauf” et d’ “hormis” permet d’envisager les trois prépositions/conjonctions comme le pivot d’un binôme, comme la plaque tournante d’une structure bipolaire. Placées au milieu du binôme, ces prépositions sont forcées par leur sémantisme originaire dûment métaphorisé de jouer le rôle de marqueurs d’inconséquence systématique entre l’élément se trouvant à leur gauche et celui qui se trouve à leur droite. L’opposition qui surgit entre les deux éléments n’est donc pas une incompatibilité naturelle, intrinsèque, mais extrinsèque, induite. Dans la plupart des cas (emplois limitatifs), cette opposition prend la forme d’un rapport entre une « classe » et le « membre (soustrait) de la classe », ou bien entre un « tout » et une « partie » ; dans d’autres (emplois exceptifs), cette opposition se manifeste au contraire comme une attaque de front portée par un « tout » à un autre « tout ». De plus, l’inconséquence induite mise en place par la préposition/conjonction paraît, en principe, tout à fait insurmontable. Dans l’assertion « les écureuils vivent partout, sauf en Australie » (que l’on peut expliciter par « Les écureuils vivent partout, sauf [qu’ils ne vivent pas] en Australie »), la préposition semble en effet capable d’impliquer le prédicat principal avec signe inverti, et de bâtir sur une telle implication une sorte de sous énoncé qui, à la rigueur, est totalement inconséquent avec celui qui le précède (si « les écureuils ne vivent pas en Australie », le fait qu’ils « vivent partout » est faux). Néanmoins, l’analyse montre qu’alors que certaines de ces oppositions peuvent enfin être dépassées, d’autres ne le peuvent pas. C’est, respectivement, le cas des relations limitatives et des relations exceptives. La relation limitative, impliquant le rapport « tout » - « partie », permet de résoudre le conflit dans les termes d’une somme algébrique entre deux sous énoncés pourvus de différent poids informatif et de signe contraire. Les valeurs numériques des termes de la somme étant déséquilibrées, le résultat est toujours autre que zéro. La relation exceptive, au contraire, qui n’implique pas le rapport « tout » - « partie », n’est pas capable de résoudre le conflit entre deux sous énoncés pourvus du même poids informatif et en même temps de signe contraire : les valeurs numériques des termes de la somme étant symétriques et égales, le résultat sera toujours équivalent à zéro

Radioactivity control strategy for the JUNO detector

602siopenJUNO is a massive liquid scintillator detector with a primary scientific goal of determining the neutrino mass ordering by studying the oscillated anti-neutrino flux coming from two nuclear power plants at 53 km distance. The expected signal anti-neutrino interaction rate is only 60 counts per day (cpd), therefore a careful control of the background sources due to radioactivity is critical. In particular, natural radioactivity present in all materials and in the environment represents a serious issue that could impair the sensitivity of the experiment if appropriate countermeasures were not foreseen. In this paper we discuss the background reduction strategies undertaken by the JUNO collaboration to reduce at minimum the impact of natural radioactivity. We describe our efforts for an optimized experimental design, a careful material screening and accurate detector production handling, and a constant control of the expected results through a meticulous Monte Carlo simulation program. We show that all these actions should allow us to keep the background count rate safely below the target value of 10 Hz (i.e. ∼1 cpd accidental background) in the default fiducial volume, above an energy threshold of 0.7 MeV. [Figure not available: see fulltext.]openAbusleme A.; Adam T.; Ahmad S.; Ahmed R.; Aiello S.; Akram M.; An F.; An Q.; Andronico G.; Anfimov N.; Antonelli V.; Antoshkina T.; Asavapibhop B.; de Andre J.P.A.M.; Auguste D.; Babic A.; Baldini W.; Barresi A.; Basilico D.; Baussan E.; Bellato M.; Bergnoli A.; Birkenfeld T.; Blin S.; Blum D.; Blyth S.; Bolshakova A.; Bongrand M.; Bordereau C.; Breton D.; Brigatti A.; Brugnera R.; Bruno R.; Budano A.; Buscemi M.; Busto J.; Butorov I.; Cabrera A.; Cai H.; Cai X.; Cai Y.; Cai Z.; Cammi A.; Campeny A.; Cao C.; Cao G.; Cao J.; Caruso R.; Cerna C.; Chang J.; Chang Y.; Chen P.; Chen P.-A.; Chen S.; Chen X.; Chen Y.-W.; Chen Y.; Chen Y.; Chen Z.; Cheng J.; Cheng Y.; Chetverikov A.; Chiesa D.; Chimenti P.; Chukanov A.; Claverie G.; Clementi C.; Clerbaux B.; Conforti Di Lorenzo S.; Corti D.; Cremonesi O.; Dal Corso F.; Dalager O.; De La Taille C.; Deng J.; Deng Z.; Deng Z.; Depnering W.; Diaz M.; Ding X.; Ding Y.; Dirgantara B.; Dmitrievsky S.; Dohnal T.; Dolzhikov D.; Donchenko G.; Dong J.; Doroshkevich E.; Dracos M.; Druillole F.; Du S.; Dusini S.; Dvorak M.; Enqvist T.; Enzmann H.; Fabbri A.; Fajt L.; Fan D.; Fan L.; Fang J.; Fang W.; Fargetta M.; Fedoseev D.; Fekete V.; Feng L.-C.; Feng Q.; Ford R.; Formozov A.; Fournier A.; Gan H.; Gao F.; Garfagnini A.; Giammarchi M.; Giaz A.; Giudice N.; Gonchar M.; Gong G.; Gong H.; Gornushkin Y.; Gottel A.; Grassi M.; Grewing C.; Gromov V.; Gu M.; Gu X.; Gu Y.; Guan M.; Guardone N.; Gul M.; Guo C.; Guo J.; Guo W.; Guo X.; Guo Y.; Hackspacher P.; Hagner C.; Han R.; Han Y.; Hassan M.S.; He M.; He W.; Heinz T.; Hellmuth P.; Heng Y.; Herrera R.; Hor Y.K.; Hou S.; Hsiung Y.; Hu B.-Z.; Hu H.; Hu J.; Hu J.; Hu S.; Hu T.; Hu Z.; Huang C.; Huang G.; Huang H.; Huang W.; Huang X.; Huang X.; Huang Y.; Hui J.; Huo L.; Huo W.; Huss C.; Hussain S.; Ioannisian A.; Isocrate R.; Jelmini B.; Jen K.-L.; Jeria I.; Ji X.; Ji X.; Jia H.; Jia J.; Jian S.; Jiang D.; Jiang X.; Jin R.; Jing X.; Jollet C.; Joutsenvaara J.; Jungthawan S.; Kalousis L.; Kampmann P.; Kang L.; Karaparambil R.; Kazarian N.; Khan W.; Khosonthongkee K.; Korablev D.; Kouzakov K.; Krasnoperov A.; Kruth A.; Kutovskiy N.; Kuusiniemi P.; Lachenmaier T.; Landini C.; Leblanc S.; Lebrin V.; Lefevre F.; Lei R.; Leitner R.; Leung J.; Li D.; Li F.; Li F.; Li H.; Li H.; Li J.; Li M.; Li M.; Li N.; Li N.; Li Q.; Li R.; Li S.; Li T.; Li W.; Li W.; Li X.; Li X.; Li X.; Li Y.; Li Y.; Li Z.; Li Z.; Li Z.; Liang H.; Liang H.; Liao J.; Liebau D.; Limphirat A.; Limpijumnong S.; Lin G.-L.; Lin S.; Lin T.; Ling J.; Lippi I.; Liu F.; Liu H.; Liu H.; Liu H.; Liu H.; Liu H.; Liu J.; Liu J.; Liu M.; Liu Q.; Liu Q.; Liu R.; Liu S.; Liu S.; Liu S.; Liu X.; Liu X.; Liu Y.; Liu Y.; Lokhov A.; Lombardi P.; Lombardo C.; Loo K.; Lu C.; Lu H.; Lu J.; Lu J.; Lu S.; Lu X.; Lubsandorzhiev B.; Lubsandorzhiev S.; Ludhova L.; Luo F.; Luo G.; Luo P.; Luo S.; Luo W.; Lyashuk V.; Ma B.; Ma Q.; Ma S.; Ma X.; Ma X.; Maalmi J.; Malyshkin Y.; Mantovani F.; Manzali F.; Mao X.; Mao Y.; Mari S.M.; Marini F.; Marium S.; Martellini C.; Martin-Chassard G.; Martini A.; Mayer M.; Mayilyan D.; Mednieks I.; Meng Y.; Meregaglia A.; Meroni E.; Meyhofer D.; Mezzetto M.; Miller J.; Miramonti L.; Montini P.; Montuschi M.; Muller A.; Nastasi M.; Naumov D.V.; Naumova E.; Navas-Nicolas D.; Nemchenok I.; Nguyen Thi M.T.; Ning F.; Ning Z.; Nunokawa H.; Oberauer L.; Ochoa-Ricoux J.P.; Olshevskiy A.; Orestano D.; Ortica F.; Othegraven R.; Pan H.-R.; Paoloni A.; Parmeggiano S.; Pei Y.; Pelliccia N.; Peng A.; Peng H.; Perrot F.; Petitjean P.-A.; Petrucci F.; Pilarczyk O.; Pineres Rico L.F.; Popov A.; Poussot P.; Pratumwan W.; Previtali E.; Qi F.; Qi M.; Qian S.; Qian X.; Qian Z.; Qiao H.; Qin Z.; Qiu S.; Rajput M.U.; Ranucci G.; Raper N.; Re A.; Rebber H.; Rebii A.; Ren B.; Ren J.; Ricci B.; Robens M.; Roche M.; Rodphai N.; Romani A.; Roskovec B.; Roth C.; Ruan X.; Ruan X.; Rujirawat S.; Rybnikov A.; Sadovsky A.; Saggese P.; Sanfilippo S.; Sangka A.; Sanguansak N.; Sawangwit U.; Sawatzki J.; Sawy F.; Schever M.; Schwab C.; Schweizer K.; Selyunin A.; Serafini A.; Settanta G.; Settimo M.; Shao Z.; Sharov V.; Shaydurova A.; Shi J.; Shi Y.; Shutov V.; Sidorenkov A.; Simkovic F.; Sirignano C.; Siripak J.; Sisti M.; Slupecki M.; Smirnov M.; Smirnov O.; Sogo-Bezerra T.; Sokolov S.; Songwadhana J.; Soonthornthum B.; Sotnikov A.; Sramek O.; Sreethawong W.; Stahl A.; Stanco L.; Stankevich K.; Stefanik D.; Steiger H.; Steinmann J.; Sterr T.; Stock M.R.; Strati V.; Studenikin A.; Sun S.; Sun X.; Sun Y.; Sun Y.; Suwonjandee N.; Szelezniak M.; Tang J.; Tang Q.; Tang Q.; Tang X.; Tietzsch A.; Tkachev I.; Tmej T.; Treskov K.; Triossi A.; Troni G.; Trzaska W.; Tuve C.; Ushakov N.; van den Boom J.; van Waasen S.; Vanroyen G.; Vassilopoulos N.; Vedin V.; Verde G.; Vialkov M.; Viaud B.; Vollbrecht M.C.; Volpe C.; Vorobel V.; Voronin D.; Votano L.; Walker P.; Wang C.; Wang C.-H.; Wang E.; Wang G.; Wang J.; Wang J.; Wang K.; Wang L.; Wang M.; Wang M.; Wang M.; Wang R.; Wang S.; Wang W.; Wang W.; Wang W.; Wang X.; Wang X.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Y.; Wang Z.; Wang Z.; Wang Z.; Wang Z.; Waqas M.; Watcharangkool A.; Wei L.; Wei W.; Wei W.; Wei Y.; Wen L.; Wiebusch C.; Wong S.C.