An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome

Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Personal Papers (MS 80-0002)

Letter from P. Casprini to Daniel W. Kempner enclosing an order for $175.00 to his deposits for two reservations

Antibodies anti-HTLV III and lymphocyte subsets of high risk subjects.

208 assay for the research into anti-HTLV III antibodies and lymphocytes subsets were carried out on the same number of patients at risk. 11 homosexual man, 143 intravenous drug users (i.d.u.) and 3 children of drug addicts from hospitals in the Marche and Abruzzo and 51 haemophiliacs from hospital in Florence were examined. 3 determination of anti-HTLV III antibodies were taken from each subject using 3 different commercial Kits. The results concur with and confirm similar epidemiological studies that have been done. The haemophiliac group had the highest positive percentage (39.2%), then came i.d.u. (11.9%) and the homosexuals (10.0%). Furthermore, of the 38 positive totals, there were 22 with only one kit, 18 with two, and 15 with all three. The evaluation of the lymphocyte subsets did not strictly correlate with the presence of the antiretrovirus antibodies

The connection between 2006 IPCC GHG inventory methodology and ISO 14064-1 certification standard – A reference point for the environmental policies at sub-national scale

The article shows how a joint application of the 2006 IPCC methodology and the ISO 14064-1 standard of certification, as well as the co-operation between academic, legislative and administrative organizations, are important points for a sustainable management of an administrative jurisdiction, providing positive environmental effects. The administrative systems can choose validated ISO 14064-1 GHG inventories, produced in time series, as a strategy tool for local management, as a compass to orient future policy decisions. The Province of Siena (Tuscany, Central Italy) was one regional system in Europe to achieve the ISO 14064-1 certification of its GHG inventories, developed in time series applying the 2006 IPCC methodology. The results of the time series (year 2006-2010) of GHG inventories elaborated for the Province of Siena point out that the performed environmental management policies may bring about a significant reduction of GHG emission released to the atmosphere over time (net emission: 449GgCO2eq in 2006, 84GgCO2eq in 2010). The experience of the Province of Siena can be considered a significant reference model for all public authorities at the micro and macro scale who are interested in reducing GHG emission. © 2014 Elsevier Ltd

Critical analysis of the models for the residual life evaluation of existing RC buildings.

Pitting phenomena due to either the presence or entrance of chloride ions in the concrete matrix have been identified as the main responsible for the mechanical deterioration of RC structural elements. In this paper, the weaknesses of empirical models for the evaluation of the residual strength of beams and the effectiveness of the analytical ones are emphasised through the critical and comparative analysis of several models among those proposed in the literature. In order to shift from the evaluation of the single element to the global structural level, a new approach is also proposed, which is based on the formulation of some equivalent para-meters, describing the behaviour of corroded elements and the effect of such decay on the rest of the structure over time