Integrating Topological Proofs with Model Checking to Instrument Iterative Design

System development is not a linear, one-shot process. It proceeds through refinements and revisions. To support assurance that the system satisfies its requirements, it is desirable that continuous verification can be performed after each refinement or revision step. To achieve practical adoption, formal verification must accommodate continuous verification efficiently and effectively. Model checking provides developers with information useful to improve their models only when a property is not satisfied, i.e., when a counterexample is returned. However, it is desirable to have some useful information also when a property is instead satisfied. To address this problem we propose TOrPEDO, an approach that supports verification in two complementary forms: model checking and proofs. While model checking is typically used to pinpoint model behaviors that violate requirements, proofs can instead explain why requirements are satisfied. In our work, we introduce a specific notion of proof, called Topological Proof. A topological proof produces a slice of the original model that justifies the property satisfaction. Because models can be incomplete, TOrPEDO supports reasoning on requirements satisfaction, violation, and possible satisfaction (in the case where satisfaction depends on unknown parts of the model). Evaluation is performed by checking how topological proofs support software development on 12 modeling scenarios and 15 different properties obtained from 3 examples from literature. Results show that: (i) topological proofs are ≈60% smaller than the original models; (ii) after a revision, in ≈78% of cases, the property can be re-verified by relying on a simple syntactic check

Fluid Petri Nets for the Performance Evaluation of MapReduce Applications

Big Data applications allow to successfully analyze large amounts of data not necessarily structured, though at the same time they present new challenges. For example, predicting the performance of frameworks such as Hadoop can be a costly task, hence the necessity to provide models that can be a valuable support for designers and developers. This paper provides a new contribution in studying a novel modeling approach based on fluid Petri nets to predict MapReduce jobs execution time. The experiments we performed at CINECA, the Italian supercomputing center, have shown that the achieved accuracy is within 16% of the actual measurements on average

Non-random retention of protein-coding overlapping genes in Metazoa

<p>Abstract</p> <p>Background</p> <p>Although the overlap of transcriptional units occurs frequently in eukaryotic genomes, its evolutionary and biological significance remains largely unclear. Here we report a comparative analysis of overlaps between genes coding for well-annotated proteins in five metazoan genomes (human, mouse, zebrafish, fruit fly and worm).</p> <p>Results</p> <p>For all analyzed species the observed number of overlapping genes is always lower than expected assuming functional neutrality, suggesting that gene overlap is negatively selected. The comparison to the random distribution also shows that retained overlaps do not exhibit random features: antiparallel overlaps are significantly enriched, while overlaps lying on the same strand and those involving coding sequences are highly underrepresented. We confirm that overlap is mostly species-specific and provide evidence that it frequently originates through the acquisition of terminal, non-coding exons. Finally, we show that overlapping genes tend to be significantly co-expressed in a breast cancer cDNA library obtained by 454 deep sequencing, and that different overlap types display different patterns of reciprocal expression.</p> <p>Conclusion</p> <p>Our data suggest that overlap between protein-coding genes is selected against in Metazoa. However, when retained it may be used as a species-specific mechanism for the reciprocal regulation of neighboring genes. The tendency of overlaps to involve non-coding regions of the genes leads to the speculation that the advantages achieved by an overlapping arrangement may be optimized by evolving regulatory non-coding transcripts.</p

Genetic parameters of fatty acids in Italian Brown Swiss and Holstein cows

The aim of this study was to estimate the genetic parameters and to predict experimental breeding values (EBVs) for saturated (SFA), unsaturated (UFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids, the ratio of fatty acids, and the productive traits in Italian Brown Swiss (BSW) and Holstein Friesian (HOL) cattle. Test-day yields from 235,658 HOL and 21,723 BSW cows were extracted from the Italian HOL and BSW Associations databases from November 2009 to October 2012 out of 3310 herds. The milk samples collected within the routine milk recording scheme were processed with the MilkoscanTM FT 6500 Plus (Foss, Hillerød, Denmark) for the identification of SFA, UFA, MUFA and PUFA composition in milk. Genetic parameters for fatty acids and productive traits were estimated on 1,765,552 records in HOL and 255,592 records in BSW. Heritability values estimated for SFA, UFA, MUFA and PUFA ranged from 0.06 to 0.18 for the BSW breed and from 0.10 to 0.29 for HOL. The genetic trends for the fatty acids were consistent between traits and breeds. Pearson's and Spearman's correlations among EBVs for SFA, UFA, MUFA and PUFA and official EBVs for fat percentage were in the range 0.32 to 0.54 for BSW and 0.44 to 0.64 for HOL. The prediction of specific EBVs for milk fatty acids and for the ratio among them may be useful to identify the best bulls to be selected with the aim to improve milk quality in terms of fat content and fatty acid ratios, achieving healthier dairy productions for consumers

Association of Tricuspid Regurgitation With Outcome in Acute Heart Failure

Background: Tricuspid regurgitation (TR) is common in chronic heart failure (HF) and is associated with negative prognosis. However, evidence on prognostic implications of TR in acute HF is lacking. We sought to investigate the association between TR and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for acute HF. Methods: We enrolled 1176 consecutive patients with a primary diagnosis of acute HF and with available noninvasive estimation of TR and pulmonary arterial systolic pressure. Results: Moderate-severe TR was present in 352 patients (29.9%) and was associated with older age and more comorbidities. The prevalence of PH (ie, pulmonary arterial systolic pressure >40 mm Hg), right ventricular dysfunction, and mitral regurgitation was higher in moderate-severe TR. At 1 year, 184 (15.6%) patients died. Moderate-severe TR was associated with higher 1-year mortality risk after adjustment for other echocardiographic parameters (pulmonary arterial systolic pressure, left ventricle ejection fraction, right ventricular dysfunction, mitral regurgitation, left and right atrial indexed volumes; hazard ratio, 1.718; P=0.009), and the association with outcome was maintained when clinical variables (eg, natriuretic peptides, serum creatinine and urea, systolic blood pressure, atrial fibrillation) were added to the multivariable model (hazard ratio, 1.761; P=0.024). The association between moderate-severe TR and outcome was consistent in patients with versus without PH, with versus without right ventricular dysfunction, and with versus without left ventricle ejection fraction <50%. Patients with coexistent moderate-severe TR and PH had 3-fold higher 1-year mortality risk compared with patients with no TR or PH (hazard ratio, 3.024; P<0.001). Conclusions: In patients hospitalized for acute HF, the severity of TR is associated with 1-year survival, regardless of the presence of PH. The coexistence of moderate-severe TR and estimated PH was associated with a further increase in mortality risk. Our data must be interpreted in the context of potential underestimation of pulmonary arterial systolic pressure in patients with severe TR

Baseline Plasma Osteopontin Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients

More than three years have passed since the first case, and COVID-19 is still a health concern, with several open issues such as the lack of reliable predictors of a patient's outcome. Osteopontin (OPN) is involved in inflammatory response to infection and in thrombosis driven by chronic inflammation, thus being a potential biomarker for COVID-19. The aim of the study was to evaluate OPN for predicting negative (death or need of ICU admission) or positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. We enrolled 133 hospitalized, moderate-to-severe COVID-19 patients in a prospective observational study between January and May 2021. Circulating OPN levels were measured by ELISA at admission and at day 7. The results showed a significant correlation between higher plasma concentrations of OPN at hospital admission and a worsening clinical condition. At multivariate analysis, after correction for demographic (age and gender) and variables of disease severity (NEWS2 and PiO2/FiO2), OPN measured at baseline predicted an adverse prognosis with an odds ratio of 1.01 (C.I. 1.0-1.01). At ROC curve analysis, baseline OPN levels higher than 437 ng/mL predicted a severe disease evolution with 53% sensitivity and 83% specificity (area under the curve 0.649, p = 0.011, likelihood ratio of 1.76, (95% confidence interval (CI): 1.35-2.28)). Our data show that OPN levels determined at the admission to hospital wards might represent a promising biomarker for early stratification of patients' COVID-19 severity. Taken together, these results highlight the involvement of OPN in COVID-19 evolution, especially in dysregulated immune response conditions, and the possible use of OPN measurements as a prognostic tool in COVID-19

Eosinophilic oesophagitis (in nickel-allergic patient) regressed after nickel oral desensitization: A case report

The eosinophilic oesophagitis (EoE) is a chronic immune/antigen disorder of the oesophagus clinically characterized by dysphagia and pathologically by mucosa eosinophilic infiltration. Th2-type allergic reactions are considered having important roles in the aetiopathogenesis of EoE. Avoidance of food allergens, administration of steroidal anti-inflammatory medications and dilation of the oesophagus are the most important treatments. 'Systemic nickel allergy syndrome' (SNAS) interests about 20% of patients with nickel contact allergy which could present systemic cutaneous manifestations (urticaria, oedema, etc.) and also respiratory and digestive symptoms (meteorism, abdominal pain, diarrhoea, etc.). In the literature, it is demonstrated that nickel oral immunotherapy is effective in reducing symptoms of SNAS and in modulating inflammatory parameters. We describe the case of a 48-year-old woman suffering from EoE not responsive to the topical steroid administration and diagnosis of SNAS. The patient started nickel oral desensitization according to the literature protocol continuing nickel-free diet. After 1\u2009year from the beginning of the treatment, during the maintenance dose (500\u2009ng three times a week), she decreased gradually the dosage of immunotherapy and reintroduced all the culprit foods. After the immunotherapy interruption, during the free diet, she repeated the oesophagogastroscopy with a complete macroscopic and histological resolution. We showed the first case of an EoE in a patient affected by SNAS responsive to the nickel-free diet and the oral immunotherapy

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective real-world experience with 200 cases outside of controlled clinical trials

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved a superior clinical benefit over Pd with a manageable toxicity profile, leading to its approval in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). We report here a real-world experience of 200 RRMMs treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was 2, with 51% of cases undergoing autologous stem cell transplant (ASCT) and 73% exposed to daratumumab. After a median follow-up of 9 months, 126 patients stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate (ORR) was 55.4%, in line with the pivotal trial results. Regarding adverse events, our cohort experienced a toxicity profile similar to the ELOQUENT-3 trial, with no significant differences between younger (&lt;70 years) and older patients. The median progression-free survival (PFS) was 7 months, shorter than that observed in the ELOQUENT-3, probably due to the different clinical characteristics of the two cohorts. Interestingly, the ISS stage III (HR:2.55) was associated with worse PFS. Finally, our series's median overall survival (OS) was shorter than that observed in the ELOQUENT-3 trial (17.5 versus 29.8 months). In conclusion, our real-world study confirms EloPd as a safe and possible therapeutic choice for RRMM who received at least two prior therapies, including lenalidomide and a PI

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk