33 research outputs found
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M. S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
- Abdullah T.
- Abecasis G. R.
- Abedalthagafi M.
- Abel L.
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- Wagstaff V.
- Wain L. V.
- Waite A. A. C.
- Wakefield P.
- Wakinshaw F.
- Waldron J.
- Walker D.
- Walker R.
- Walker S.
- Walker S.
- Wall A.
- Walsh T.
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- Woodford C.
- Woodruff M.
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- Woodyatt W.
- Woolley A. E.
- Worner R.
- Worsley L.
- Wray G.
- Wren L.
- Wright D.
- Wright J.
- Wright M.
- Wrobel N.
- Wu Y.
- Wulandari R.
- Wyllie D. H.
- Wynter I.
- Xavier K.
- Xue X.
- Yadav A.
- Yang J.
- Yassen A. M.
- Yates B.
- Ye C.
- Yun N.
- Zainy T.
- Zak A.
- Zaki A.
- Zamikula J.
- Zanella I.
- Zborowski A. C.
- Zeberg H.
- Zechner M.
- Zguro K.
- Zhang M.
- Zhao J. H.
- Zheng C.
- Zhou W.
- Zitter L.
- Zlatopolsky M.
- Zollner S.
- Zongo O.
- Zucchi P.
- Zyndorf M.
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Get PDFCritical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2â4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genesâincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)âin critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
- Author
- A. Abraheem
- A. Agasou
- A. Ahmed
- A. Ali
- A. Allan
- A. Altabaibeh
- A. Alvaro
- A. Aspinwall
- A. Ayers
- A. Bamford
- A. Barron
- A. Bashyal
- A. Bellini
- A. Bociek
- A. Botello
- A. Bowes
- A. Brady
- A. Brayne
- A. Brown
- A. Brown
- A. Butler
- A. Carter
- A. Collins
- A. Cowley
- A. Cowton
- A. Cowton
- A. Cox
- A. Crew
- A. Dance
- A. Daniel
- A. Daniels
- A. Dela Rosa
- A. Drummond
- A. Durie
- A. E. Heron
- A. Easthope
- A. Easthorpe
- A. Evans.
- A. Fofano
- A. Gales
- A. Ganesan
- A. Gardner
- A. Garg
- A. Gherman
- A. Gordon
- A. Gratrix
- A. Gulati
- A. Gupta
- A. Haigh
- A. Haldeos
- A. Harrison
- A. Harvey
- A. Hayes
- A. Higham
- A. Higham
- A. Hilldrith
- A. Holden
- A. Hormis
- A. Hutcheon
- A. Javaid
- A. Joseph
- A. Kaliappan
- A. Katary
- A. Kay
- A. Kayani
- A. Kent
- A. Kirkby
- A. Knight
- A. Kubisz-Pudelko
- A. Kuravi
- A. Lewis
- A. Loveridge
- A. Lyle
- A. Mayer
- A. McAlpine
- A. McCarthy
- A. McGregor
- A. McGregor
- A. Meikle
- A. Mitchell
- A. Mitra
- A. Morris
- A. Morrison
- A. Naranjo
- A. Nicholson
- A. Nicholson
- A. Noakes
- A. Patel
- A. Pickard
- A. Price
- A. Puxty
- A. Quinn
- A. Quinn
- A. Raithatha
- A. Rattray
- A. Reddy
- A. Reed
- A. Reyes
- A. Rose
- A. Rose
- A. Rostron
- A. Roy
- A. Roynon-Reed
- A. S. Raj
- A. Salberg
- A. Sanderson
- A. Serrano-Ruiz
- A. Solesbury
- A. Sukha
- A. Swain
- A. Tariq
- A. Thomas
- A. Thomas
- A. Todd
- A. Tomas
- A. Tridente
- A. Tucci
- A. Turnbull
- A. Uriel
- A. Ustianowski
- A. Vochin
- A. Vuylsteke
- A. Waite
- A. Walden
- A. Whileman
- A. Wilkinson
- A. Williams
- A. Williams
- A. Wilson
- A. Zak
- A. Zaki
- Achille Iolascon
- Adam Brown
- Adam KreÌštowski
- Adriana RozÌy
- Agnese Verzuri
- Agnieszka Adamek
- Agnieszka Bielska
- Agostino Ognibene
- Agostino Riva
- Ailsa Golightly
- Alan Maclean
- Albert Tenesa
- Aleksandra Berkan-Kawinska
- Aleksandra Jezela-Stanek
- Aleksandra Starosz
- Alessandra Guarnaccia
- Alessandra Renieri &
- Alessandra Stella
- Alessandra Vergori
- Alessandro Pancrazzi
- Alessia Giorli
- Alice Donati
- Alison Meynert
- Alistair Nichol
- Anders Larsson
- Andrea Antinori
- Andrea Cossarizza
- Andrea Gabbuti
- Andrea Tommasi
- Andrew D. Bretherick
- Andrew Law
- Andrew Stenhouse
- Andrzej Eljaszewicz
- Andrzej Horban
- Andy Law
- Angelica Pagliazzi
- Angie Fawkes
- Anke Hinney
- Anna Canaccini
- Anna Kruk
- Anna Maria Pinto
- Anna Moniuszko-Malinowska
- Anna Parfieniuk-Kowerda
- Anna Piekarska
- Anna SzaĆkowska
- Annarita Giliberti
- Anne Richmond
- Antonella D. âArminio Monforte
- Antonella Vincenti
- Antonia Ho
- Antonio Di Biagio
- Antonio Perrella
- Arianna Emiliozzi
- Arianna Gabrieli
- Arsalin Azzadin
- Asma Al Thani &
- Athanasios Kousathanas
- Audrey Coutts
- Axel Schmidt
- Axel Schmidt
- B. Anwar
- B. Attwood
- B. Baines
- B. Blackledge
- B. Borislavova
- B. Chandler
- B. Charles
- B. Creagh-Brown
- B. David
- B. Deacon
- B. Deacon
- B. Digby
- B. Faulkner
- B. Fuller
- B. Gumbrill
- B. Gurung
- B. Hadebe
- B. Hairsine
- B. Hopkins
- B. Johnson
- B. Lenagh
- B. Masunda
- B. Ogg
- B. Patel
- B. Player
- B. Purewal
- B. Scholefield
- B. Shelley
- B. Sloan
- B. Thomas
- B. Wadams
- B. Welsh
- B. Wilkinson
- B. Winter-Goodwin
- B. Yates
- Barbara Rossetti
- Barbara Shih
- Barbara Sobala-Szczygiel
- Beata Puzanowska
- Benedetta Romanin
- BjoÌrn Jensen
- Bo Wang
- Brent Richards
- Bruno Frediani
- C. Adams
- C. Ahmed
- C. Almaden-Boyle
- C. Ashbrook-Raby
- C. Basikolo
- C. Battle
- C. Beazley
- C. Beith
- C. Borra
- C. Brandwood
- C. Brantwood
- C. Burnett
- C. Castro Delgado
- C. Clark
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- C. Lynch
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- C. McParland
- C. McParland
- C. Murphy
- C. Parmar
- C. Pawley
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- C. Pothecary
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- C. Wrey Brown
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- Charles Hinds
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- Chenqing Zheng
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- Chiara Fallerini
- Chiara Gabbi
- Chiara Spertilli Raffaelli
- Chris P. Ponting
- Chris Ponting
- Christian Herr
- Christof Winter
- Christoph D. Spinner
- Clark D. Russell
- Claudia Suardi
- Claudio Ferri
- Clemens M. Wendtner
- Cristina Mussini
- D. Antcliffe
- D. Bakthavatsalam
- D. Banach
- D. Baptista
- D. Bell
- D. Branney
- D. Brealey
- D. Brealey
- D. Butcher
- D. Butcher
- D. Childs
- D. Clarke
- D. Collier
- D. Collier
- D. Cristiano
- D. Dawson
- D. Donaldson
- D. Duffin
- D. Golden
- D. Griffin
- D. Hawcutt
- D. Hope
- D. Horner
- D. Kallon
- D. Kaye
- D. Kelly
- D. Loader
- D. Lomas
- D. Martin
- D. McGlynn
- D. McLaughlanv
- D. Melia
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- D. Mullan
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- D. Purohit
- D. Raynard
- D. Salutous
- D. Salutous
- D. Scaletta
- D. Shaw
- D. Skinner
- D. Smyth
- D. Strachan
- D. Tetla
- D. Thornton
- D. Trodd
- D. Vedage
- D. Walker
- D. Warren
- D. Williams
- D. Wood
- D. Wright
- Daniela Francisci
- Danilo Tacconi
- Danny McAuley
- David Bennett
- David Harrison
- David Maslove
- Davide Grassi
- Davide Romani
- Dawn Law
- Diana Alaverdian
- Diana Martonik
- Diego Ripamonti
- Domenico A. Coviello
- Dorota Pasko
- Dorota ZareÌšbska-Michaluk
- E. Abaleke
- E. Allan
- E. Anastasescu
- E. Andrews
- E. Apetri
- E. Beech
- E. Beranova
- E. Bevan
- E. Black
- E. Brinkworth
- E. Collins
- E. Combes
- E. Davies
- E. Dobson
- E. Dooks
- E. Fisher
- E. Gendall
- E. Goff
- E. Goodwin
- E. Gordon
- E. Heeney
- E. Horsley
- E. Hughes
- E. Johnson
- E. Jude
- E. Knights
- E. Lee
- E. London
- E. Maccacari
- E. Massey
- E. McKenna
- E. Meadows
- E. Moncur
- E. Morino
- E. Mwaura
- E. Peasgood
- E. Perkins
- E. Radford
- E. Raith
- E. Salciute L. Grauslyte
- E. Smith
- E. Smithson
- E. Stoddard
- E. Stones
- E. Thomas
- E. Tilney
- E. Timlick
- E. Treus Gude
- E. Virgilio
- E. Watson
- E. Wilby
- E. Wraith
- Edoardo Conticini
- Elena Andreucci
- Elena Bargagli
- Elena Desanctis
- Elisa Benetti
- Elisa Frullanti
- Elisabetta Menatti
- Elisabetta Schiaroli
- Ellie Mcmaster
- Elvina Gountouna
- Emanuele Catena
- Enrico Cabri
- Enrico Martinelli
- Erika Fiorentini
- Erola Pairo-Castineira
- Erola Pairo-Castineira
- Esther Duncan
- Eugenia Quiros-Roldan
- Eva C. Schulte
- Eva C. Schulte
- F. Anderson
- F. Auld
- F. Bibi
- F. Davies
- F. Farquhar
- F. Fisher
- F. Hurford
- F. Kibutu
- F. McNeela
- F. Moore
- F. Nasir
- F. Trim
- F. Wakinshaw
- F. Williams
- Fabian Brand
- Fabio Lena
- Faisal Almalki
- Federica Gaia Miraglia
- Federico Anedda
- Federico Franchi
- Ferdinando Giannattasio
- Filip Taneski
- Filippo Aucella
- Filippo Biscarini
- Fiona Griffiths
- Floriana Valentino
- Francesca Andretta
- Francesca Ariani
- Francesca Colombo
- Francesca Fava
- Francesca Gatti
- Francesca Mari
- Francesca Minnai
- Francesca Montagnani
- Francesca Vichi
- Francesco Bianchi
- Francesco Brancati
- Francesco Castelli
- Francesco Menichetti
- Francesco Paciosi
- Francesco Raimondi
- Francesco Vladimiro Segala
- Francis P. Crawley
- Franco Maggiolo
- Franco Marinangeli
- G. Andrew
- G. Arbane
- G. Bell
- G. Bercades
- G. Croston
- G. Debreceni
- G. Durrant
- G. Hambrook
- G. Hobden
- G. Houston
- G. Hughes
- G. Jones
- G. Lubimbi
- G. Maloney
- G. Martir
- G. Millen
- G. Mills
- G. OâConnor
- G. Randell
- G. Sadera
- G. Seddon
- G. Sera Howe
- G. Sloane
- G. Subramanian
- G. Tsinaslanidis
- G. Turner
- G. Watson
- G. Wray
- Gabriela SokoĆowska
- Gabriella Coiro
- Gabriella Doddato
- Gabriella Maria Squeo
- GEN-COVID Multicenter Study
- Genni Spargi
- GenOMICC Consortium
- Giada Beligni
- Gian Piero Caldarelli
- Gianfranco Parati
- Giovanna Morelli
- Giulia Gori
- Giuseppe Fiorentino
- Giuseppe Merla
- Giusy Tiseo
- Graeme Grimes
- Guillaume Butler-Laporte
- Guillaume Butler-Laporte
- H. Bancroft
- H. Bates
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- H. Blackman
- H. Blakemore
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- H. Button
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- H. Jeffrey
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- H. Prady
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- H. Rehman
- H. Reschreiter
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- H. Tench
- H. Tiveran
- H. Turner
- H. Whittle
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- H. Wood
- Hadeel AlBardis
- Hamdi Mbarek
- Hanning Mal
- Helen Szoor-McElhinney
- Hugh Montgomery
- Hugo Zeberg
- Hugo Zeberg
- I. Ali Mohamed Ali
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- I. Wynter
- Ilaria Meloni
- Ilaria Rancan
- Immacolata Andolfo
- Isabella Zanella
- Iwona Mozer-Lisewska
- J. Allan
- J. Barker
- J. Bewley
- J. Biddle
- J. Birch
- J. Birch
- J. Bradley-Potts
- J. Brent Richards
- J. brown
- J. Bryant
- J. Butler
- J. Camsooksai
- J. Camsooksai
- J. Carter
- J. Caterson
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- J. Jones
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- J. Kassam
- J. Kenneth Baillie
- J. Kenneth Baillie
- J. Kenneth Baillie
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- J. Little
- J. Mallinson
- J. Martin
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- J. Parkin
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- J. Perez
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- J. Pheby
- J. Philbin
- J. Pinnell
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- J. Reid
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- J. Scriven
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- J. Zamikula
- Jacek Bogocz
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- Valentina Anemoli
- Valentina Borgo
- Valentina Perticaroli
- Verena Keitel
- Veronique Vitart
- W. Harrison
- W. Khaliq
- W. Khaliq
- W. McCormick
- W. Woodyatt
- Wadha Al-Muftah
- WES/WGS Working Group Within the HGI
- Wiktoria Izdebska
- Wilna Oosthuyzen
- X. Qiu
- Xia Shen
- Y. Baird
- Y. Choudhury
- Y. Hussain
- Y. Jackson
- Y. Thirlwall
- Yanara Marincevic-Zuniga
- Yang Wu
- Yaser Al-Sarraj
- Z. Alldis
- Z. Belagodu
- Z. Bradshaw
- Z. Coton
- Z. Daly
- Z. Farzad
- Z. Fernandez
- Z. Garland
- Z. Maqsood
- Z. Omar
- Z. Prime
- Z. Scott
- Zhijian Yang
- Publication venue
- Publication date
- 01/01/2022
- Field of study
Get PDFThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)
Genetic mechanisms of critical illness in COVID-19.
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- A Agasou
- A Ahmed
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- A Allan
- A Altabaibeh
- A Alvaro
- A Aspinwall
- A Ayers
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- A Daniel
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- A Dela Rosa
- A Drummond
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- A E Heron
- A Easthope
- A Easthope
- A Evans
- A Fofano
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- A Gherman
- A Gordon
- A Gratrix
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- A Gupta
- A Haigh
- A Haldeos
- A Harrison
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- A Hayes
- A Higham
- A Higham
- A Hilldrith
- A Holden
- A Hormis
- A Hutcheon
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- A Joseph
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- A Katary
- A Kay
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- A Kent
- A Kirkby
- A Knight
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- A Kuravi
- A Lewis
- A Loveridge
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- A McGregor
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- A Mitra
- A Morris
- A Morrison
- A Naranjo
- A Nicholson
- A Nicholson
- A Nilsson
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- A Zak
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- Achille Iolascon
- Adam Auton
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- Agnese Verzuri
- Agostino Ognibene
- Agostino Riva
- Ailsa Golightly
- Alan Maclean
- Alessandra
- Alessandra Stella
- Alessandra Vergori
- Alessia Giorli
- Alexander J Mentzer
- Alice Donati
- Alison M Meynert
- Alistair Nichol
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- Anjali J Shastri
- Anna Canaccini
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- Annarita Giliberti
- Annemarie B Docherty
- Antonella D'Arminio Monforte
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- Audrey Coutts
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- Teresa Filshtein-Sonmez
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- Trevor Paterson
- Tullio Trotta
- Turtle Lance
- U Poultney
- V Amin
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- V Waugh
- Valentina Anemoli
- Vanessa Sancho-Shimizu
- Victoria Shaw
- Vitart Veronique
- W Harrison
- W Khaliq
- W Khaliq
- W McCormick
- W Woodyatt
- Walker Susan
- Walsh Timothy
- Wang Bo
- Wei Shen Lim
- Wendy S Barclay
- William A Paxton
- William Greenhalf
- Wilson James F
- Wrobel Nicola
- Wu Yang
- X Qiu
- Y Baird
- Y Choudhury
- Y Hussain
- Y Jackson
- Y Thirlwall
- Yang Jian
- Yang Zhijian
- Z Alldis
- Z Belagodu
- Z Bradshaw
- Z Coton
- Z Daly
- Z Farzad
- Z Fernandez
- Z Garland
- Z Maqsood
- Z Omar
- Z Prime
- Z Scott
- Zechner Marie
- Zhai Ranran
- Zheng Chenqing
- Publication venue
- Nature
- Publication date
- 01/01/2020
- Field of study
Get PDFHost-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, PÂ =Â 1.65Â ĂÂ 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, PÂ =Â 2.3Â ĂÂ 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, PÂ =Â 3.98Â ĂÂ Â 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, PÂ =Â 4.99Â ĂÂ 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
Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial
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- Abani O.
- Abbas A.
- Abbas F.
- Abbas M.
- Abbasi S.
- Abbass H.
- Abbott A.
- Abdallah N.
- Abdelaziz A.
- Abdelfattah M.
- Abdelqader B.
- Abdo D.
- Abdul Rasheed A.
- Abdul B.
- Abdul-Kadir R.
- Abdul-Raheem R.
- Abdulakeem A.
- Abdulle A.
- Abdulmumeen A.
- Abdulshukkoor N.
- Abdusamad K.
- Abed El Khaleq Y.
- Abedalla M.
- Abeer Ul Amna A.U.A.
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- Abo-Leyah H.
- Aboaba A.
- Abou-Haggar A.
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- Zuriaga-Alvaro A.
- Zuurbier W.
- Zyengi S.
- Publication venue
- 'Elsevier BV'
- Publication date
- 29/05/2021
- Field of study
Get PDFBackground:
Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19.
Methods:
This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.
Findings:
Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93â1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94â1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93â1·05; p=0·79).
Interpretation:
In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.
Funding:
UK Research and Innovation (Medical Research Council) and National Institute of Health Research
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M.S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
- Abdullah T.
- Abecasis G.R.
- Abecasis G.R.
- Abedalthagafi M.
- Abel L.
- Abernathy C.
- Abraheem A.
- Abul-Husn N.S.
- Acquilini D.
- Adams C.
- Adams E.L.
- Adams K.
- Adamsara A.
- Adanini O.
- Adeleye O.
- Adra D.
- Afilalo J.
- Afilalo M.
- Afolabi D.
- Afrasiabi Z.
- Agasou A.
- Agrawal S.
- AgĂŒero D.
- Ahmad N.
- Ahmadi S.
- Ahmed A.
- Ahmed C.
- Akeroyd L.
- Akhtar M.N.
- Akinkugbe O.
- Aksentijevich A.
- Al Harthi F.
- Al Mutairi A.
- Al-Afghani H.
- Al-Awdah L.
- Alaamery M.
- Alahmadey Z.Z.
- Alaverdian D.
- Alavere H.
- Albader A.
- Albaiceta G.M.
- Albakri J.K.
- AlBardis H.
- Albeladi M.
- Albesher N.
- Albrich W.
- AlDhawi N.
- Aldridge J.
- Aleagha A.E.
- Alexander P.
- Alfonso J.
- Alghamdi B.
- Alghamdi J.
- Ali A.
- Ali A.
- Ali I.A.M.
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- Aliannejad R.
- Aljawini N.
- AlJohani S.
- Alkwai S.
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- Allan J.
- Alldis Z.
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- Allen S.
- Allibone S.
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- Allos R.
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- AlMalik A.
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- Almohammed I.
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- Alowayn A.M.
- Alqahtani S.
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- Alshareef A.
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- Ă svold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Get PDFCritical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genesâincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)âin critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
- Author
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- Publication venue
- 'Elsevier BV'
- Publication date
- 01/05/2021
- Field of study
Get PDFBackground:
In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.
Methods:
This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein â„75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mgâ800 mg (depending on weight) given intravenously. A second dose could be given 12â24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).
Findings:
Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21â550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76â0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12â1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77â0·92; p<0·0001).
Interpretation:
In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
Funding:
UK Research and Innovation (Medical Research Council) and National Institute of Health Research
Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial
- Author
- Abani Obbina
- Abbas Ali
- Abbas Fatima
- Abbas Mustafa
- Abbasi Sadia
- Abbass Hakam
- Abbott Alfie
- Abdallah Nabeel
- Abdelaziz Ashraf
- Abdelfattah Mohamed
- Abdelqader Bushra
- Abdo David
- Abdul Rasheed Althaf
- Abdul Basir
- Abdul-Kadir Rezan
- Abdul-Raheem Rasheed
- Abdulakeem Ajibode
- Abdulle Amina
- Abdulmumeen Abdulfatahi
- Abdulshukkoor Niyaz
- Abdusamad Kula
- Abed El Khaleq Yazeed
- Abedalla Mai
- Abeer Ul Amna Abeer Ul Amna
- Abernethy Katrina
- Abo-Leyah Hani
- Aboaba Adebanke
- Abou-Haggar Ahmed
- Abouibrahim Mahmoud
- Abraham Miriam
- Abraham Tizzy
- Abraheem Abraheem
- Abrams Judith
- Abu Hyacinth-John
- Abu-Arafeh Ahmed
- Abubacker Syed M
- Abung Akata
- Aceampong Yaa
- Achara Amaka
- Acharya Devikumar
- Acheampong Sarah
- Acheson Janet
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- Adell Vicki
- Ademokun Debo
- Adenwalla Sherna
- Adesemoye Oluwasegun A
- Adewunmi Emmanuel O
- Adeyemi Joyce
- Adhikary Rina
- Adkins Gabrielle
- Adnan Adnan
- Aeron-Thomas John
- Affleck Debbie
- Affron Dominic
- Afnan Carmel
- Afridi Muhammad
- Aftab Zainab A
- Agarwal Meenakshi
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- Aghababaie Arameh
- Ahamed Sadiq Shafana
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- Ahmed Liban
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- Ahmed Maria C
- Ahmed Muhammad S
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- Bull Thomas
- Bulteel Naomi
- Bumunarachchi Kasun
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- Burchett Caroline
- Burda Dorota
- Burden Christy
- Burden Thomas G
- Burgess Mika
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- Burgess Richard
- Burgess Sophia
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- Burman Adrian
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- Burnett John
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- Butler Aaron
- Butler Jessica
- Butler Joanne
- Butler Joshua
- Butler Lesley
- Butler Peter
- Butler Susan
- Butt Al-Tahoor
- Butt Mohammad M
- Butt Sophia
- Butterworth Caryl
- Butterworth-Cowin Nicola
- Buttery Robert
- Buttle Tom
- Button Heather
- Buttress Daniel
- Publication venue
- 'Elsevier BV'
- Publication date
- 13/02/2021
- Field of study
Get PDFSummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87â1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98â1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87â1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
- Author
- ?ivko Iris
- Abbass Hakam
- Abdeladim Lilia
- Abdelhady Hesham
- Abdelkharim Hussam
- Abdelrazik Marwa
- Abdi Zakee
- Abdukahil Sheryl Ann
- Abel Lynn
- Abraham Jacinta
- Abrahamson Gail
- Abusamra Yousuf
- Aceto Romina
- Adams Nick
- Adams Peter
- Adebambo Olumide
- Adhikari Neill
- Adhikari Sheetal
- Affleck Julia
- Agha Gloria
- Aghemo Alessio
- Agno Ronan
- Ahmad Norfaizan
- Ain Quratul
- Ainscough Kate
- Ainsworth James
- Aitken Lindianne
- Akamp Ceren
- Al Enezi Farhan
- Al-Bassam Wisam
- Al-Beidh Farah
- Albert Martin
- Albrett Jonathan
- Alderman Meera
- Aldo Bonizzoni Matteo
- Alegria Ana
- Alessandro CarĂ Gianmarco
- Alexander Brian
- Alexander Peter
- Alfonso Jordan
- Ali Maryam
- Ali Murtaza
- Allam Hayat
- Allen Barbara
- Allen Louise
- Allibone Suzanne
- Almeshhedani Hasham
- AlQahtani Samah
- Alswaidan Lolowa
- Altomy Mohammed
- Al Amri Ali
- Al Qasim Eman
- Amatya Sameena
- Ambrosino Richard
- Anderson Thomas
- Andreae Mark
- Aneman Anders
- Angus Derek C.
- Anjum Aisha
- Ankert Juliane
- Annane Djillali
- Anne-Laure Fedou
- Anstey Matthew
- Antcliffe David
- Anthony Alpha
- Antoine Marchalot
- Antoine Pierre
- Antoine Studer
- Anumakonda Vikram
- Aparicio Christelle
- Aquino Maia
- Arabi Yaseen M.
- Arachchige Malka
- Aravindan Latha
- Arbane Gill
- Archambault Patrick
- Archer Simon
- Aref Noah
- Arias Ana-Marie
- Arias Sonia
- Arishi Hatim
- Arnold Donald
- Arnold John
- Arnott Andrew
- Arora Anand
- Aryal Diptesh
- Asghar Adeeba
- Asif Namra
- Aspinwall Angelique
- Attokaran Antony
- Attwood Ben
- Au Carly
- Audry Mathilde
- Austin Karen
- Austin Pauline
- Auvet Adrien
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- Depuydt Pieter
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- Derde Lennie P. G.
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- Detry Michelle A.
- Deye Nicolas
- de la Fuente Carmen
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- Hey Samuel
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- Higgins Alisa M.
- Hill Claire
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- Horvat Christopher M.
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- Huang David T.
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- Kremling Julius
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- Krishnamoorthy S
- Krishnamurthy Vinodh
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- Yu Haili
- Yusuff Hakeem
- Zaharia Mihaela
- Zaidi Abbas
- Zaki Ahmed
- Zaman Mohsin
- Zarychanski Ryan
- Zdanavidiene Ausra
- Zhao Xiao
- Zinzoni Vanessa
- Zitter Letizia
- Zouita Louisa
- Publication venue
- 'American Medical Association (AMA)'
- Publication date
- 11/04/2023
- Field of study
Get PDFIMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
In vitro human metabolism and interactions of repellent N,N-diethyl-mtoluamide.
- Publication venue
- Publication date
- 01/01/2002
- Field of study
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- Author
- Publication venue
- 'Informa UK Limited'
- Publication date
- Field of study
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