46 research outputs found
Aluminum-fueled rockets for the space transportation system
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- Publication venue
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- Field of study
Aluminum-fueled engines, used to propel orbital transfer vehicles (OTV's), offer benefits to the Space Transportation System (STS) if scrap aluminum can be scavenged at a reasonable cost. Aluminum scavenged from Space Shuttle external tanks could replace propellants hauled from Earth, thus allowing more payloads to be sent to their final destinations at the same Shuttle launch rate. To allow OTV use of aluminum fuel, two new items would be required: a facility to reprocess aluminum from external tanks and an engine for the OTV which could burn aluminum. Design of the orbital transfer vehicle would have to differ substantially from current concepts for it to carry and use the aluminum fuel. The aluminum reprocessing facility would probably have a mass of under 15 metric tons and would probably cost less that 200,000,000.Developmentofanaluminum−burningenginewouldnodoubtbeextremelyexpensive(1to2billiondollars),butthisamountwouldbeadequatelyrepaidbyincreasedSTSthroughput.Engineproductioncostisdifficulttoestimate,butevenanextremelyhighcost(e.g.,250,000,000 per engine) would not significantly increase orbit-raising expenses
Tethers
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- Field of study
A tether of sufficient strength, capable of being lengthened or shortened and having appropriate apparatuses for capturing and releasing bodies at its ends, may be useful in propulsion applications. For example, a tether could allow rendezvous between spacecraft in substantially different orbits without using propellant. A tether could also allow co-orbiting spacecraft to exchange momentum and separate. Thus, a reentering spacecraft (such as the Shuttle) could give its momentum to one remaining on orbit (such as the space station). Similarly, a tether facility could gain momentum from a high I(sub sp)/low thrust mechanism (which could be an electrodynamics tether) and transfer than momentum by means of a tether to payloads headed for many different orbits. Such a facility would, in effect, combine high I(sub sp) with high thrust, although only briefly. An electrodynamic tether could propel a satellite from its launch inclination to a higher or lower inclination. Tethers could also allow samples to be taken from bodies such as the Moon. Three types of tether operations are illustrated. The following topics are discussed: (1) tether characteristics; (2) tether propulsion methods--basics, via momentum transfer, and electrodynamic tether propulsion; and (3) their use in planetary exploration
Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- Author
- Aeschbacher Stefanie
- Alonso Alvaro
- Araujo Nathalia M.
- Arking Dan E.
- Arnar David O.
- Assa Solmaz
- Avery Christy L.
- Barnes Catriona L. K.
- Barnes Michael R.
- Benjamin Emelia J.
- Biggs Mary L.
- Bis Joshua C.
- Boerwinkle Eric
- Bottinger Erwin P.
- Boutin Thibaud
- Brody Jennifer A.
- Campbell Harry
- Cartwright James H.
- Caulfield Mark J.
- Chaffin Mark D.
- Choi Seung Hoan
- Concas Maria Pina
- Conen David
- Cook James P.
- Correa Adolfo
- Cranley James J.
- Cucca Francesco
- Cutler Michael J.
- De Grandi Alessandro
- de Mutsert Renee
- Del Greco Fabiola M.
- Ding Jun
- Doerr Marcus
- Dominiczak Anna
- Ehret Georg B.
- Ellinor Patrick T.
- Fatkin Diane
- Felix Stephan B.
- Foco Luisa
- Ford Ian
- Fuchsberger Christian
- Gasparini Paolo
- Giedraitis Vilmantas
- Gogarten Stephanie M.
- Gogele Martin
- Gudbjartsson Daniel F.
- Gudnason Vilmundur
- Guo Xiuqing
- Haessler Jeffrey
- Hall Amelia Weber
- Harris Tamara B.
- Havulinna Aki S.
- Hayward Caroline
- Heckbert Susan R.
- Hicks Andrew A.
- Holm Hilma
- Huang Paul L.
- Hutri-Kahonen Nina
- Ingelsson Erik
- Isaacs Aaron
- Jackson Rebecca D.
- Jamshidi Yalda
- Joshi Peter K.
- Jukema J. Wouter
- Jula Antti
- Kaab Stefan
- Kahonen Mika
- Kerr Kathleen F.
- Kolcic Ivana
- Kooperberg Charles
- Kors Jan A.
- Lakatta Edward G.
- Lambiase Pier D.
- Launer Lenore J.
- Laurie Cathy C.
