VULVAR HISTOPATHOLOGICAL AND IMMUNOHISTOCHEMICAL CHANGES IN PATIENTS WITH PRIMARY SJÖGREN SYNDROME

Background: Primary Sjogren Syndrome (pSS) is an autoimmune disease mostly affecting women, characterized by a lymphocyte-mediated infiltration and destruction of several exocrine glands, which causes mucosal dryness. Genital involvement is frequent and characterized by vulvar and vaginal dryness, dyspareunia and pruritus, that significantly impairs sexual function. However, despite the high frequency of genital involvement, few data were published about the histopathology of external genitalia in pSS. The studies performed until now show that vaginal and vulvar dryness are due to the presence of a vulvar inflammatory infiltrate and to the atrophy of minor and major vestibular glands, whose secretions are important for the sexual function. Objectives: To evaluate the presence and the characteristics of histopathological and immunohistochemical changes in vulvar tissues in women with pSS. Methods: Women with pSS (21 patients) underwent vulvar biopsies that have been evaluated for histopathological and immunohistochemical changes and finally compared with those obtained from 26 patients with lichen sclerosus. Results: An inflammatory infiltrate (composed predominantly by T lymphocytes (CD3+), sparse CD20+ B cells and mean CD4:CD8 T-cell ratio of 1.5) was evidenced in all 21 biopsies and classified in mild (10), moderate (11) and severe (0). No correlation was shown between vulvar inflammatory infiltrate score and salivary Chisholm e Mason score. No differences were found neither in gynecological symptoms neither in clinical and demographical characteristics between patients with mild and those with moderate vulvar inflammatory score. A higher prevalence of moderate inflammatory infiltrate was observed in biopsies from women with lichen sclerosus than in pSS

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.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

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

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Linea Guida per l'implementazione di un sistema di Enterprise Risk Management: Il Caso: Codyeco S.p.A.

SOMMARIO Il presente lavoro di tesi è frutto di un percorso di tirocinio della durata di cinque mesi, svoltosi presso l’azienda Codyeco S.p.a. la cui sede centrale è ubicata a Santa Croce sull'Arno. Tale realtà ha per oggetto la produzione ed il commercio di una vasta gamma di prodotti chimici e coloranti, per qualsiasi tipo di industria che opera nel settore conciario. Il forte cambiamento organizzativo presentatosi negli ultimi anni, la necessità di competere in un contesto sempre più dinamico, ha fatto emergere l’esigenza di esplicitare all'interno dell’azienda un modello integrato di gestione dei rischi. Quest’ultimo dovrà permettere all'organizzazione il monitoraggio e la gestione del macro-ambiente organizzativo da potenziali eventi aleatori, che, se non correttamente governati, potrebbero minare il futuro sviluppo dell’impresa. Pertanto, l’obiettivo di questo progetto è stato quello di fornire all’azienda una base, per lo sviluppo di un simile modello globale ed integrato di gestione del rischio. Inizialmente, è stata effettuata un’analisi del profilo di rischio dell’impresa e, successivamente, è stata ideata una linea guida per lo sviluppo di un sistema di gestione del rischio organizzativo. La linea guida è rivolta sia alla realtà oggetto di studio sia a qualsiasi altra, che similmente a Codyeco, necessiti di un sistema simile al proprio interno. ABSTRACT This thesis is the result of a five months internship, held at the company Codyeco whose headquarters is located in Santa Croce sull’Arno. This company manufactures and trades a wide range of chemicals and dyes for any type of industry operating in the tanning sector. The strong organizational change that has occurred in recent years, the need to compete in an increasingly dynamic context, has highlighted the need to clarify an internal integrated risk management system. This system, will allow to monitor and manage the organizational environment from potential random events that if not properly managed could compromise the future development of the company. Therefore, the purpose of this project was to provide a basis for the development of a comprehensive and integrated Enterprise risk management system. Initially, was analyzed the company risk-profile and then, subsequently, was developed a guideline for the implementation of an Enterprise risk management system. The guideline is directed both to the reality, which has been studied, and to other companies, that as Codyeco, have a similar internal situation