Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Uso endoscópico del colgajo pericraneal para la reconstrucción nasal y de base de cráneo

[spa] INTRODUCCIÓN: El colgajo pericraneal (CP) ha sido habitualmente utilizado en las reconstrucciones cráneo faciales y de base de cráneo. Su utilidad en los abordajes abiertos se encuentra ampliamente descrita en la literatura. Sin embargo, el avance de las técnicas endoscópicas ha relegado el uso del CP por el de los colgajos endonasales. Al mismo tiempo, este avance representa una oportunidad para ampliar las indicaciones del CP a aquellos abordajes endoscópicos en los que los colgajos endonasales no se encuentren disponibles. OBJETIVO: Este trabajo tiene como objetivo estudiar y analizar el uso del CP en la reconstrucción endoscópica de base de cráneo y del septum nasal. MATERIALES Y MÉTODOS: Se realiza un estudio en tres áreas: 1. Se realiza un estudio anatómico en cadáver fresco en el que se ejecutan reconstrucciones de los distintos abordajes de base de cráneo (abordaje transcribiforme, abordaje transplanum, abordaje clival y abordaje de la unión cráneo-vetebral) y del septum nasal. En todos los especímenes, tras recrear el defecto que se a reconstruir, se realizar una disección clásica del CP y posteriormente se introduce a través de una osteotomía del seno frontal. Por último con un manejo endoscópico se realiza la reconstrucción del defecto. 2. En segundo lugar, se realiza un análisis radiológico en tomografías computerizadas (TC) de los límites de reconstrucción que permite el CP y la estandarización del tamaño del mismo según el defecto que se vaya a reconstruir. Se toma como referencia la pared posterior del conducto auditivo interno. 3. Posteriormente, se realiza un estudio clínico en pacientes con tumores de base de cráneo y perforación septal total en los que no existen opciones reconstructivas endonasales o estas no alcanzan el tamaño suficiente. En ellos, se realiza una reconstrucción endoscópica con CP de sus defectos. RESULTADOS: Las mediciones anatómicas mostraron que el tabique nasal tiene una longitud media de 5,8 ± 0,7 cm, mientras que el colgajo pericraneal presenta un promedio de 18,4 ± 1,3; 18,3 ± 1,3 cm de largo (área media 121,6 ± 17,7; 121,5 ± 19,4 cm2). En todos los especímenes se logró la reconstrucción total de los defectos. En el estudio radiológico, se determinó que para reconstruir defectos secundarios a abordajes transcribriforme, transtuberculum, clival y craneovertebrales, la incisión distal del colgajo pericraneal debe colocarse respectivamente a -3,7 ± 2,0 cm (ángulo -17,4 ± 8,5º), -0,2 ± 2,0 cm (ángulo -1,0 ± 9,3º), +5,5 ± 2,3 cm (ángulo +24,4 ± 9,7º), +8,4 ± 2,4 cm (ángulo +36,6 ± 11,5º), en relación con el punto de referencia. En el caso de la reconstrucción septal, las mediciones radiológicas revelaron que el área del colgajo pericraneal necesaria para reconstruir una perforación septal total sería de 40,9 ± 4,2 cm2, teniendo en cuenta un 30% adicional por la posible retracción durante la cicatrización. Para la reparación total del tabique, el borde distal del colgajo pericraneal debe situarse a 0,8 ± 2,0 cm (3,4 ± 8,78º) del punto de referencia (proyección vertical del canal auditivo externo). Los defectos de la base del cráneo (n = 6) y de la perforación septal total (n=1) en nuestra cohorte clínica se reconstruyeron completamente sin complicaciones. CONCLUSIONES: Este trabajo concluye que el CP presenta un área suficiente para la reconstrucción endoscópica de los distintos abordajes de base de cráneo y septal total. El uso del seno frontal como puerta de entrada a las fosa nasales y el manejo endoscópico del CP en las reconstrucciones es una técnica factible y simple.[eng] The pericranial flap (PCF) has been commonly used in craneo-facial and skull base reconstructions. However, the advance of endoscopic techniques has relegated the use of PCF. At the same time, this advance represents an opportunity to extend the indications of the PCF to those endoscopic approaches in which the endonasal flaps are not available. The aims of this study is to analyze the use of the PCF in the endoscopic reconstruction of the skull base and the nasal septum. An anatomical study on fresh cadaver specimens in which reconstructions of the different skull base defects and nasal septum were carried out. The PCF was introduced through an osteotomy of the frontal sinus. Then, the defects were endoscopically repair. A radiological analysis in computed tomography was performed. The reconstruction limits allowed by the PCF and the standardization of the size of the PCF according to the defect were measured. A clinical study is performed in patients with tumors of the skull base and total septal perforation. In the anatomical study, the nasal septum length and the PCF length and area were obtained. In all the specimens, the total reconstruction of the defects was achieved. The radiological study determined that to reconstruct defects secondary to transcribriform, transtuberculum, clival and craniovertebral approaches, the distal incision of the PCF should be placed respectively at -3.7 ± 2.0 cm, -0,2 ± 2,0 cm, +5,5 ± 2,3 cm, +8,4 ± 2.4 cm, from the reference point (external auditory canal). For total repair of the septum, the distal edge of the PCF should be located 0.8 ± 2.0 cm from the reference point. Defects of the skull base (n = 6) and total septal perforation (n = 1) in our clinical cohort were completely reconstructed. This work concludes that the CP presents enough area for the endoscopic reconstruction of the different approaches of the skull base and total septal perforation. The use of the frontal sinus as the entrance and the endoscopic management of the CP in the reconstructions is a feasible and simple technique

Ethyl alcohol threshold test: a fast, reliable and affordable olfactory Assessment tool for COVID-19 patients

International audienceObjective: COVID-19 patients may present mild symptoms. The identification of paucisymptomatic patients is paramount in order to interrupt the transmission chain of the virus. Olfactory loss could be one of those early symptoms which might help in the diagnosis of COVID-19 patients. In this study, we aim to develop and validate a fast, inexpensive, reliable and easy-to-perform olfactory test for the screening of suspected COVID-19 patients. Study design: Phase I was a case–control study and Phase II a transversal descriptive study. Subjects and methods: Olfaction was assessed with the ethyl alcohol threshold test and symptoms with visual analogue scales. The study was designed in two phases: In Phase I, we compared confirmed COVID-19 patients and healthy controls. In Phase II, patients with suspected COVID-19 infection referred for testing were studied. Results: 275 participants were included in Phase I, 135 in Phase II. The ROC curve showed an AUC of 0.749 in Phase I, 0.737 in Phase II. The cutoff value which offered the highest amount of correctly classified patients was ≥ 2 (10% alcohol) for all age intervals. The odds ratio was 8.19 in Phase I, 6.56 in Phase II with a 75% sensitivity. When cases report normal sense of smell (VAS < 4), it misdiagnoses 57.89% of patients detected by the alcohol threshold test. Conclusion: The olfactory loss assessed with the alcohol threshold test has shown high sensitivity and odds ratio in both patients with confirmed COVID-19 illness and participants with suspected SARS-CoV-2 infection

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability: Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)