-F.; Wonsak B.; Wu D.; Wu F.; Wu Q.; Wu Z.; Wurm M.; Wurtz J.; Wysotzki C.; Xi Y.; Xia D.; Xie X.; Xie Y.; Xie Z.; Xing Z.; Xu B.; Xu C.; Xu D.; Xu F.; Xu H.; Xu J.; Xu J.; Xu M.; Xu Y.; Xu Y.; Yan B.; Yan T.; Yan W.; Yan X.; Yan Y.; Yang A.; Yang C.; Yang C.; Yang H.; Yang J.; Yang L.; Yang X.; Yang Y.; Yang Y.; Yao H.; Yasin Z.; Ye J.; Ye M.; Ye Z.; Yegin U.; Yermia F.; Yi P.; Yin N.; Yin X.; You Z.; Yu B.; Yu C.; Yu C.; Yu H.; Yu M.; Yu X.; Yu Z.; Yu Z.; Yuan C.; Yuan Y.; Yuan Z.; Yuan Z.; Yue B.; Zafar N.; Zambanini A.; Zavadskyi V.; Zeng S.; Zeng T.; Zeng Y.; Zhan L.; Zhang A.; Zhang F.; Zhang G.; Zhang H.; Zhang H.; Zhang J.; Zhang J.; Zhang J.; Zhang J.; Zhang J.; Zhang P.; Zhang Q.; Zhang S.; Zhang S.; Zhang T.; Zhang X.; Zhang X.; Zhang X.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Y.; Zhang Z.; Zhang Z.; Zhao F.; Zhao J.; Zhao R.; Zhao S.; Zhao T.; Zheng D.; Zheng H.; Zheng M.; Zheng Y.; Zhong W.; Zhou J.; Zhou L.; Zhou N.; Zhou S.; Zhou T.; Zhou X.; Zhu J.; Zhu K.; Zhu K.; Zhu Z.; Zhuang B.; Zhuang H.; Zong L.; Zou J.Abusleme, A.; Adam, T.; Ahmad, S.; Ahmed, R.; Aiello, S.; Akram, M.; An, F.; An, Q.; Andronico, G.; Anfimov, N.; Antonelli, V.; Antoshkina, T.; Asavapibhop, B.; de Andre, J. P. A. M.; Auguste, D.; Babic, A.; Baldini, W.; Barresi, A.; Basilico, D.; Baussan, E.; Bellato, M.; Bergnoli, A.; Birkenfeld, T.; Blin, S.; Blum, D.; Blyth, S.; Bolshakova, A.; Bongrand, M.; Bordereau, C.; Breton, D.; Brigatti, A.; Brugnera, R.; Bruno, R.; Budano, A.; Buscemi, M.; Busto, J.; Butorov, I.; Cabrera, A.; Cai, H.; Cai, X.; Cai, Y.; Cai, Z.; Cammi, A.; Campeny, A.; Cao, C.; Cao, G.; Cao, J.; Caruso, R.; Cerna, C.; Chang, J.; Chang, Y.; Chen, P.; Chen, P. -A.; Chen, S.; Chen, X.; Chen, Y. -W.; Chen, Y.; Chen, Y.; Chen, Z.; Cheng, J.; Cheng, Y.; Chetverikov, A.; Chiesa, D.; Chimenti, P.; Chukanov, A.; Claverie, G.; Clementi, C.; Clerbaux, B.; Conforti Di Lorenzo, S.; Corti, D.; Cremonesi, O.; Dal Corso, F.; Dalager, O.; De La Taille, C.; Deng, J.; Deng, Z.; Deng, Z.; Depnering, W.; Diaz, M.; Ding, X.; Ding, Y.; Dirgantara, B.; Dmitrievsky, S.; Dohnal, T.; Dolzhikov, D.; Donchenko, G.; Dong, J.; Doroshkevich, E.; Dracos, M.; Druillole, F.; Du, S.; Dusini, S.; Dvorak, M.; Enqvist, T.; Enzmann, H.; Fabbri, A.; Fajt, L.; Fan, D.; Fan, L.; Fang, J.; Fang, W.; Fargetta, M.; Fedoseev, D.; Fekete, V.; Feng, L. -C.; Feng, Q.; Ford, R.; Formozov, A.; Fournier, A.; Gan, H.; Gao, F.; Garfagnini, A.; Giammarchi, M.; Giaz, A.; Giudice, N.; Gonchar, M.; Gong, G.; Gong, H.; Gornushkin, Y.; Gottel, A.; Grassi, M.; Grewing, C.; Gromov, V.; Gu, M.; Gu, X.; Gu, Y.; Guan, M.; Guardone, N.; Gul, M.; Guo, C.; Guo, J.; Guo, W.; Guo, X.; Guo, Y.; Hackspacher, P.; Hagner, C.; Han, R.; Han, Y.; Hassan, M. S.; He, M.; He, W.; Heinz, T.; Hellmuth, P.; Heng, Y.; Herrera, R.; Hor, Y. K.; Hou, S.; Hsiung, Y.; Hu, B. -Z.; Hu, H.; Hu, J.; Hu, J.; Hu, S.; Hu, T.; Hu, Z.; Huang, C.; Huang, G.; Huang, H.; Huang, W.; Huang, X.; Huang, X.; Huang, Y.; Hui, J.; Huo, L.; Huo, W.; Huss, C.; Hussain, S.; Ioannisian