- Lehtimaki Terho
- Levy Daniel
- Lima-Costa Maria Fernanda
- Lin Henry J.
- Lin Honghuang
- Lind Lars
- Lindgren Cecilia M.
- London Barry
- Loos Ruth J. F.
- Lubitz Steven A.
- Lunetta Kathryn L.
- Lyytikainen Leo-Pekka
- Maan Arie C.
- Macfarlane Peter W.
- Mahajan Anubha
- Mangino Massimo
- Marten Jonathan
- Mei Hao
- Meitinger Thomas
- Mifsud Borbala
- Mishra Pashupati P.
- Mononen Nina
- Montasser May E.
- Mook-Kanamori Dennis O.
- Morris Andrew P.
- Mueller-Nurasyid Martina
- Munroe Patricia B.
- Murray Alison D.
- Nadkarni Girish N.
- Nelson Christopher P.
- Newton-Cheh Christopher H.
- Nikus Kjell
- Noordam Raymond
- Ntalla Ioanna
- O'Connell Jeff R.
- Olesen Morten
- Orini Michele
- Padmanabhan Sandosh
- Pattaro Cristian
- Peters Annette
- Peters Ulrike
- Polasek Ozren
- Porteous David J.
- Pramstaller Peter P.
- Preuss Michael H.
- Psaty Bruce M.
- Qian Yong
- Raitakari Olli T.
- Ramirez Julia
- Reiner Alexander P.
- Riaz Muhammad B.
- Ribeiro Antonio Luiz P.
- Rice Kenneth
- Rienstra Michiel
- Risch Lorenz
- Roden Dan M.
- Roselli Carolina
- Rotter Jerome
- Rudan Igor
- Ryan Kathleen
- Said M. Abdullah
- Salomaa Veikko
- Samani Nilesh J.
- Schramm Katharina
- Seyerle Amanda A.
- Shoemaker M. Benjamin
- Shuldiner Alan R.
- Sinagra Gianfranco
- Sinner Moritz F.
- Smith Albert
- Smith Blair H.
- Smith J. Gustav
- Soliman Elsayed Z.
- Sotoodehnia Nona
- Souza Renan P.
- Spector Timothy D.
- Stefansson Kari
- Stilp Adrienne
- Strauch Konstantin
- Stricker Bruno H.
- Sulem Patrick
- Sundstrom Johan
- Sveinbjornsson Gardar
- Sääksjärvi Katri
- Tarasov Kirill
- Tarazona-Santos Eduardo
- Taylor Kent D.
- Theriault Sebastien
- Thorleifsson Gudmar
- Thorolfsdottir Rosa B.
- Thorsteinsdottir Unnur
- Tinker Andrew
- Trompet Stella
- Tucker Nathan R.
- Uitterlinden Andre
- Ulivi Sheila
- van de Vegte Yordi J.
- van den Berg Marten E.
- van der Ende M. Yldau
- van der Harst Pim
- van Duijn Cornelia M.
- Van Duijvenboden Stefan
- Verweij Niek
- Voelker Uwe
- Waldenberger Melanie
- Warren Helen R.
- Weiss Stefan
- Weng Lu-Chen
- Whitsel Eric A.
- Wilson James
- Wilson James F.
- Yao Jie
- Publication venue
- Publication date
- 01/01/2020
- Field of study
The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe
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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
- Author
- Abbass Hakam
- Adhikari Neill
- Affleck Julia
- Agno Sathianathan Ronan
- Ahmad Norfaizan
- Ahmed Iram
- Ainscough Kate
- Al Qasim Eman
- Al Swaidan Lolowa
- Al-Bassam Wisam
- Al-Beidh Farah
- Al-Beidh Farah
- Albert Martin
- Alegria Ana
- Alexander Brian
- Alexander Peter
- Allan Angela
- Allan Elizabeth
- Allen Louise
- Allibone Suzanne
- Amaro dos Santos Catorze Teodoro
- Anderson Tom
- Andric Zdravko
- Angus Derek
- Angus Derek C
- Anjum Aisha
- Ankert Juliane
- Annane Djillali
- Annane Djillali
- Anstey Matthew
- Antcliffe David
- Aparicio Christelle
- Appelt Peter
- Arabi Yaseen
- Arabi Yaseen
- Arbane Gill
- Archer Simon
- Aref Noah
- Arias Ana-Marie
- Arishi Hatim
- Arnold Donald
- Asghar Adeeba
- Ashelford Angela
- Attwood Ben
- Austin Karen
- Aysel Florescu Simin
- Azaiz Amine
- Babel Jakša
- Babio-Galan Maite
- Badie Julio
- Bagshaw Sean
- Baillie Kenneth
- Baker Evelyn
- Bakthavatsalam Dhanalakshmi
- Bamford Peter
- Banach Dorota
- Bannard-Smith Jonathan
- Barbazza Leanne
- Barber Russell
- Barge Deborah
- Barnes Nicky
- Baršić Bruno
- Bashyal Archana
- Basile Kim
- Bass Frances
- Bates Michelle
- Bauchmuller Kris
- Bean Sarah
- Beane Abigail
- Beane Abigail
- Beasley Richard
- Begin Phillipe
- Bellemare David
- Benettaib Fatna
- Benzekri Dalila
- Berdaguer Fernando Daniel
- Bergin Colin
- Berry Lindsay
- Berry Lindsay
- Berry Scott
- Berry Scott
- Bhimani Zahra
- Bhimani Zahra
- Bihari Shailesh
- Bihari Shilesh
- Binnie Alexandra
- Bion Julian
- Biradar Vishwanath
- Birch Janine
- Birch Jenny
- Birchall Katie
- Birkinshaw Isobel
- Black Ethel
- Bloos Frank
- Board Jasmin
- Bone Allsion
- Bonner Stephen
- Bonten Marc
- Bonten Marc
- Borgatta Barbara
- Borrill Zoe
- Bosch Ziekenhuis Jeroen
- Boschert Catherine
- Bossard Isabelle
- Boumahni Dounia
- Bourgoin Charlotte
- Bourne Michelle
- Bourne Richard
- Bouwman Wietske
- Bowler Helen
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- Bracke Stephanie
- Bradbury Charlotte
- Bradbury Charlotte
- Bradley-Potts Joanne
- Brailsford Jane
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- Brinkerhoff Gail
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- Brunkhorst Frank
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- Buehner Ulrike
- Buhr Heidi
- Bullman Laetitia
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- Buzgau Adrian
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- Chablani Manish
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- Chan Carmen
- Chan Charles
- Chan Peter
- Charlewood Richard
- Charron Cyril
- Chartier Delphine
- Chasse Michael
- Chassé Michaël
- Chen Yan
- Cheng Allen
- Cheng Allen C
- Cherian Shiney
- Cheung Winston
- Chhablani Manish
- Chudeau Nicolas
- Cirstea Emanuel
- Clarey Emma
- Claridge Helen
- Clark Michele
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- Codreanu Daniel
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- Connor Jason
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- Cort Jon
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- de Lima Pereira Tiago Nuno Alfaro
- de Man Angelique
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- Howle Ryan
- Huang David
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- Hugill Keith
- Hullegie Sebastiaan
- Hullegie Sebastiaan J
- Hulley Amanda
- Hulme Jonathan
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- Isgro Graziella
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- Jackson Shane
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- Jacquier Sophie
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- Jarczak Dominik
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- Johnson Rebekah
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- Jones Jo
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- Khalid Imrana
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- Kosa Alma Gabriela
- Kotarski Viktor
- Kovács Sándor
- Kreß Gabriele
- Krishnamurthy Vinodh
- Kruger Peter
- Kruger Peter
- Kuitunen Anne
- Kumar Anand
- Kumar Nikhil
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- Kurenda Catherine
- Kutleša Marko
- Kušan Ira
- KyereDiabour Thyra
- Kyeremeh Lynsey
- Labbe Vincent
- Laffan Mike
- Laffey John
- Laha Shondipon
- Lai Vivian
- Lamb Thomas
- Lamonagne Francois
- Lamontagne Francois
- Lamontagne Francois
- Lamontagne François
- Landais Mickaël
- Lane Janis-Best
- Lankester Liana
- Laver Russell
- Lawler Patrick
- Lawler Patrick R
- Lawless Patrick
- Lazaro Juan Martin
- Leaver Susannah
- Leblond Julie
- Lee Kelvin
- Lee Stephanie
- Leparco Cécile
- Lesona Eden
- Leszkoven János
- Lewis Roger
- Lewis Roger J
- Lewis Sarah
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- Linstrum Kelsey
- Litton Ed
- Litton Edward
- Litton Edward
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- London Emily
- Lorenzi Elizabeth
- Lorenzi Elizabeth
- Lother Sylvain
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- Mackay Euan
- MacLennan Sheila
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- Maiden Matthew
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- Malakoutis Salim
- Malfroy Sylvain
- Malissin Isabelle
- Maloney Carolyn
- Manax Victoria
- Mandadapu Vineela
- Mangindaan Yara
- Maquigneau Natacham
- Marabi Yaseen
- Mariappa Vasanth
- Marin-Corral Judith
- Markgraf Rene
- Marroquin Oscar
- Marshall John
- Marshall John
- Marshall Nicola
- Mart Emma
- Marten Nicole
- Martin Jane
- Martin Timothy
- Martynoga Robert
- Maselli Astrid
- Masse Marie-Helene
- Mateo López Maria Isabel
- Matsa Ramprasad
- Mattocks Lehentha
- Maxime Virginie
- Mc Goldrick Clare
- Mc Master Moyra
- McArthur Colin
- McArthur Colin
- McAuley Daniel
- McAuley Daniel
- McAuley Danny
- McCallum Peter
- McClintock Declan
- McConnochie Rachael
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- McVerry Bryan
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- Montgomery Stephanie
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- Mouncey Paul
- Moviat M
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- Murthy Srinivas
- Murthy Srinivas
- Music Edvin
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- Mwaura Esther
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- Nichol Alistair
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- Orford Neil
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- O’Neill Aisling
- Page Valerie
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- Panwar Rakshit
- Paramasivam Elankumaran
- Parekh Dhruv
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- Parke Rachael
- Parker Jane
- Parker Lorraine
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- Pereira Sousa Bastos Joana Margarida
- Pereira Rita
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- Philbin Jennifer
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- Pillai Suresh
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- Quayle Rachael
- Quinn Kevin
- Qureshi Hafiz
- Rad Laura
- Rademaker Emma
- Rae Nicola
- Raithatha Ajay
- Ramali Mohamed
- Ramanan Mahesh
- Ramos Lidia
- Randell Georgina
- Rauniyar Rashmi
- Raymakers Kik
- Reddy Amie
- Reddy Harsha
- Rees Tabitha
- Reeve Brenda
- Regli Adrian
- Reill Lorenz
- Rengers Els
- Reschreiter Henrik
- Reynolds Claire
- Reynolds John
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- van de Veerdonk Frank
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- Wedd Steve
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- Writing Committee for the REMAP-CAP Investigators
- Xavier Kugan
- Xia Le Tai Charlotte
- Yarad Elizabeth
- Yates David
- Young Chelsea
- Young Ian
- Young Meredith
- Young Paul
- Yusuff Hakeem
- Zaharia Miahela Florentina
- Zaidi Abbas
- Zaki Ahmed
- Zaman Mohsin
- Zammit Claire
- Zapalac Marija
- Zarychanski Ryan
- Zarychanski Ryan
- Zhao Xiao Bei
- Zinzoni Vanessa
- Zitter Letizia
- Đimoti Renata
- Publication venue
- JAMA: Journal of the American Medical Association
- Publication date
- 06/10/2020
- Field of study
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Genetic mechanisms of critical illness in COVID-19.
- Author
- A A Roger Thompson
- A Abraheem
- A Agasou
- A Ahmed
- A Ali
- A Allan
- A Altabaibeh
- A Alvaro
- A Aspinwall
- A Ayers
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- Stephanie Roberts
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- Summers Charlotte
- Susanna Croci
- Susanna Guerrini
- T Anderson
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- Tammy Gilchrist
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- Trevor Paterson
- Tullio Trotta
- Turtle Lance
- U Poultney
- V Amin
- V Anumakonda
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- 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
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
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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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 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 genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in 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
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 Carà 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
- Avard Bronwyn
- Awan Sidra
- Ayee Robert
- Azaiz Amine
- Azzaui Harun
- Babu Suresh
- Bacon Gina
- Badalamenti Salvatore
- Badie Julio
- Bagavathy Kavitha
- Bagot Catherine
- Bagshaw Sean
- Baig Nadia
- Baikady Ravishankar
- Bailey Lucy
- Baillie Kenneth
- Bain William
- Baker Alice
- Baker Evelyn
- Baker Stuart
- Bakthavatsalam Dhanalakshmi
- Balaie Morteza
- Balls-Burgess Sam
- Bamford Amy
- Bamford Peter
- Banach Dorota
- Bannard-Smith Jonathan
- Barbash Ian
- Barber Russell
- Barbier François
- Barge Deborah
- Bariola Ryan
- Barker Gareth
- Barker Stephanie
- Barnes Nicky
- Baron Rebecca M.
- Barreau Amelie
- Barreau Amélie
- Bart Robert
- Bartholomew Jazz
- Bartley Shauna
- Barton David
- Barton Frances
- Bashyal Archana
- Basile Kim
- Bass Frances
- Bassford Christopher
- Bastos Joana Margarida Pereira Sousa
- Bates Michelle
- Bates Samantha
- Batista Teresa Margarida Oliveira
- Bauchmuller Kris
- Bayne Madeleine
- Bean Sarah
- Beane Abi
- Beane Abigail
- Beard Gregory
- Beasley Richard
- Beaudoin Rosalie
- Beavis Sarah
- Beddows Seonaid
- Bedford Caroline
- Beer Deborah
- Beer Sally
- Begin Phillipe
- Begum Salma
- Bell Gillian
- Bellemare David
- Belletti Allesandro
- Bendjemar Lynda
- Benettaib Fatna
- Bensen Nicole
- Bentley Andrew
- Benyon Sarah
- Benzekri Dalila
- Beqai Besa
- Berdaguer Fernando
- Beresford Stephanie
- Bergin Colin
- Berry Lindsay R.
- Berry Scott
- Berryman Emily
- Bertel Melanie
- Best-Lane Janis
- Besten Henny
- Bevan Emily
- Bewley Jeremy
- Beyerl Ashley
- Bhagani Sanjay
- Bhandal Khushpreet
- Bharaj Kiranjit
- Bhattarai Bina
- Bhattarai Binita
- Bhonagiri Deepak
- Biddie Simon
- Bigas Judit
- Bihari Shailesh
- Bin Hasan Mohd Shahnaz
- Bindels Manon
- Binnie Alexandra
- Biradar Vishwanath
- Birch Catherine
- Birch Janine
- Birch Sophie
- Birchall Kathrine
- Birkinshaw Isobel
- Black Ethel
- Blackledge Bethany
- Blakemore Hayley
- Blanck Wendy
- Bland Yvonne
- Blank Elisabeth
- Bleasdale John
- Bloomfield Jack
- Bloos Frank
- Board Jasmin
- Boardman Melanie
- Boari Gianluca
- Bocher Simon
- Bociek Aneta
- Boivin Anne-Helene
- Boivin Anne-Hélène
- Bojunga Jörg
- Bomken Charlotte
- Bonaccorso Allesandra
- Bongaerts Katherine
- Bonner Stephen
- Bonten Marc J. M.
- Borgatta Barbara
- Borislavova Borislava
- Borrill Zoe
- Boschert Catherine
- Bossard Isabelle
- Bothma Pieter
- Boudineau Michel
- Boulanger Marie-Claude
- Boumahni Dounia
- Bouman Angela
- Bounab Rania
- Bourgoin Charlotte
- Bourne Michelle
- Bourne Richard
- Boutin Mireille
- Bouvier Elodie
- Bouw-Ruiter Marianne
- Boué Yvonnick
- Bowen James
- Bowler Helen
- Boyd Craig
- Boyles Rebecca
- Bracke Stephanie
- Bradbury Charlotte A.
- Bradley Paul
- Brady Kara
- Brailsford Jane
- Brain Matthew
- Brakké Karen
- Brant Emily
- Brasselet Aurélie
- Breen Patrick
- Bremmer Pamela
- Brend Morwenna
- Brennan Aoife
- Bretagnol Anne
- Brett Stephen
- Brewer Chris
- Brickell Kathy
- Bridges Sarah
- Brieger Klaus-Gerd
- Brightling Chris
- Brimfield Lutece
- Brittain Michael
- Britton Kate
- Brochard Laurent
- Brodbeck Andreas
- Brohi Farooq
- Brooks Nicole
- Brown Cynthia
- Brown Julia
- Brown Louise
- Brown Nerissa
- Brown Zarah
- Brugman Curt
- Brunetta Enrico
- Brunkhorst Frank M.
- Brunskill Nigel
- Bryan-Morris Kayla
- Bryden Emma
- Budd Joanna
- Buehner Ulrike
- Buhay Megan
- Buhr Heidi
- Burbee Dylan
- Burda Dorota
- Burgess Richard
- Burke David
- Burke Tara
- Burkey Jason
- Burnish Rachel
- Burns Dean
- Burns Karen
- Burrell Aidan
- Burt Karen
- Buscher Hergen
- Butler Amelia
- Butler Magdalena
- Butler Susan
- Buxton Meredith
- Buzgau Adrian
- Byrne Kathleen
- Byrne Rahim
- Cabrelli Louise
- Cabreros Leilani
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- Orlikowska Izabela
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- Yamashita Chizuru
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- Youngstein Taryn
- 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
IMPORTANCE 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 non–critically 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 (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free 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 support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (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 support–free 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
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M.S.
- Abdel-Aziz M.
- Abdelrazik M.
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- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Critical 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 genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in 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
Thigh-length compression stockings and DVT after stroke
- Author
- Abbas M
- Abbasi S
- Abbasi S
- Abdelaziz A
- Abdelfattah M
- Abdul B
- Abdulmumeen A
- Abdulshukkoor N
- Abdusamad K
- Aboaba A
- Abouibrahim M
- Abraham M
- Abraham T
- Abrams J
- Abung A
- Acharya D
- Acharya D
- Acheson J
- Acosta A
- Acosta A
- Acton C
- Adam M
- Adams C
- Adams K
- Adamus M
- Adegoke K
- Adenwalla S
- Adeyeye E
- Adnan A
- Agbo C
- Aggarwal S
- Agwada-Akeru J
- Agyapong K Ansu
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- Thozthumparambil P
- Thrasyvoulou L
- Thraves H
- Thwaites G
- Thwaites G
- Tiberi S
- Tierney C
- Tierney C
- Tilbey S
- Tiller A
- Timms H
- Tinkler H
- Tinkler M
- Tisi S
- Todd J
- Todd S
- Todd S
- Tohfa M
- Tomasova N
- Tomlin S
- Tomlinson J
- Topham K
- Torabi P
- Tousis R
- Tovey P
- Trafford MT
- Travill C
- Traynor S
- Trotter A
- Trudgill N
- Truslove M
- Trussell T
- Tsakiridou K
- Tsang C
- Tsilimpari K Karali
- Tucker S
- Tully R
- Turbitt K
- Turgut T
- Turnbull A
- Turner A
- Turner A
- Turner C
- Turner G
- Turner H
- Turner K
- Turner K
- Turner L
- Turner S
- Turney S
- Twohey E
- Tyagi B
- Tyagi V
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- Tzavaras P
- Uddin M Saif
- Ul Hassan W
- Ullah S
- Ullah S
- Umaipalan A
- Umeojiako W
- Unsworth A
- Uppal V Singh
- Urruela S
- Usher M
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- Ustianowski A
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- Vaccari L Cheyenne
- Valeria B
- Vamplew L
- van de Venne M
- van der Meer A
- van der Stelt N
- van Someren C
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- Vara S
- Varghese A
- Varghese M
- Varnier G
- Vasadi V
- Vasu V
- Vasudevan V
- Vathenen R
- Vatish M
- Vattekkat R Renu
- Vayalaman H
- Vaz C
- Veale N
- Velan B
- Velauthar L
- Vella N
- Venables I
- Venditti M
- Venkataramakrishnan R
- Veres M
- Vergnano S
- Verma A
- Vertue M
- Vethanayagam N
- Vilimiene N
- Vinay S
- Vincent R
- Vincent R
- Visentin E
- Vithian K
- Vyras E
- Wadd S
- Waddington N
- Wadsworth K
- Wafa SEI
- Wagstaff D
- Wagstaff L
- Wahbi Z
- Wake R
- Wakefield E
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- Wakeford W
- Wakinshaw F
- Walden A
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- Whittam L
- Whittington A
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- Wibli L
- Widdrington J
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- Wildsmith T
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- Wiliams T
- Wilkinson I
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- Wilkinson S
- Willetts S
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- Williams K Barker
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- Willis J
- Wilson A
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- Wilson A
- Wilson D
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- Wiselka M
- Wittes J
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- Wood F
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- Woodford J
- Woodhead L
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- Woodward Z
- Wooldridge G
- Woollen L
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- Wootton D
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- Yanney M
- Yasmin S
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- Yelnoorkar F
- Yip K
- Ynter I
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- Zaher S
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- Publication venue
- 'Elsevier BV'
- Publication date
- 01/07/1994
- Field of study
Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease