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

Plasma levels of tumor necrosis factor-alpha in patients with visceral leishmaniasis (Kala-Azar). Association with activity of the disease and clinical remisson following antimonial therapy Níveis plasmáticos do fator de necrose tumoral-alfa (TNF-alfa) em pacientes com leishmaniose visceral (Calazar). Associação com atividade da doença e remissão clínica com terapia antimonial

Evaluation of TNF-alpha in patients with Kala-azar has drawn increasing interest due to its regulatory role on the immune system, in addition to its cachetizing activity. The objective of this study was to examine the association between plasma levels of TNF-alpha, measured by immunore-activity (ELISA) and bioactivity (cytotoxicity assay with L-929 cells), and clinical manifestations of visceral leishmaniasis. Plasma samples from 19 patients with Kala-azar were obtained before, during and at the end of antimonial therapy. TNF-alpha determinations was done by using the cytotoxicity assay (all patients) and the enzyme-linked immunoassay (ELISA - 14 patients). A discrepancy between results obtained by ELISA and cytotoxicity assay was observed. Levels of circulating TNF-alpha, assessed by ELISA, were higher in patients than in healthy controls, and declined significantly with improvement in clinical and laboratory parameters. Plasma levels before treatment were 124.7 &plusmn; 93.3 pg/ml (mean &plusmn; SD) and were higher than at the end of therapy 13.9 &plusmn; 25.1 pg/ml (mean &plusmn; SD) (p = 0.001). In contrast, plasma levels of TNF-alpha evaluated by cytotoxicity assay did not follow a predicted course during follow-up. Lysis, in this case, might be not totally attributed to TNF-alpha. The discrepancy might be attributed to the presence of factor(s) known to influence the release and activity of TNF-alpha.<br>Avaliação de TNF-alfa em pacientes com calazar tem despertado grande interesse devido ao seu papel no sistema imunológico e à sua atividade caquetizante. O objetivo deste estudo foi examinar a associação entre os níveis plasmáticos de TNF-alfa, medidos através de sua imunorreatividade (ELISA) e bioatividade (ensaio citotóxico sobre as células L-929), e as manifestações clínicas da leishmaniose visceral. Amostras de 19 pacientes foram obtidas para determinação do TNF-alfa antes, durante e após a terapia antimonial, utilizando o ensaio de citotoxicidade (todos os pacientes) e o ELISA (14 pacientes). Resultados discrepantes entre os ensaios de citotoxicidade e o ELISA foram observados. Níveis circulantes de TNF-alfa, medidos pelo ELISA, foram mais altos nos pacientes que nos controles e declinaram significantemente com a melhora clínica e laboratorial. Níveis plasmáticos antes do tratamento (média = 124,7 pg/ml; DP = 93,3) foram mais elevados que ao final da terapêutica (13,9 pg/ml; DP = 25,1; p = 0,001). Por outro lado, níveis plasmáticos de TNF-alfa, avaliados pela citotoxicidade, não seguiram um curso previsível durante a evolução. Esta discrepância pode ser devida à presença de fatores no plasma que podem influenciar a liberação e atividade do TNF-alfa. Ainda, a lise observada pode não ser totalmente atribuída ao TNF-alfa