, A.; Isocrate, R.; Jelmini, B.; Jen, K. -L.; Jeria, I.; Ji, X.; Ji, X.; Jia, H.; Jia, J.; Jian, S.; Jiang, D.; Jiang, X.; Jin, R.; Jing, X.; Jollet, C.; Joutsenvaara, J.; Jungthawan, S.; Kalousis, L.; Kampmann, P.; Kang, L.; Karaparambil, R.; Kazarian, N.; Khan, W.; Khosonthongkee, K.; Korablev, D.; Kouzakov, K.; Krasnoperov, A.; Kruth, A.; Kutovskiy, N.; Kuusiniemi, P.; Lachenmaier, T.; Landini, C.; Leblanc, S.; Lebrin, V.; Lefevre, F.; Lei, R.; Leitner, R.; Leung, J.; Li, D.; Li, F.; Li, F.; Li, H.; Li, H.; Li, J.; Li, M.; Li, M.; Li, N.; Li, N.; Li, Q.; Li, R.; Li, S.; Li, T.; Li, W.; Li, W.; Li, X.; Li, X.; Li, X.; Li, Y.; Li, Y.; Li, Z.; Li, Z.; Li, Z.; Liang, H.; Liang, H.; Liao, J.; Liebau, D.; Limphirat, A.; Limpijumnong, S.; Lin, G. -L.; Lin, S.; Lin, T.; Ling, J.; Lippi, I.; Liu, F.; Liu, H.; Liu, H.; Liu, H.; Liu, H.; Liu, H.; Liu, J.; Liu, J.; Liu, M.; Liu, Q.; Liu, Q.; Liu, R.; Liu, S.; Liu, S.; Liu, S.; Liu, X.; Liu, X.; Liu, Y.; Liu, Y.; Lokhov, A.; Lombardi, P.; Lombardo, C.; Loo, K.; Lu, C.; Lu, H.; Lu, J.; Lu, J.; Lu, S.; Lu, X.; Lubsandorzhiev, B.; Lubsandorzhiev, S.; Ludhova, L.; Luo, F.; Luo, G.; Luo, P.; Luo, S.; Luo, W.; Lyashuk, V.; Ma, B.; Ma, Q.; Ma, S.; Ma, X.; Ma, X.; Maalmi, J.; Malyshkin, Y.; Mantovani, F.; Manzali, F.; Mao, X.; Mao, Y.; Mari, S. M.; Marini, F.; Marium, S.; Martellini, C.; Martin-Chassard, G.; Martini, A.; Mayer, M.; Mayilyan, D.; Mednieks, I.; Meng, Y.; Meregaglia, A.; Meroni, E.; Meyhofer, D.; Mezzetto, M.; Miller, J.; Miramonti, L.; Montini, P.; Montuschi, M.; Muller, A.; Nastasi, M.; Naumov, D. V.; Naumova, E.; Navas-Nicolas, D.; Nemchenok, I.; Nguyen Thi, M. T.; Ning, F.; Ning, Z.; Nunokawa, H.; Oberauer, L.; Ochoa-Ricoux, J. P.; Olshevskiy, A.; Orestano, D.; Ortica, F.; Othegraven, R.; Pan, H. -R.; Paoloni, A.; Parmeggiano, S.; Pei, Y.; Pelliccia, N.; Peng, A.; Peng, H.; Perrot, F.; Petitjean, P. -A.; Petrucci, F.; Pilarczyk, O.; Pineres Rico, L. F.; Popov, A.; Poussot, P.; Pratumwan, W.; Previtali, E.; Qi, F.; Qi, M.; Qian, S.; Qian, X.; Qian, Z.; Qiao, H.; Qin, Z.; Qiu, S.; Rajput, M. U.; Ranucci, G.; Raper, N.; Re, A.; Rebber, H.; Rebii, A.; Ren, B.; Ren, J.; Ricci, B.; Robens, M.; Roche, M.; Rodphai, N.; Romani, A.; Roskovec, B.; Roth, C.; Ruan, X.; Ruan, X.; Rujirawat, S.; Rybnikov, A.; Sadovsky, A.; Saggese, P.; Sanfilippo, S.; Sangka, A.; Sanguansak, N.; Sawangwit, U.; Sawatzki, J.; Sawy, F.; Schever, M.; Schwab, C.; Schweizer, K.; Selyunin, A.; Serafini, A.; Settanta, G.; Settimo, M.; Shao, Z.; Sharov, V.; Shaydurova, A.; Shi, J.; Shi, Y.; Shutov, V.; Sidorenkov, A.; Simkovic, F.; Sirignano, C.; Siripak, J.; Sisti, M.; Slupecki, M.; Smirnov, M.; Smirnov, O.; Sogo-Bezerra, T.; Sokolov, S.; Songwadhana, J.; Soonthornthum, B.; Sotnikov, A.; Sramek, O.; Sreethawong, W.; Stahl, A.; Stanco, L.; Stankevich, K.; Stefanik, D.; Steiger, H.; Steinmann, J.; Sterr, T.; Stock, M. 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Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice