Individualized treatment of genotype 1 Naïve patients : an Italian multicenter field practice experience

Background: Triple therapy including Telaprevir or Boceprevir still represents in many European countries the standard of care for patients with Hepatitis C Virus genotype 1 infection. The number of patients who received this treatment resulted generally lower than expected. We investigated, among na\u131\ua8ve patients, number and characteristics of treatment candidates who were started on triple or dual therapy in comparison to those who were deferred. Patients and Methods: 621 na\u131\ua8ve treatment candidates were prospectively evaluated at each center. Factors associated with decision to defer or treat with dual or triple therapy were investigated by univariate and multivariate analyses. Rates of Sustained Virological Response and safety profile were analysed. Results: Of candidates to treatment, 33% did not received it. It was mostly due to high risk of Interferon-induced decompensation. Of 397 patients who were started on treatment, 266 (67%) received triple, 131 dual. Among patient receiving treatment, unfavorable IL28B, severe liver damage and higher albumin were independently associated with the physician decision to administer triple therapy. Sustained Virological Response after dual therapy was 66.4%, after triple 73.7% (p = 0.14). 142 patients received Telaprevir. The choice of Telaprevir-based therapy was associated with higher Body Mass Index and advanced liver disease. Sustained Virological Response rates were 71.1% after Telaprevir and 76.6% after Boceprevir. Conclusions: Individualizing treatment with available regimens allows to maximize Sustained Virological Response and to reduce the number of patients who remain untreated. High proportion of patients with severe liver damage urgently need Interferon free treatment

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Formal definition of metrics upon the CORBA component model

Abstract. Objective: In this paper we present a formalization of the definition of metrics to assess quality attributes of CORBA components and assemblies. The focus is on the formalization technique, rather than on the evaluation of the metrics themselves. Method: We represent a component assembly as an instantiation of the CORBA Component Model metamodel. The resulting meta-object diagram can then be traversed using Object Constraint Language clauses. With these clauses we construct a formal and executable definition of the metrics. Results: We demonstrate the expressiveness of our technique by formally defining metrics proposed informally by several authors on different aspects of components and assemblies ’ quality attributes. Conclusion: Providing a formal and executable definition of metrics for CORBA components and assemblies is an enabling precondition to allow for independent scrutiny of such metrics, which is, in turn, essential to increase practitioners ’ confidence on predictable quality attributes.

PREVALENCE OF CHRONIC LIVER-DISEASE IN THE GENERAL-POPULATION OF NORTHERN ITALY - THE DIONYSOS STUDY

Data on the prevalence of chronic liver disease, derived from selected series of hospitalized patients or from mortality registers, underestimate the prevalence of chronic liver disease. The Dionysos Study is a cohort study that investigated for the first time the prevalence of chronic liver disease in a general population. All the citizens of two towns in northern Italy, Campogalliano and Cormons, aged 12 to 65 yr were contacted by letter. From March 1991 through March 1993, 6,917 of a total of 10,150 citizens were enrolled (compliance, 69%). The standardized protocol for each enrollee included (a) a color-illustrated food questionnaire on dietary habits and alcohol intake; (b) a detailed medical history, including questions on risk factors for chronic liver disease; (c) a physical examination; and (d) blood tests for AST, ALT, \u3b3-glutamyl-transpeptidase, mean cell volume, platelet count and hepatitis B virus and hepatitis C virus markers. Signs suggestive of chronic liver disease were seen in 21.3% of the subjects, and who then underwent further liver function tests, upper abdominal ultrasonography and, when necessary, liver biopsy. Persistent signs of chronic liver disease were present in 17.5% of the subjects, including 1.1% with cirrhosis and 0.07% with hepatocellular carcinoma. The prevalence rates of hepatitis B virus and hepatitis C virus positivity (second-generation enzyme-linked immunosorbent assay) were 1.3% and 3.2%, respectively. Alcohol abuse was the etiological agent in 23%. Other factors which predisposed subjects to chronic liver disease were age older than 35 yr, male sex, body mass index higher than 27, history of blood transfusion, drug addiction and presence of chronic liver disease in the subject's family. Cirrhosis was due to hepatitis B virus or hepatitis C virus in 37%, and alcohol was the cause in 26%. In those subjects with alcohol abuse, viral infection, especially hepatitis C virus, played an important role in the deterioration of chronic liver disease and its progression to hepatocellular carcinoma. We conclude that the Dionysos study, the first study of the prevalence of chronic liver disease in a general population of northern Italy, found a much higher prevalence of chronic liver disease than reported previously in selected populations from Western countries. Hepatitis viral infections and alcoholism were the most important causative agents

Search for short-lived particles in high-energy neutrino interactions identified using a hybrid emulsion--spark-chamber arrangement

Seventeen litres of nuclear photographic emulsion have been exposed to the wide-band neutrino beam at Fermilab. Tracks of secondaries from neutrino interactions in the emulsion were observed in a wide-gap spark chamber and a system of narrow-gap spark chambers and counters down beam. From measurements on the tracks in the wide-gap chamber the positions of vertices from which the secondaries diverged were predicted and 37 neutrino interactions in emulsion were located. Factors affecting the efficiency of location of events searched for (∼20% in this experiment) are assessed and conclusions drawn about means of optimizing the design of experiments employing emulsion hybrid techniques. In one of the interactions a secondary track gave rise to three tracks after a distance of 182 μm. Further measurements made on this event do not alter the previous conclusion of its most likely interpretation as the decay of a short-lived particle of lifetime ∼6×10-13 sec. © 1979 The American Physical Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Observation of a likely example of the decay of a charmed particle produced in a high energy neutrino interaction

In a study of neutrino interactions occurring in nuclear emulsion, an event has been found that is most readily interpreted as the decay of a charmed particle with lifetime a few times 10-13 s. © 1976.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The role of the thymus in multiple sclerosis

The presence of numerous changes in T lymphocyte activity found in MS patients points to the involvement of the thymus in multiple sclerosis. The etiophathogenetic mechanism of MS is probably an autoimmune reaction that is triggered by a viral infection caused by one or more viruses and that perpetuates itself, causing the disease to progress. It has been proved that the thymus maintains its immunocompetence even in adulthood and that it has a role in the pathogenesis in several autoimmune diseases. In exacerbations of MS there is a decrease in T suppressor lymphocytes while histological and lymphocyte subset changes have been demonstrated in the thymus of MS patients. The lymphocyte response to mitogens is also depressed in MS. The clinical results of thymectomy in MS are not uniform and are on the whole inconclusive, probably through the lack of criteria of selection of patients for surgical treatment. We consider that the morphological and functional study of the thymus biopsy specimen should supply the appropriate criteria of suitability for surgical treatment