18 research outputs found
The infection risk after transjugular intrahepatic portosystemic shunt: A multiple competing risk analysis from a tertiary care center
No full textBackground: Infections following transjugular intrahepatic portosystemic shunt (TIPS) placement have been poorly described. We aim to investigate the rate and the potential predictors of infections occurring after TIPS placement. Methods: Single center, retrospective, observational study. All patients who had undergone TIPS placement in the last 10 years with a minimum 1-year FU, were considered. Multiple competing risk analyses were performed to identify infection risk factors and a multivariable Cox proportional-hazard regression model to evaluate the predictors of death. Results: Forty-nine patients were considered. Among these, 23 (46%) developed at least 1 infection during the FU, at a median time of 237.7 days (IQR 151.5) from the TIPS placement. We did not find any predictor of infection, while MELD score and cancer were associated with death (p = .04; HR 1.14; CI 1.00- 1.30). Conclusion: We found a high rate of all-type infections during the FU times. However, most of these infections occurred as late-onset infections and were caused by Gram-positive microorganisms. Thus, TIPS procedure itself does not seem to be burdened with high infectious perioperative risk
La responsabilità civile nelle competizioni automobilistiche: spunti di riflessione tra società organizzatrici e altri soggetti
No full textItL'articolo si occupa della responsabilità civile nelle competizioni motoristiche. L'autore si concentra sulle diverse tipologie di responsabilità civile applicabili in Italia agli eventi motoristici, attraverso lo studio della più recente giurisprudenza e della normativa sportiva. Inoltre egli affronta il tema della responsabilità e distingue tra responsabilità dell'organizzatore, del proprietario della struttura, dei funzionari, dei concorrenti e degli spettatori.EnThe article investigates the civil liability in motorsport competitions. The author focuses on the different types of civil liability in Italy applicable to the motorsport events, through the study of the most recent jurisprudence and the sporting regulations. Furthermore the author discusses the subject of responsibility and makes a distinction among the liability of organizer, owner of structure, officials, competitors and spectators
Reduction of BSI associated mortality after a sepsis project implementation in the ER of a tertiary referral hospital
No full textAbstract The emergency room (ER) is the first gateway for patients with sepsis to inpatient units, and identifying best practices and benchmarks to be applied in this setting might crucially result in better patient’s outcomes. In this study, we want to evaluate the results in terms of decreased the in-hospital mortality of patients with sepsis of a Sepsis Project developed in the ER. All patients admitted to the ER of our Hospital from the 1st January, 2016 to the 31stJuly 2019 with suspect of sepsis (MEWS score ≥ of 3) and positive blood culture upon ER admission were included in this retrospective observational study. The study comprises of two periods: Period A: From the 1st Jan 2016 to the 31st Dec 2017, before the implementation of the Sepsis project. Period B: From the 1st Jan 2018 to the 31stJul 2019, after the implementation of the Sepsis project. To analyze the difference in mortality between the two periods, a univariate and multivariate logistic regression was used. The risk of in-hospital mortality was expressed as an odds ratio (OR) and a 95% confidence interval (95% CI). Overall, 722 patients admitted in ER had positive BC on admissions, 408 in period A and 314 in period B. In-hospital mortality was 18.9% in period A and 12.7% in period B (p = 0.03). At multivariable analysis, mortality was still reduced in period B compared to period A (OR 0.64, 95% CI 0.41–0.98; p = 0.045). Having an infection due to GP bacteria or polymicrobial was associated with an increased risk of death, as it was having a neoplasm or diabetes. A marked reduction in in-hospital mortality of patients with documented BSI associated with signs or symptoms of sepsis after the implementation of a sepsis project based on the application of sepsis bundles in the ER
Minimum Inhibitory Concentration Increase in Clostridioides difficile Isolates from Patients with Recurrence: Results from a Retrospective Single-Centre Cohort Study
No full textAntimicrobial susceptibility testing (AST) is not routinely performed for C. difficile infection (CDI); however, reports of antimicrobial resistance to various antibiotics have increased. This study aimed to assess the rate of antimicrobial resistance to four antimicrobials (vancomycin, metronidazole, tigecycline, and ciprofloxacin) to assess risk factors for antimicrobial resistance and evaluate MIC variation in patients with recurrence. Data from consecutive patients with CDI admitted to our institution between 1 January 2022 and 30 April 2023 were collected. We performed AST with gradient diffusion and NAAT to evaluate the presumptive presence of R027/NAP1 and toxin production genes. Antimicrobial susceptibility testing was performed on 108 available isolates. We did not find any resistance to vancomycin (median MIC 0.5 μg/mL), metronidazole (median MIC 1 μg/mL), and tigecycline (median MIC 0.016 μg/mL), while resistance to ciprofloxacin was detected in all the samples. Among the recurrent isolates, 37.5% displayed a 2-fold MIC increase for vancomycin, 75% for metronidazole, and 37.5% for tigecycline. After stratifying clinical outcomes according to vancomycin MIC, patients with higher MIC experienced increased 28-day mortality (p value 0.009). Our results were concordant with European surveillance data. MIC increase in all tested antibiotics in patients with CDI warrants further research since decreased susceptibility has been associated with clinical failure
The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males
No full textThe 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. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
No full textThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)
Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features
No full textThe impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%
Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19
No full textThrombosis 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
An explainable model of host genetic interactions linked to COVID-19 severity
No full textWe 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
Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder
No full textBackground: 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 )
