Assessing the Association between Biomarkers and COVID-19 Mortality Using the Joint Modelling Approach.

We evaluated the association between biomarkers and COVID-19 mortality. Baseline characteristics of 403 COVID-19 patients included sex and age; biomarkers, measured throughout the follow-up, included lymphocytes, neutrophils, ferritin, C-reactive protein, glucose, and LDH. Hazard ratios (HRs) and corresponding 95% credible intervals (CIs) were estimated through joint models (JMs) using a Bayesian approach. We fitted univariable (a single biomarker) and multivariable (all biomarkers) JMs. In univariable analyses, all biomarkers were significantly associated with COVID-19 mortality. In multivariable analysis, HRs were 1.78 (95% CI: 1.13-2.87) with a doubling of neutrophils levels, 1.49 (95% CI: 1.19-1.95) with a doubling of C-reactive protein levels, 2.66 (95% CI: 1.45-4.95) for an increase of 100 mg/dL of glucose, and 1.31 (95% CI: 1.12-1.55) for an increase of 100 U/L of LDH. No evidence of association was observed for lymphocytes and ferritin in multivariable analysis. Men had a higher COVID-19 mortality risk than women (HR = 1.75; 95% CI: 1.07-2.80) and age showed the strongest effect with a rapid increase from 60 years. These findings using JM confirm the usefulness of biomarkers in assessing COVID-19 severity and mortality. Monitoring trend patterns of such biomarkers can provide additional help in tailoring the appropriate care pathway.

Leishmania Promastigotes Enhance Neutrophil Recruitment through the Production of CXCL8 by Endothelial Cells.

Endothelial cells represent one of the first cell types encountered by Leishmania promastigotes when inoculated into the skin of the human hosts by the bite of phlebotomine sand flies. However, little is known on their role in the early recruitment of phagocytic cells and in the establishment of the infection. Initially, neutrophils, rapidly recruited to the site of promastigotes deposition, phagocytize Leishmania promastigotes, which elude the killing mechanisms of the host cells, survive, and infect other phagocytic cells. Here, we show that Leishmania promastigotes co-incubated with HMEC-1, a microvascular endothelial cell line, exhibited significant morphological changes and loss of infectivity. Moreover, promastigotes of different Leishmania species stimulated the production of CXCL8 by HMEC-1 in a dose- and TLR4-dependent manner. Interestingly, we observed that the conditioned media from Leishmania-stimulated HMEC-1 cells attracted leukocytes, mostly neutrophils, after 2 h of incubation. After 24 h, a higher percentage of monocytes was detected in conditioned media of unstimulated HMEC-1 cells, whereas neutrophils still predominated in conditioned medium from Leishmania-stimulated cells. The same supernatants did not contain CCL5, a chemokine recruiting T cells and monocytes. On the contrary, inhibition of the production of CCL5 induced by TNF-α was seen. These data indicate that the interaction of Leishmania promastigotes with endothelial cells leads to the production of chemokines and the recruitment of neutrophils, which contribute to the establishment of Leishmania infection.

Isolation of SARS-CoV-2 strains carrying a nucleotide mutation, leading to a stop codon in the ORF 6 protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was isolated from the oro/pharyngeal swabs of two Italian COVID-19 patients, physicians in a COVID-19 division hospital, with different courses of the disease. The complete genome sequences show that the two isolates belong to the B1.1 lineage, but contain a nucleotide mutation in the ORF6, leading to a stop codon and to the deletion of 6 amino acids in the C terminus. This deletion was unique, compared to the currently available sequences deposited in the GISAID and GenBank database. It did not affect the in vitro viral replication, neither the neutralizing activities of the patients' antibodies. Based on homology analysis with other Coronaviruses, the two isolated lacked the ORF6 aminoacidic portion responsible for the inhibition of the antiviral Interferon (IFN)-based host response. IFN seems to have a dual role of in SARS-CoV-2 infected patients: not only antiviral activity, but also a detrimental role in case of excessive production. A deletion in the SARS-CoV-2 ORF6 protein might have a specific, still unknown role in the viral pathogenesis.