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

Enzootic bovine leukosis as a possible risk factor in the development of breast cancer in humans: a systematic review

La leucosis bovina enzoótica es una enfermedad infecciosa que causa pérdidas económicas importantes en la ganadería, principalmente en el sector lechero, y en los últimos años se ha evidenciado la presencia del virus causante de esta enfermedad en los humanos. El cáncer de mama es la patología neoplásica que más afecta a las mujeres en el mundo, sin embargo, no todos los factores de riesgo son conocidos. Este artículo tiene como finalidad la revisión de la literatura para establecer si el virus de la leucosis bovina enzoótica (VLB) podría considerarse como factor de riesgo para el desarrollo de cáncer de mama en humanos y así mismo poder encaminar estrategias para la erradicación de ésta en Colombia. Materiales y métodos Se realizó una revisión de la literatura actual de 2011 a abril de 2022 y se revisaron 9 bases, evaluando la elegibilidad de acuerdo con los criterios de inclusión y exclusión y la revisión de calidad metodológica por medio de la matriz CASPe. Se realizó un metanálisis de efectos aleatorios en STATA 14, se evaluó el OR de cada estudio (IC 95%) y la heterogeneidad se realizó por el estadístico Q e I², y, finalmente, el sesgo de publicación se estableció por la prueba de Eggs. Resultados Se evaluaron en total 6 artículos los cuales reportaban estudios de casos y control. Al realizar el metanálisis de todos los artículos se evidenció una posible asociación del virus de la leucosis bovina con el cáncer de mama (OR=2.281, IC (95%) = 1.351-3.851), lo cual podría interpretarse que el virus de leucosis bovina puede ser considerado un factor de riesgo para el desarrollo de esta neoplasia. Conclusiones Si bien los resultados de esta publicación reportan una asociación entre el virus de la leucosis bovina enzoótica y el cáncer de mama en humanos, es necesario realizar nuevos estudios clínicos con un tamaño de población más amplio, así mismo se requiere evaluar el mecanismo de transmisión hacia el humano. De igual forma es preciso implementar políticas agropecuarias que minimicen el riesgo de que la leucosis bovina enzoótica se convierta en un problema de salud pública.Magíster en EpidemiologíaMaestríaEnzootic bovine leukosis (EBL) is an infectious disease that causes significant economic losses in livestock farming, mainly in the dairy sector, and in recent years the presence of the virus that causes this disease in humans has become evident. Breast cancer is a neoplastic pathology that affects women worldwide; however, not all risk factors are known. The purpose of this article is to review the literature to establish whether the bovine leukosis virus (BLV) could be considered a risk factor for the development of breast cancer in humans and, thus, to establish strategies for its eradication in Colombia. Materials and methods A review of the current literature was performed from 2011 to April 2022, and 9 databases were reviewed, assessing eligibility according to inclusion and exclusion criteria and methodological quality review utilizing the CASPe matrix. Random effects meta-analysis was performed in STATA 14, the OR of each study was evaluated (95% CI), the Q statistic and I² performed heterogeneity, and, finally, Egger's test was used to identify publication bias. Results A total of six articles reporting case-control studies were selected for this systematic review, and a meta-analysis of all the articles showed a possible association between the bovine leukosis virus and breast cancer (OR=2.281, CI (95%) = 1.351-3.851), which points to the conclusion that the bovine leukosis virus can be considered a risk factor for the development of this neoplasm. Conclusions Although the results of this publication report an association between the enzootic bovine leukosis virus and breast cancer in humans, it is necessary to conduct new clinical studies with larger population sizes and evaluate the mechanism of transmission to humans. Additionally, it is also necessary and crucial to implement agriculture policies that minimize the public health risk that the enzootic bovine leukosis represents

Novel genes and sex differences in COVID-19 severity.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)