47 research outputs found
Vergleichende Untersuchungen zu GPCR-induzierten dynamischen KonformationsĂ€nderung in ÎČ-arrestin1 und 2
- Author
- Publication venue
- Publication date
- 01/01/2022
- Field of study
G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in human physiology, comprising more than 800 different genes. They sense diverse extracellular signals and initiate intracellular signaling responses via the activation of specific G proteins. The downregulation of GPCR signaling is mediated by four ubiquitously expressed GPCR kinases (GRK2, 3, 5, and 6) and two ÎČ-arrestin isoforms (ÎČ-arrestin1 and 2). GRKs phosphorylate intracellular domains of active receptors to facilitate high-affinity ÎČ-arrestin-binding. Depending on the specific GPCRâÎČ-arrestin interaction, ÎČ-arrestins undergo different conformational changes to mediate receptor desensitization, internalization, and mitogen-activated protein kinase (MAPK) signal-amplification. However, the impact of individual GRK isoforms on these processes has not been comprehensively assessed until now. Moreover, whether ÎČ-arrestin1 and 2 undergo different conformational changes upon binding to the same GPCR is still unknown. The first part of this thesis focusses on the elaboration of GRK isoform-specific aspects of GPCR signaling. For this, a panel of elven in-house created combinatorial HEK293 knockout cell clones, lacking GRK2/3/5/6 (including four single, two double, four triple, and a quadruple GRK knockout cell line), was extensively used. To investigate GRK isoform-specific ÎČ-arrestin recruitment, a NanoLucâHaloTag-based BRET system was established and combined with the unique possibility to vary individual GRK expression levels using different ÎGRK knockout cell lines. Hence, the GRK-specificity of ÎČ-arrestin-binding was assessed with two different strategies: first, utilizing the triple GRK knockout cell lines, featuring the endogenous expression of only one GRK isoform (ÎGRK3/5/6, ÎGRK2/5/6, ÎGRK2/3/6, ÎGRK2/3/5), and additionally by re-introduction of a single GRK isoform in the quadruple GRK knockout cell line (ÎQ-GRK)
Differential regulation of GPCRs: Are GRK expression levels the key?
- Publication venue
- 'Frontiers Media SA'
- Publication date
- 24/05/2021
- Field of study
G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and their signal transduction is tightly regulated by GPCR kinases (GRKs) and ÎČ-arrestins. In this review, we discuss novel aspects of the regulatory GRK/ÎČ-arrestin system. Therefore, we briefly revise the origin of the âbarcodeâ hypothesis for GPCR/ÎČ-arrestin interactions, which states that ÎČ-arrestins recognize different receptor phosphorylation states to induce specific functions. We emphasize two important parameters which may influence resulting GPCR phosphorylation patterns: (A) direct GPCRâGRK interactions and (B) tissue-specific expression and availability of GRKs and ÎČ-arrestins. In most studies that focus on the molecular mechanisms of GPCR regulation, these expression profiles are underappreciated. Hence we analyzed expression data for GRKs and ÎČ-arrestins in 61 tissues annotated in the Human Protein Atlas. We present our analysis in the context of pathophysiological dysregulation of the GPCR/GRK/ÎČ-arrestin system. This tissue-specific point of view might be the key to unraveling the individual impact of different GRK isoforms on GPCR regulation
Fluorescence Lifetime Imaging Unravels C. trachomatis Metabolism and Its Crosstalk with the Host Cell
- Author
- A Harper
- A Harper
- A Matsumoto
- A Roth
- CC Fjeld
- D Li
- D Li
- D Wilson
- DK Bird
- DM Ojcius
- DP Wilson
- DP Wilson
- E Brunner
- EI Shaw
- ER Iliffe-Lee
- GA Wagnieres
- Gereon HĂŒttmann
- HC Gerard
- HD Vishwasrao
- I Haferkamp
- Inke R. König
- Jan Rupp
- JR Lakowicz
- K Blinova
- K Yaraei
- Kensuke Shima
- L Guarente
- MA Scidmore
- MC Skala
- MC Skala
- MW Taylor
- MĂĄrta SzaszĂĄk
- N Pollak
- ND Evans
- O Trentmann
- Philipp Steven
- Q Yu
- Q Zhang
- Q Zhang
- R Niesner
- RA Heinzen
- Raphael H. Valdivia
- Regina Orzekowsky-Schröder
- RJ Belland
- RS Stephens
- S Haider
- S Huang
- S Michan
- ST Rao
- TH Chia
- TP Hatch
- Werner Solbach
- WL Beatty
- Publication venue
- Public Library of Science
- Publication date
- 01/07/2011
- Field of study
Chlamydia trachomatis is an obligate intracellular bacterium that alternates between two metabolically different developmental forms. We performed fluorescence lifetime imaging (FLIM) of the metabolic coenzymes, reduced nicotinamide adenine dinucleotides [NAD(P)H], by two-photon microscopy for separate analysis of host and pathogen metabolism during intracellular chlamydial infections. NAD(P)H autofluorescence was detected inside the chlamydial inclusion and showed enhanced signal intensity on the inclusion membrane as demonstrated by the co-localization with the 14-3-3ÎČ host cell protein. An increase of the fluorescence lifetime of protein-bound NAD(P)H [Ï2-NAD(P)H] inside the chlamydial inclusion strongly correlated with enhanced metabolic activity of chlamydial reticulate bodies during the mid-phase of infection. Inhibition of host cell metabolism that resulted in aberrant intracellular chlamydial inclusion morphology completely abrogated the Ï2-NAD(P)H increase inside the chlamydial inclusion. Ï2-NAD(P)H also decreased inside chlamydial inclusions when the cells were treated with IFNÎł reflecting the reduced metabolism of persistent chlamydiae. Furthermore, a significant increase in Ï2-NAD(P)H and a decrease in the relative amount of free NAD(P)H inside the host cell nucleus indicated cellular starvation during intracellular chlamydial infection. Using FLIM analysis by two-photon microscopy we could visualize for the first time metabolic pathogen-host interactions during intracellular Chlamydia trachomatis infections with high spatial and temporal resolution in living cells. Our findings suggest that intracellular chlamydial metabolism is directly linked to cellular NAD(P)H signaling pathways that are involved in host cell survival and longevity
Pan-cancer analysis of whole genomes
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- The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium View Correspondence (jump link)
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- zd Gershenwald
- Zenklusen
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- zf Ghossein
- Zhang
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- Zhang
- Zhang
- Zhang
- Zhang
- Zhang H. b
- Zhao
- Zheng
- Zhou
- Zhou
- Zhu
- Zhu
- zi zj
- zm Jayaseelan
- Zou
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- zt Kim
- zw Lewis
- Ă. A. th
- Ă. sk
- Publication venue
- Publication date
- 11/12/2019
- Field of study
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe
Recommended from our members
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
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- Abascal F.
- Abeshouse A.
- Aburatani H.
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- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 02/03/2020
- Field of study
Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658âtumors from 38âcancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer
Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries
- Author
- Abad-Motos A.
- Abbas A.M.
- Abbas M.
- Abbasi M.
- Abbott T.
- Abdalaal I.
- Abdel-Galil K.
- Abdelemam R.
- Abdelgawad A.
- Abdelkarim M.
- Abdelkhalek M.
- Abdelmageed A.
- Abdelmawgoud S.
- Abdelmohsen S.
- Abdelrahman A.S.
- Abdelrahman M.
- Abdelwahab K.
- Abdou H.
- Abdulai D.R.
- Abdulkhaleq M.
- Abdullah B.
- Abdulsalam K.
- Abdulsalam S.
- Abdur-Rahman L.
- Abdus-Salam R.
- Abdussalam H.O.
- Abebrese J.T.
- Abeldaño A.
- Abou-Khalil J.
- Abou-Taleb H.
- Abozid A.
- Abozied H.
- Abrate A.
- Abu-Zaid A.
- Abubakar M.K.
- Abud B.
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- Adam A.A.
- Adamina M.
- Adamou H.
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- Adebara I.
- Adebola O.
- Ademuyiwa A.
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- Adepiti A.
- Aderogba A.A.
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- Ć imko K.
- ĆœateckĂœ J.
- Publication venue
- Oxford University Press (OUP)
- Publication date
- 01/07/2023
- Field of study
Background
Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres.
Methods
This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and lowâmiddle-income countries.
Results
In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of âsingle-useâ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for lowâmiddle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia.
Conclusion
This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both highâ and lowâmiddleâincome countries
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
- Author
- 't Hart Ellen P.
- ?a?inkovĂĄ Pavla
- Aaserud Olaf
- Abbruzzese Giovanni
- Acharya T.
- Akhtar Shahbana
- Albanese Alberto
- Alegre Javier
- Alegre Javier
- Allain Philippe
- Alusi Sundus
- Amico Enrico
- Andrade Carlos
- Andrews S. C.
- Andrews Thomasin
- Andrews Thomasin
- Anheim Mathieu
- Antczak Jakub
- Armstrong Matthew
- Armstrong Richard
- Arques Penelope Navas
- Arran N.
- Arran Natalie
- Artiga MarĂa JosĂ© Saiz
- Axelson E.
- Azulay Jean-Philippe
- Baake Verena
- Babiloni Blandine
- Bachoud-LĂ©vi Anne-Catherine
- Banaszkiewicz Krzysztof
- Bandmann Oliver
- Barbera Miquel Aguilar
- Bardinet E.
- Barker Roger A.
- Barrero Francisco
- Barth Katrin
- Barth Katrin
- Barthélémy Rekha
- Bas Jordi
- Bascuñana Mónica
- Bechtel N.
- Bechtel Natalie
- Beckmann Heike
- Bek Judith
- Bellonet Marcellin
- Bentivoglio Anna Rita
- Bentivoglio Rita
- Berglund Peter
- Berna C.
- Berrissoul Hassan
- Bertini Elisabetta
- Betz Sabrina
- Biunno Ida
- BjĂžrgo Kathrine
- BjĂžrnevoll Inga
- Blaszcyk Magdalena
- Blin Stéphanie
- Bocwinska Dorota
- Boczarska-Jedynak Magdalena
- Boelmans Kai
- Bohlen S.
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- Bojakowska-Jaremek Kamila
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- Buck Andrea
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- Castaldo Anna
- Catena Judit LĂłpez
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- Ciach-Wysocka Ewelina
- Ciesielska Anna
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- De Michele Giuseppe
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- di Poggio Monica Bandettini
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- Dixon Kathryn
- Doherty Karen
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- Dressler Dirk
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- Dunnett Stephen
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- Dupuit Michel
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- Ellrichmann Gisa
- Esposito Chiara
- Eusebio Alexandre
- Evans Carole
- Fairtlough Helen
- Fannemel Madeleine
- Fasquel VĂ©ronique
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- Grant Janet
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- Gross Diana
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- Guerra Maria RosĂĄlia
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- GĂžrvell Per F.
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- Hotter Anna
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- Hussl Anna
- Hvalstedt Carina
- Hyppönen Hannele
- Hölzner Eva
- HĂžsterey-Ugander Ulrika
- Ialongo Tamara
- Idiago JesĂșs Miguel Ruiz
- Illmann Torsten
- Jachinska Katarzyna
- Jack Roisin
- Jacobsen Oda
- Jacopini Gioia
- Jameau Laetitia
- Jamieson Stuart
- Jamrozik Zygmunt
- Janik Piotr
- Jasinska-Myga Barbara
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- Johnson H.
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- Jones Lesley
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- Jones Una
- Julié Celine
- Jung Hans H.
- Jurgens C.
- Justo D.
- Kaelin Alain
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- Kapfhammer Hans-Peter
- Kavalier Fred
- Kazoka Mbombe
- Keenan S.
- Kennard C.
- Kershaw Ann
- Kesse Andrea
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- KlempĂr JirĂ
- Klimberg Aneta
- Klodowska-Duda Gabriela
- Klöppel Stefan
- Koivisto Susana Pro
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- Kremer B.
- Kremer Berry
- Krysa Wioletta
- Krystkowiak Pierre
- Kwiecinski Hubert
- Labuschagne I.
- LafoucriĂšre Danielle
- Lahiri N.
- Lahiri Nayana
- Laing Hana
- Lamanna Claudia
- Lambeck Johann
- Landwehrmeyer B.
- Landwehrmeyer Bernhard
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- Lang Christina
- Langbehn Douglas
- Lange Herwig
- Lange Herwig
- Larsen Ida Unmack
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- Lau Puay Ngoh
- LaurĂ Matilde
- Laver Fiona
- Leavitt Blair R.
- Lee S.
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- Lo Kitty
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- Lopera MĂłnica Rodriguez
- Lorentzen Eirin
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- Lucena Carolina Mendez
- Löhle Matthias
- Maass Antonia
- Magnet Markus
- Maiwald Robert
- MajerovĂĄ Veronika
- Malone I.
- Man A. Hoff
- Mandich Paola
- Manouvrier Sylvie
- Mantaux BĂ©atrice
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- Marchese Roberta
- Marcinkowski Jerzy
- Marelli C.
- Mariotti Caterina
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- Markova Ivana
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- Martinez-Horta SaĂŒl
- Martinez-Jaurrieta Maria Dolores
- MartĂn Esther SuarĂ©z San
- MartĂnez-Descals AsunciĂłn
- Mason Sarah
- Massarelli Marco
- Massaro Francesca
- Matheson Kirsty
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- McKenzie Sue
- Mead Simon
- Mechi Claudia
- Mendes Tiago
- Mestre Tiago
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- Morales Blas
- Moreau Laura Vivancos
- Moreno Jose Manuel Garcia
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- Mundler Laura
- Murch Ann
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- Musgrave Hannah
- Möller Jens Carsten
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- Rialland Amandine
- Riballo Antonio Villa
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- RibaĂŻ Pascale
- Ribbat Michael
- Richter Przemyslaw
- Rickards Hugh
- Rissling Ida
- Rivadeneyra Perez Jessica
- Rizzo Giovanni
- Robert Misericordia Floriach
- Robertson Dene
- Robertson Nicola
- Robertson Nicola
- Robowski Piotr
- Roca Alessandro
- RodrĂguez MarĂa JosĂ© Torres
- Rogers Dawn
- Rohm Stefanie
- Rola Rafal
- Romano Silvia
- Romero Irene
- Romoli Anna Maria
- Roos Raymund
- Roos Raymund A. C.
- Roos Raymund A. C.
- Rosas H. D.
- Rosser Anne
- Rosser Elisabeth
- Roth Jan
- Rothery Jean
- Roussel Martine
- Rowett Liz
- Ruddy Deborah
- Rudolf Gabrielle
- Rudzinska Monika
- Rumpf Silke
- Russo Cinzia Valeria
- RuĂz Pedro J. GarcĂa
- Ryglewicz Danuta
- RĂžren Niini
- SablonniĂšre Bernard
- Saft Carsten
- Salvador Carlos
- Salvatore Elena
- Samara Husam
- Sando Sigrid Botne
- Santhouse Alastair
- Santos R. Dar
- Sass Christian
- Say M.
- Scaglione Cesa
- Scahill R.
- Scheibl Monika
- Schepers Sigrun
- Scherer-Gagou Clarisse
- Schiefer Johannes
- Schlangen Christiane
- Schmalfeld Jenny
- Schmidt Simone
- Schneider Ariane
- Schrader Christoph
- Schwenk Daniela
- Schöggl Helmut
- SchĂŒpbach Michael
- Sciruicchio Vittorio
- SebastiĂĄn A. Rojo
- SebastiĂĄn Ana Rojo
- Sempolowicz Justyna
- Seppi Klaus
- Serpino Claudia
- Sienkiewicz-Jarosz Halina
- Sieradzan Kasia
- Silva Mark
- Simonin Clémence
- Simpson Sheila A.
- Sitek Emilia
- Siuda Gill
- Slawek Jaroslaw
- Smith Paul
- Snowden Julie
- Soleti Francesco
- Soliveri Paola
- Sollom Andrea
- Soltan Witold
- Soltysiak Beverley
- Somers Nele
- Sorbi Sandro
- Sorrentino Pierpaolo
- Spadaro Maria
- Spampinato Umberto
- Sprenger Fabienne
- Spruth Eike Jakob
- Squitieri Ferdinando
- Stattin Eva-Lena
- Stebler Yanik
- Stepniak Iwona
- Stokke Bodil
- Stompel Daniel
- Stopford C.
- Stopford Cheryl
- Storch Alexander
- Stout J.
- Stubbe Lars
- Sturrock A.
- StĂĄrkovĂĄ Irena
- StÀdtler Michael
- Suarez MarĂa JosĂ© Lama
- Sulek Anna
- Summers Fiona
- Swain Rachel
- Szczudlik Andrzej
- Szczygiel Elzbieta
- Szinwelski Michal
- SĂĄnchez Vicenta
- SĂŒĂmuth Sigurd
- t'Hart E. P.
- Tabrizi Sarah
- Tabrizi Sarah
- Tabrizi Sarah J.
- Tacik Pawel
- Tan Louis
- Taylor Cat
- Taylor Rachel
- Thibault-Tanchou Stéphanie
- Thomas Gareth
- Thompson Catherine
- Thompson Jennifer
- Thomson Aileen
- Tidswell Katherine
- Timewell Erika
- Tobin A.
- Tomasello Chiara
- Torres MarĂa Martirio Antequera
- Toscano Jean
- Townhill Jenny
- Townhill Jenny
- TRACK-HD investigators
- Tranchant Christine
- Trautmann Sonja
- Trender-Gerhard Iris
- Tuuha Katri
- Uhrova Tereza
- Ullah Jasmin
- Ure Alexandra
- ValabrĂšgue R.
- Valadas Anabela
- Valentine Ruth
- van den Bogaard S. J. A.
- van den Bogaard Simon J. A.
- van der Grond J.
- van Hout Monique S. E.
- van Oostrom J. C. H.
- van Paemel Dominique
- van Reijen Dimphna
- van Vugt Jeroen P. P.
- van Walsem Marleen R.
- van Walsem Marleen R.
- Vandenberghe Wim
- Vandenberghe Wim
- Vargas-GonzĂĄlez Laura
- Vaughan Vivien
- Ventura Marta FatĂĄs
- Verellen-Dumoulin Christine
- Verellen-Dumoulin Christine
- Verhoeven Marloes E.
- Verny Christophe
- Verstappen C. C. P.
- Verstraelen Nichola
- Viladrich Celia Mareca
- Vilaplana Garcia Carmen PeirĂł
- Villanueva Clara
- Vinther-Jensen Tua
- Vuillaume Isabelle
- Wahlström Jan
- Wahlström Jan
- Wang C.
- Wannepain Sandrine
- Warner Thomas
- Wasielewska Anna
- Weber Zaugg Sabine
- Weber Natalia
- Wehus Ragnhild
- Weindl Adolf
- Wenning Gregor
- Wentzel Magnus
- Werner Cornelius J.
- Westman Laila
- Westmoreland Leann
- Weydt Patrick
- Whaite Anna
- Whalstedt Carina
- Whitehead D.
- Whitlock K.
- Wiedemann Alexandra
- Wikström Birgitta
- Wild E.
- Wild Edward
- Wild Sue
- Wild Sue
- Winkelmann Juliane
- Witjes-Ane M.-N.
- Witjes-Ané Marie-Noelle
- Witkowski Grzegorz
- Witkowski Grzegorz
- Wolz Annett
- Wolz Martin
- Wright Abigail
- Wright Abigail
- Wright Jan
- WĂłjcik Magdalena
- Yardumian Pam
- Yardumian Pam
- Yates Shona
- Zaremba Jacek
- Zaremba Jacek
- Zdzienicka Elzbieta
- Ziegler Cornelia
- Zielonka Daniel
- Zielonka Daniel
- Zielonka Eugeniusz
- Zieora-Jakutowicz Karolina
- Zimmermann Marie-Agathe
- Zinzi Paola
- Zinzi Paola
- Zittel Simone
- Zucker Birgit
- Publication venue
- 'Elsevier BV'
- Publication date
- 01/01/2017
- Field of study
Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008â11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003â13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 Ă 10â10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 Ă 10â8 DHFR p=8·37 Ă 10â7 MTRNR2L2 p=2·15 Ă 10â9) and to a lesser extent in REGISTRY (MSH3 p=9·36 Ă 10â4 DHFR p=8·45 Ă 10â4 MTRNR2L2 p=1·20 Ă 10â3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 Ă 10â8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16â0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06â0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation
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- Aali Amirali
- Ababneh Hazim S
- Abate Yohannes Habtegiorgis
- Abbafati Cristiana
- Abbasgholizadeh Rouzbeh
- Abbasi-Kangevari Mohsen
- Abbasian Mohammadreza
- Abbastabar Hedayat
- Abd ElHafeez Samar
- Abd-Elsalam Sherief
- Abdelmasseh Michael
- Abdelwahab Ahmed
- Abdollahi Mohammad
- Abdollahifar Mohammad-Amin
- Abdoun Meriem
- Abdulah Deldar Morad
- Abdullahi Auwal
- Abebe Mesfin
- Abebe Samrawit Shawel
- Abedi Aidin
- Abegaz Kedir Hussein
- Abhilash E S
- Abidi Hassan
- Abiodun Olumide
- Aboagye Richard Gyan
- Abolhassani Hassan
- Abolmaali Meysam
- Abouzid Mohamed
- Aboye Girma Beressa
- Abreu Lucas GuimarĂŁes
- Abrha Woldu Aberhe
- Abtahi Dariush
- Abu Rumeileh Samir
- Abu-Gharbieh Eman
- Abu-Rmeileh Niveen ME
- Abu-Zaid Ahmed
- Abualruz Hasan
- Abubakar Bilyaminu
- Aburuz Salahdein
- Accrombessi Manfred Mario Kokou
- Adal Tadele Girum
- Adamu Abdu A
- Addo Isaac Yeboah
- Addolorato Giovanni
- Adebiyi Akindele Olupelumi
- Adekanmbi Victor
- Adepoju Abiola Victor
- Adetunji Charles Oluwaseun
- Adetunji Juliana Bunmi
- Adeyeoluwa Temitayo Esther
- Adeyinka Daniel Adedayo
- Adeyomoye Olorunsola Israel
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- Adnani Qorinah Estiningtyas Sakilah
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- Aghamiri Shahin
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- Agodi Antonella
- Agrawal Anurag
- Agyemang-Duah Williams
- Ahinkorah Bright Opoku
- Ahmad Aqeel
- Ahmad Danish
- Ahmad Firdos
- Ahmad Muayyad M
- Ahmad Sajjad
- Ahmad Shahzaib
- Ahmad Tauseef
- Ahmadi Keivan
- Ahmadzade Amir Mahmoud
- Ahmed Ali
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- Ahmed Luai A
- Ahmed Mehrunnisha Sharif
- Ahmed Meqdad Saleh
- Ahmed Muktar Beshir
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- Al-Maweri Sadeq Ali Ali
- Al-Mekhlafi Hesham M
- Al-Omari Basem
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- Alalwan Tariq A
- Alam Khurshid
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- Alanzi Turki M
- Albakri Almaza
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- Alcalde-Rabanal Jacqueline Elizabeth
- Aldawsari Khalifah A
- Aldhaleei Wafa A
- Aldridge Robert W
- Alema Haileselasie Berhane
- Alemayohu Mulubirhan Assefa
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- Almazan Joseph Uy
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- Alqalyoobi Shehabaldin
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- Amin Tarek Tawfik
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- Andrei Tudorel
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- Ayatollahi Haleh
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- B Darshan B
- Babu Abraham Samuel
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- Beran Azizullah
- Berezvai Zombor
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- Bhagavathula Akshaya Srikanth
- Bhala Neeraj
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- Bhandari Dinesh
- Bhangdia Kayleigh
- Bhardwaj Nikha
- Bhardwaj Pankaj
- Bhardwaj Prarthna V
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- Bhaskar Sonu
- Bhat Vivek
- Bhatti Gurjit Kaur
- Bhatti Jasvinder Singh
- Bhatti Manpreet S
- Bhatti Rajbir
- Bhutta Zulfiqar A
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- Bishai Jessica Devin
- Bisignano Catherine
- Bisulli Francesca
- Biswas Atanu
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- Bitaraf Saeid
- Bitew Bikes Destaw
- Bitra Veera R
- BjĂžrge Tone
- Boachie Micheal Kofi
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- Bobirca Anca Vasilica
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- Borzutzky Arturo
- Bouaoud Souad
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- Boxe Christopher
- Boyko Edward J
- Brady Oliver J
- Braithwaite Dejana
- Brant Luisa C
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- Brazinova Alexandra
- Brazo-Sayavera Javier
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- Carvalho MĂĄrcia
- Castaldelli-Maia Joao Mauricio
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- Castelpietra Giulio
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- Chaurasia Akhilanand
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- Chen Angela W
- Chen Catherine S
- Chen Haowei
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- Chimoriya Ritesh
- Ching Patrick R
- Chirinos-Caceres Jesus Lorenzo
- Chitheer Abdulaal
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- Chong Bryan
- Chopra Hitesh
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- Xu Yvonne Yiru
- Yadollahpour Ali
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- Yang Danting
- Yang Lin
- Yano Yuichiro
- Yao Yao
- Yaribeygi Habib
- Ye Pengpeng
- Yehualashet Sisay Shewasinad
- Yesiltepe Metin
- Yesuf Subah Abderehim
- Yezli Saber
- Yi Siyan
- Yigezu Amanuel
- Yip Paul
- Yismaw Malede Berihun
- Yismaw Yazachew
- YiÄit Arzu
- YiÄit Vahit
- Yon Dong Keon
- Yonemoto Naohiro
- Yoon Seok-Jun
- You Yuyi
- Younis Mustafa Z
- Yousefi Zabihollah
- Yu Chuanhua
- Yu Yong
- Yuh Faith H
- Zadey Siddhesh
- Zadnik Vesna
- Zafari Nima
- Zakham Fathiah
- Zaki Nazar
- Zaman Sojib Bin
- Zamora Nelson
- Zand Ramin
- Zangiabadian Moein
- Zar Heather J
- Zare Iman
- Zarrintan Armin
- Zeariya Mohammed G M
- Zeinali Zahra
- Zhang Haijun
- Zhang Jianrong
- Zhang Jingya
- Zhang Liqun
- Zhang Yunquan
- Zhang Zhi-Jiang
- Zhao Hanqing
- Zhong Chenwen
- Zhou Juexiao
- Zhu Bin
- Zhu Lei
- Ziafati Makan
- ZieliĆska Magdalena
- Zitoun Osama A
- Zoladl Mohammad
- Zou Zhiyong
- Zuhlke Liesl J
- Zumla Alimuddin
- Zweck Elric
- Zyoud Samer H
- Ărnlöv Johan
- Ć ekerija Mario
- Publication venue
- Elsevier
- Publication date
- 01/01/2024
- Field of study
BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56â604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100â000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100â000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100â000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100â000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100â000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation
Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
- Author
- A Gordon Robertson
- Abdullah Kahraman
- Abel Gonzalez-Perez
- Adam A Margolin
- Adam Abeshouse
- Adam Grundhoff
- Adam J Struck
- Adam J Struck
- Adam J Wright
- Adam Lambert
- Adam P Butler
- Adam P Butler
- Adel El-Naggar
- Adnan M Nagrial
- Adrian Ally
- Adrian Baez-Ortega
- Adrian Thorogood
- Adriana Salcedo
- Adrienne M Flanagan
- Ake Borg
- Akihiro Fujimoto
- Akihiro Suzuki
- Akinyemi I Ojesina
- Alain Viari
- Alan J Robertson
- Alan P Hoyle
- Alan Thompson
- Alasdair Stenhouse
- Alastair M Thompson
- Aldo Scarpa
- Alessandro Pastore
- Alex Buchanan
- Alex Buchanan
- Alexander Claviez
- Alexander J Lazar
- Alexander Martinez-Fundichely
- Alfonso Muñoz
- Alfonso Valencia
- Aliaksei Z Holik
- Alice Meng
- Alicia L Bruzos
- Allison Creason
- Allison P Heath
- Alvin Wei Tian Ng
- Alvis Brazma
- Amaro Taylor-Weiner
- Amber L Johns
- Amie Radenbaugh
- Amit G Deshwar
- Ana Dueso-Barroso
- Ana Mijalkovic Mijalkovic-Lazic
- Ana Milovanovic
- Ana Milovanovic
- Andre Kahles
- Andrea Haake
- Andrea Holbrook
- Andrea L Richardson
- Andrea Mafficini
- Andrea Ruzzenente
- Andreas Behren
- Andreas Rosenwald
- Andreia V Pinho
- Andrew Berchuck
- Andrew D Cherniack
- Andrew J Dunford
- Andrew J Mungall
- Andrew J Spillane
- Andrew Menzies
- Andrew Menzies
- Andrew P Barbour
- Andrew Tutt
- Andrew V Biankin
- Andrey Korshunov
- Andrés Lanzós
- Andy Cafferkey
- Andy G Lynch
- Angela Chou
- Angela N Brooks
- Angela Tam
- Angelica Ochoa
- Angelika N Christ
- Angelo P Dei Tos
- Anieta M Sieuwerts
- Anil K Sood
- Anita LangerĂžd
- Anja FĂŒllgrabe
- Anke K Bergmann
- Ann-Marie Patch
- Anna deFazio
- Anna Ehinger
- Anna Fitzgerald
- Anne Hamilton
- Anne Vincent-Salomon
- Anne Y Warren
- Anne-Lise BĂžrresen-Dale
- Annegien Broeks
- Anthony DiBiase
- Anthony J Gill
- Anthony Ng
- Anthony R Green
- Antonia L Pritchard
- Antonio Pea
- Antonios Koures
- Aparna Prasad
- Apurva M Hegde
- Aquila Fatima
- Arcadi Navarro
- Arie B Brinkman
- Arif O Harmanci
- Arindam Maitra
- Armando Lopez-Guillermo
- Arndt Borkhardt
- Arnoud Boot
- Asger Hobolth
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- Atul J Butte
- Aurélien Chateigner
- Austin J Hepperla
- Axel Aretz
- Aya Sasaki-Oku
- Ayellet V Segre
- B F Francis Ouellette
- Bailey Matthew H
- Barbara Hutter
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- Beifang Niu
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- Benita Kiat Tee Tan
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- Benjamin P Berman
- Benjamin Raeder
- Bernardo Rodriguez-Martin
- Bernhard Radlwimmer
- Bernice H Wong
- Beth Karlan
- Bin Tean Teh
- Bin Zhu
- Birgit Burkhardt
- Bishoy M Faltas
- Bodil Bjerkehagen
- Bogdan Czerniak
- Boris Winterhoff
- Borislav C Rusev
- Bradly G Wouters
- Brandi N Davis-Dusenbery
- Brian Craft
- Brian D O'Connor
- Brian Patrick O'Neill
- Brice Aminou
- Calvin Wing Yiu Chan
- Cameron M Soulette
- Carl Herrmann
- Carl Morrison
- Carlo Gambacorti-Passerini
- Carlos Caldas
- Carlos D Bustamante
- Carlos LĂłpez-OtĂn
- Carlota Rubio-Perez
- Carmen Gomez
- Carolien H M van Deurzen
- Carolyn M Hutter
- Carolyn M Hutter
- Carrie Cibulskis
- Caterina Vicentini
- Catherine A Shang
- Catherine D Moser
- Catherine J Kennedy
- Catrina C Fronick
- Chad J Creighton
- Chandra Sekhar Pedamallu
- Chang Li
- Charles David Imbusch
- Charles M Perou
- Charles Saller
- Charles Short
- Charlie E Massie
- Chawalit Pairojkul
- Chen Hong
- Chen Ye
- Cheng-Zhong Zhang
- Chin-Lee Wu
- Chip Stewart
- Chip Stewart
- Chip Stewart
- Choon Kiat Ong
- Chris Lawerenz
- Chris Mitchell
- Chris Sander
- Christian von Mering
- Christiane Buchholz
- Christina K Yung
- Christina K Yung
- Christina Yau
- Christine A Iacobuzio-Donahue
- Christine Chomienne
- Christine Desmedt
- Christine P'ng
- Christof von Kalle
- Christoph Borst
- Christoph Plass
- Christopher A Miller
- Christopher Benz
- Christopher J Scarlett
- Christopher J Yoon
- Christopher K Wong
- Christopher M Lalansingh
- Christopher M Lalansingh
- Christopher Ogden
- Christopher S Foster
- Christopher Umbricht
- Christopher W Toon
- Christos Sotiriou
- Cindy Bell
- Cinzia CantĂč
- Ciyue Shen
- Claes Wadelius
- Clare Verrill
- Clarissa Gerhauser
- Claudia Calabrese
- Claudio Bassi
- Claudio Luchini
- Claudiu Farcas
- Clemency Jolly
- Colin A Purdie
- Colin A Semple
- Colin C Collins
- Colin S Cooper
- Conrad R Leonard
- Constance H Li
- Corbin D Jones
- Craig Shriver
- Cristina LĂłpez
- Cyriac Kandoth
- Cyril Fisher
- D Neil Hayes
- Dai-Ying Wu
- Daiming Fan
- Daisuke Komura
- Dale W Garsed
- Daniel A Leongamornlert
- Daniel Baumhoer
- Daniel HĂŒbschmann
- Daniel J Turner
- Daniel J Weisenberger
- Daniel M Berney
- Daniel Rosebrock
- Daniel S Brewer
- Daniela S Gerhard
- Danielle Pasternack
- Darell Bigner
- Dariush Etemadmoghadam
- Darlene Lee
- Darrin F Taylor
- Dave Larson
- David A Wheeler
- David A Wheeler
- David C Wedge
- David Craft
- David D L Bowtell
- David E Neal
- David Haan
- David Haussler
- David Haussler
- David Hedley
- David Huntsman
- David I Heiman
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- David J Van Den Berg
- David K Chang
- David K Miller
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- David Mutch
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- David Torrents
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- Davide Antonello
- Declan Cahill
- Denis Larsimont
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- Denise Brooks
- Deniz DemircioÄlu
- Dennis C Sgroi
- Dennis Karsch
- Dennis T Maglinte
- Dennis Wigle
- Derek W Wright
- Dianne E Chadwick
- Dido Lenze
- Dieter Kube
- Dieter Weichenhan
- Dilip D Giri
- Dimitri Livitz
- Dimitri Livitz
- Dimple Chakravarty
- Ding
- Dirk Schadendorf
- Dmitry A Gordenin
- Dominik Glodzik
- Don Chalmers
- Dong Guanlan
- Dongbing Liu
- Donghoon Lee
- Donghui Tan
- Donna M Muzny
- Dorthe Grabau
- Douglas A Levine
- Douglas F Easton
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- Xiaotong Yao
- Xing Hua
- Xingmin Liu
- Xinyue Li
- Xiuqing Zhang
- Xiuqing Zheng
- Xose S Puente
- Xuan Le
- Xuanping Zhang
- Xuemei Luo
- Xueqing Zou
- Yan Shi
- Yan Zhang
- Yang Wu
- Yang Yang
- Yann Joly
- Yanxun Xu
- Yao He
- Yasin Senbabaoglu
- Yassen Assenov
- Yasser Riazalhosseini
- Yasuhito Arai
- Yasushi Rino
- Yasushi Totoki
- Yeng Ang
- Yi Huang
- Yi Huang
- Yifei Men
- Yiling Lu
- Yilong Li
- Yingyan Yu
- Yiwen Chen
- Yogesh Kumar
- Yogesh Kumar
- Yoke-Eng Chiew
- Yong Hou
- Yong Zhou
- Yong-Jie Lu
- Yongzhan Nie
- Yosef E Maruvka
- Yosef E Maruvka
- Yoshiiku Kawakami
- Young Seok Ju
- Youngchoon Woo
- Youngil Koh
- Youngwook Kim
- Youyong Lu
- Yu Fan
- Yu Fan
- Yu Fan
- Yu-Jia Shiah
- Yuan Ji
- Yuan Yuan
- Yuichi Shiraishi
- Yulia Newton
- Yulia Rubanova
- Yumeng Wang
- Yupeng Cun
- Yussanne Ma
- Zachary Heins
- Zechen Chong
- Zechen Chong
- Zemin Zhang
- Zhaohong Chen
- Zhenggang Wu
- Zhenggang Wu
- Zhining Wang
- Zhongming Zhao
- Ziao Lin
- Zsofia Kote-Jarai
- Ălafur Andri StefĂĄnsson
- Ăystein Garred
- Publication venue
- Nature Communications
- Publication date
- 01/01/2020
- Field of study
Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts
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
- 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
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- Board Jasmin
- Boardman Melanie
- Boari Gianluca
- Bocher Simon
- Bociek Aneta
- Boivin Anne-Helene
- Boivin Anne-HĂ©lĂšne
- 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
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- Burke David
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- Burnish Rachel
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- Butler Susan
- Buxton Meredith
- Buzgau Adrian
- Byrne Kathleen
- Byrne Rahim
- Cabrelli Louise
- Cabreros Leilani
- Cairns Tom
- Calfee Carolyn
- Callahan Jean-Christophe
- Cambalova Lenka
- Campbell Andrew
- Campbell Bridget
- Campbell Debbie
- Campbell Hilary
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- Campbell Marion
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- Campion Alexandra
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- Caplin Cecile
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- Carpio Lillian
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- Carrier François
- Carrier Marc
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- Carter Brittney
- Carter David
- Carter Jay
- Carter Michael
- Casali Sherry
- Casey Ruth
- Casey Siobhan
- Castelain Vincent
- Castle James
- Cathcart Susanne
- Catorze Nuno José Teodoro Amaro dos Santos
- Cattelan Jessy
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- Cawley Kathryn
- Cecconi Maurizio
- Centofanti John
- Chambers Emma
- Champanerkar Shreekant
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- Chan Charles
- Chan Peter
- Chapman Rachel
- Chapman Susan
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- Charles Walton
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- Charlton Sam
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- Chartier Delphine
- Chasse Michael
- Chassé Michaël
- Chen Jonathan
- Chen Lixian
- Chen Yan
- Cheng Allen C.
- Cherian Shiney
- Chhablani Manish
- Chin Teri
- Chudeau Nicolas
- Chukkambotla Sri
- Ciccarelli Michele
- Cirstea Emanuel
- Clair Bernard
- Clark Amy
- Clark Michele
- Clark Richard
- Clark Sarah
- Clarke Frances
- Clarke Jennifer
- Claxton Andrew
- Cleary Joanne
- Clement Ian
- Clere-Jehl Raphael
- Clermont Giles
- Clermont Gilles
- Clinton Alison
- Cloutier Ăve
- Cockrell Maeve
- Codreanu Daniel
- Coetzee Samantha
- Coghlan Phoebe
- Cole Jade
- Coles Jennifer
- Colin Gwenhael
- Collier Dawn
- Collins Amy
- Collins Daniel
- Collins Emma
- Collins Joanne
- Collins Ărin
- Collis Matthew
- Combaux Daniele
- Commons Robert
- Comp Susan
- Concha Pablo
- Connolly Karen
- Constantini Elena
- Constantino-Occhipinti Claudia
- Contou Damien
- Convery Karen
- Conway Robert
- Conzelmann Nadine
- Cook Deborah
- Cook Tim
- Cooke Jill
- Cooke Justin
- Cooper Jamie
- Cooper Josh
- Cooper Lauren
- Cooper Melanie
- Cooper Nichola
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- Corcoran Ele
- Corcoran Kathleen
- Cornell Sarah
- Cornell Thomas
- Cort Jon
- Costerousse Olivier
- Couillard-ChĂ©nard Ămilie
- Courtin Laura
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- Couture Lourie
- Cove Matthew
- Cowdrey Keri-Anne
- Cowley Nicholas
- Cowton Amanda
- Coyne Mark
- Craddock Richard
- Craner Michelle
- Craven Thomas
- Crawshaw Sarah
- Creagh-Brown Ben
- Creange Vanessa
- Cremer Olaf
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- Croft Maria
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- Cudlipp Joanna
- Cuesta Jeronimo
- Cuffaro Raffaele
- Curley Gerard
- Currie Andrew
- Cusack Rebecca
- Cuthbertson Brian
- Cutler Sean
- CĂĄrcel Sheila
- CĂŽtĂ© Ămilie
- D?Amato Fabiola
- D?Aragon Frédérick
- Daebis Admad
- Daher Rana
- Dale Katie
- Daley Jessica
- Dalton James
- Daly James
- Daly Zoe
- Daneman Nick
- Dark Paul
- Darnell Robert
- Darreau Cedric
- Daugherty Jason
- Davey Miriam
- Davidson Neil
- Davies Ellie
- Davies Gwyneth
- Davies Jennifer
- Davies Louisa
- Davies Michelle
- Davies Rhys
- Dawson Laura Ann
- Dawvda Ashlish
- Day Christopher
- Da Rocha Joana
- De Bus Liesbet
- de Courcy-Golder Kim
- de Groot Klaas
- de Jong Menno
- de Jonge Evert
- De Keulenaer Bart
- de la Torre Cisneros Julian
- de Man Angelique
- De Neef Mark
- De Smeytere Anouska
- Deacon Bethan
- Dean Steven
- Dean Tessa
- Dearden Joy
- Dechert William
- Declercq Pierre-Louis
- Degracia Anna
- del Sorbo Lorenzo
- Dela Rosa Arnold
- Delaney Kirsha
- Dell Abbie
- del Prado Michael
- Demetriou Carrie
- Dempster Debra
- Denham Lynn
- Denmade Craig
- Dent Martin
- Depante Maria
- Depuydt Pieter
- Dequin Pierre-François
- Derde Lennie P. G.
- Deshpande Kush
- Detry Michelle A.
- Deye Nicolas
- de la Fuente Carmen
- De Waele Jan
- Dheke Krishan
- Di Lucca Giuseppe
- Dias Priya
- Dice Julie
- Digby Stephen
- Diridis Kristina
- Distler Michael
- Dobell-Brown Kelsey
- Doble Patricia
- Dobson Jade
- Doherty Kaleigh
- Doherty Ronan
- Doi Yohei
- Dolman Rozzie
- Domingo-Marco Joana
- Donadee Chenell
- Donaldson Kate
- Dondrop Arjen
- Donegan Clare
- Donlon Sinead
- Donnelly Adrian
- Donnelly Kieran
- Donnison Phil
- Doonan Reece
- Doran Peter
- Dore Rachael
- Dormand Natalie
- Dos Santos Filipa
- Douillard Thomas
- Drake Chelsea
- Drapola Debra
- Drayss Maria
- Drummond Andrew
- Drury Kay
- Duan Erick
- Duberley Stephen
- Duffy Eamon
- Duffy Oscar
- Duke Graeme
- Duke Zoe
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- Duplaix Mathilde
- Duric Natalie
- Duroux Maree
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- Dyas Sarah
- Eapen Beena
- Eastgate Christine
- Ebenezer R
- Edmunds Natasha
- Edwards Alexandra
- Efford Georgia
- Egreteau Pierre
- Ehrmann Stephan
- Eichenauer Dennis
- Eisenbeis Simone
- Ekhérian Jean-Michel
- El-Khawas Khaled
- Elender Corinna
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- Estensen Kristen
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- Howell Alice
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- Jongebloed Katherine
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- Juhaz Vera
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- Kamata Kazuhiro
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- Kamra Maneesha
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- Kanwal Darakhshan
- Karachi Tim
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- Karlikowski Michal
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- Kassir Sandy
- Katary Amro
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- Kayani Abdul
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- Kaye Callum
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- Kendrick Sara
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- Kester Esmee
- Khade Reena
- Khalid Imrana
- Khan Meherunnisa
- Khanal Kishor
- Khanal Sushil
- Khare Divya
- Khoso Nasir
- Khoud Ahmed
- Khwaja Kosar
- Kidwai Aneela
- Kiiski Heikki
- Kilner Mari
- Kim Edy Y.
- Kimpton Sarah
- King Andrew
- Kinney Fiona
- Kirk Jill
- Kirk Rosemary
- Kirkby Amy
- Kirkham Simon
- Kit Barbara
- Kitsios Georgios
- Kittridge Lauren
- Klein Daniela
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- Wood Erica
- Wood Hannah
- Wood Tracy
- Woods Jane
- Woods Lindsey
- Woodward Robert
- Woolett Melissa
- Worner Ruth
- Wren Jess
- Wren Lynn
- Wrey Brown Caroline
- Wright Chris
- Wright Kim
- Wunderley Renee
- Wyatt Rachel
- Wylie Katharine
- Xavier Kugan
- Yamagishi Yoshiaki
- Yamashita Chizuru
- Yang Yang
- Yarad Elizabeth
- Yates Bryan
- Yates David
- Yealy Donald
- Young Ian
- Young Meredith
- Young Paul
- 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 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