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To ensure environmental and public safety, critical facilities require rigorous seismic hazard analysis to define seismic input for their design. We consider the case of the Trans Adriatic Pipeline (TAP), which is a pipeline that transports natural gas from the Caspian Sea to southern Italy, crossing active faults and areas characterized by high seismicity levels. For this pipeline, we develop a Probabilistic Seismic Hazard Assessment (PSHA) for the broader area, and, for the selected critical sites, we perform deterministic seismic hazard assessment (DSHA), by calculating shaking scenarios that account for the physics of the source, propagation, and site effects. This paper presents a DSHA for a compressor station located at Fier, along the Albanian coastal region. Considering the location of the most hazardous faults in the study site, revealed by the PSHA disaggregation, we model the ground motion for two different scenarios to simulate the worst-case scenario for this compressor station. We compute broadband waveforms for receivers on soft soils by applying specific transfer functions estimated from the available geotechnical data for the Fier area. The simulations reproduce the variability observed in the ground motion recorded in the near-earthquake source. The vertical ground motion is strong for receivers placed above the rupture areas and should not be ignored in seismic designs; furthermore, our vertical simulations reproduce the displacement and the static offset of the ground motion highlighted in recent studies. This observation confirms the importance of the DSHA analysis in defining the expected pipeline damage functions and permanent soil deformations.

The design of critical facilities needs a targeted computation of the expected ground motion levels. The Trans Adriatic Pipeline (TAP) is the pipeline that transports natural gas from the Greek-Turkish border, through Greece and Albania, to Italy. We present here the probabilistic seismic hazard analysis (PSHA) that we performed for this facility, and the deaggregation of the results, aiming to identify the dominant seismic sources for a selected site along the Albanian coast, where one of the two main compressor stations is located. PSHA is based on an articulated logic tree of twenty branches, consisting of two models for source, seismicity, estimation of the maximum magnitude, and ground motion. The area with the highest hazard occurs along the Adriatic coast of Albania (PGA between 0.8 and 0.9 g on rock for a return period of 2475 years), while strong ground motions are also expected to the north of Thessaloniki, Kavala, in the southern Alexandroupolis area, as well as at the border between Greece and Turkey. The earthquakes contributing most to the hazard of the test site at high and low frequencies (1 and 5 Hz) and the corresponding design events for the TAP infrastructure have been identified as local quakes with MW 6.6 and 6.0, respectively.

Coseismic surface displacements, soil liquefaction effects, and induced landslides are among the most critical issues to be accounted for evaluating the exposure and vulnerability of pipelines. However, tectonic plates and crustal blocks are in an almost continuous relative movement, most pronounced in the narrow zones between tectonic plates, where we observe differential velocities from a few mm to some cm per year. Hence, even without the occurrence of strong earthquakes, a pipeline crossing active tectonic plate boundaries must cope during its lifetime, with remarkable differential motions along its length, due to the interseismic elastic strain-accumulation within the upper crust. Such movements, leading to permanent ground deformation, can distress the pipe and cause operation interruptions, while the anchor points can result in local stress concentrations.Here, we analyze the Southern Gas Corridor’s final part, a route highlighted in the European Energy Security and Energy Union Strategies. This route, which will be occupied by the TransAdriatic pipeline, crosses one of the world’s most seismically active zones. Our study aims to identify areas where critical differential motions could be expected along the route over the nominal 50-years pipeline-lifespan. We analyzed the available GNSS data and interpolated the sparsely available velocity vectors to have regular information along the pipeline path in two ways. In the first, we considered the region as a continuum; in the second, we applied an original blocky approach. We subdivided the path into segments, characterized by a relatively homogenous deformational behavior, or a specific tectonic setting, independently upon the neighboring ones. We compared the results of the two methods with the input observation. We calculated the maximum displacement that would cumulate in the next 50 years and the differential displacements that could cause possible critical bending to the pipeline structure. The approach followed in this research could be applied to other infrastructures to identify the segments prone to localized deformation because of interseismic tectonic loading.The work was done within the Trans Adriatic Pipeline Seismological Investigation RfP Seismic Hazard Assessment Evaluation for E.ON New Build & Technology GmbH. We thank Dario Slejko and the other project partners for valuable information, data, advice, and fruitful discussions. For our GIS-based strain velocity system, we used Quantum GIS (QGIS), a user-friendly Open Source Geographic Information System (GIS) licensed under the GNU General Public License (https://hub.qgis.org/). For the interpolation, we used the function TriScatteredInterp from MATLAB® library (MATLAB R2011a).

In this article, we describe the infrastructure developed and managed by the Italian National Institute of Oceanography and Applied Geophysics – OGS for the seismological and geodetic monitoring of northeastern Italy. The infrastructure was constituted in response to the ML 6.4 Friuli destructive earthquake of 1976, with the main mandate of supporting civil protection emergency activities. The OGS monitoring infrastructure is presently composed of a seismometric and a strong-motion network, complemented by a number of Global Navigation Satellite Systems stations, each delivering observational data in real time, which are collected and processed by the headquarters of the Center for Seismological Research of OGS in Udine. The OGS networks operate in close cooperation with Italian and international networks from neighboring countries, within the framework of the agreements for real-time data exchange, to obtain improved rapid earthquake location and magnitude estimations. Information regarding seismic events is released to the public through a dedicated web portal and, since 2013, through social media. Aside from the standard monitoring activities (>30,000 events have been recorded since 1976), the OGS has progressively increased the number of services to the public and to the Civil Protection of the Friuli Venezia Giulia and Veneto regions. The high availability of good quality data has resulted in the enhancement of scientific products, including advanced seismological studies of the area, spanning broadly from seismic source characterization to engineering seismology. In the future, the OGS networks are expected to further contribute to the development of seismological research and monitoring infrastructures of the Central European region.

The Global Navigation Satellite Systems (GNSS) provide a globally extended dataset of primordial importance for a wide range of applications, such as crustal deformation, topographic measurements, or near surface processes studies. However, the high costs of GNSS receivers and the supporting software can represent a strong limitation for the applicability to landslide monitoring. Low-cost tools and techniques are strongly required to face the plausible risk of losing the equipment during a landslide event.Centro di Ricerche Sismologiche (CRS) of Istituto Nazionale di Oceanografia e di Geofisica Sperimentale OGS in collaboration with SoluTOP, in the last years, has developed a cost-effective GNSS device, called LZER0, both for post-processing and real-time applications. The aim is to satisfy the needs of both scientific and professional communities which require low-cost equipment to increase and improve the measurements on structures at risk, such as landslides or buildings, without losing precision.The landslide monitoring system implements single-frequency GNSS devices and open source software packages for GNSS positioning, dialoguing through Linux shell scripts. Furthermore a front-end web page has been developed to show real-time tracks. The system allows measuring real-time surface displacements with a centimetre precision and with a cost ten times minor than a standard RTK GPS operational system.This monitoring system has been tested and now applied to two landslides in NE- Italy: one near Tolmezzo municipality and one near Brugnera village. Part of the device development has been included inside the project CLARA 'CLoud plAtform and smart underground imaging for natural Risk Assessment' funded by the Italian Ministry of Education, University and Research (MIUR).

In this work, global navigation satellite system (GNSS) observations from the northern tip of the Adria microplate are analysed to differentiate non-periodic (transient) tectonic signals from other deviations from the linear trends primarily due to hydrological loading effects. We tested a recently proposed hypothesis that a porosity wave generated by fault-valve mechanisms in a seismogenic fault in the Bovec basin (western Slovenia) propagated throughout the surrounding region. After excluding potential spatially correlated common-mode errors in the considered time series, we investigated the relationship between the GNSS observations and periodic hydrological loading variations. The tests demonstrated that subtracting the hydrological term was effective at the global scale and that the frequency band of the transient signal (1.5 < T < 3.5 years) was not correlated with hydrological effects at the local scale (within a few kilometres of the station). Next, the results of previous works are used to calculate the permeability values and pore-pressure state at the source of the transient signal. The permeability values for the four main rock formations in the region are consistent with independent observations for similar lithotypes. The ratio between the effective stress and lithostatic load for different vertical profiles in the Bovec area indicated a state of overpressure, with pore-pressure close to the value of the lithostatic load. Thus, our results help define a scenario in which the porosity wave could have originated. Indeed, the formation of the domains of interconnected fractures, such as during the formation of a porosity wave, increases the permeability values, thereby relieving overpressure and restoring a state of equilibrium.

Objective To study the epidemiological and clinical features of Hepatitis E Virus (HEV) infection in a migrant population. Methods We performed a retrospective chart review, identifying a cohort of 21 symptomatic patients of migrant origin with confirmed HEV infection admitted in the period between January 1995–November 2014. Results 20 (95%) patients came from South Asian countries highly endemic for HEV, all positive for HEV genotype 1. Recent travel to a highly endemic country was the most consistent risk factor identified in 90% of cases, duration from return to Italy to hospitalization ranged from 10 to 120 days. Nausea and vomiting (100%), jaundice (95.2%), and anorexia (85.7%) were the most common reported symptoms. Fever was present in 57.1% of cases. Transaminase values were elevated in all patients and serum bilirubin was raised in 86% of patients. We found no statistically significant differences between clinical symptoms, laboratory results or duration of hospitalization in patients with co-morbidities compared to those without. We also report a secondary case of HEV genotype 1 transmitted within Italy. Conclusion Our study highlights the epidemiological risk factors and clinical features of HEV infection in a migrant population in Italy and should stimulate further research regarding the prevalence and morbidity of HEV within migrant populations in Europe.

The main aim of this paper is to show the potential benefits for the Securitisation process, both in terms of the setup of operations and in the entire product life cycle, derived from the adoption of the Blockchain Technology. For this purpose, we focused on the different aspects, starting from the securitisation market in which we analysed the causes of the decrease in the number of operations occurred in the last decade, although there still is a strong need to securitise some types of assets such as NPL’s and Trade Receivables. Specifically, for these two types of assets we represent the securitisation process with the As-Is limits and improvements made possible by the blockchain technology application. Along this “path” we have deepened some key aspects of the blockchain and how the application of this technology may help Financial Institutions to experience a strong reduction in operational risks and costs, liquidity risk and credit risk on managing the underlying assets. At the same time, the new framework might give to a wider category of individuals access to a product that otherwise would have been available only to a limited number of more sophisticated investors, tapping from more structured, controlled and certified information. All this being achieved at no additional costs but rather with stronger and more organized and transparent product structures.

Background & Aims Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. Methods All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. Results A total of 179 patients were included: median age 57 (18–88) years, 74% males, median HCV-RNA 1,081,817 (482–25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). Conclusions SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. Lay summary This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Due to the development of denser permanent Global Navigation Satellite System (GNSS) networks over the last decade, the observation of transient deformations has significantly increased, mainly in high strain-rate zones. We analyzed the data from a group of permanent GNSS sites on the N-Adria microplate, where anomalous southward tilting and low-frequency tremors preceded the 1976 M w = 6.4 earthquake. We present records from different stations of a transient signal with an approximately 2-year period that propagated through the northern edge of Adria, in a region 150 km wide. This represents the first time a transient deformation event has been observed in a continental collision area. We exclude surface and groundwater hydrological load effects because we corrected the data for such effects at seasonal, annual, and multiyear scales. The movement is initially upward, except in one location, with slight tilting parallel to the direction of the main tectonic structures. Later, the opposite behavior is observed. The novel methods used include earthquake location techniques and tomographic inversion of the arrival times. These methods demonstrated that the transient source was located spatially and temporally close to the 2004 M w = 5.2 event in Bovec (Slovenia), attributed to the activity of the Ravne fault. We interpret the transient rises as the expression of a porosity wave, possibly produced by fault valve behavior of the NW tip of the Ravne fault. The propagation velocity is consistent with this hypothesis. As a further test, we invert the arrival times of the transient through hydraulic tomography to obtain hydraulic diffusivity: the values are compatible with the lithotypes present in the region and the literature. By substituting the tomographic velocity and diffusivity in the solitary/porosity wave equation, we infer an initial effective stress of approximately 0.23 bar, sufficient to alter the equilibrium of some fault segments and influence the subsequent seismicity.

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

Ten years’ geodetic observations (2006–2016) in a natural cave of the Cansiglio Plateau (Bus de la Genziana), a limestone karstic area in northeastern Italy, are discussed. The area is of medium–high seismic risk: a strong earthquake in 1936 below the plateau (Mm = 6.2) and the 1976 disastrous Friuli earthquake (Mm = 6.5) are recent events. At the foothills of the karstic massif, three springs emerge, with average flow from 5 to 10 m3/s, and which are the sources of a river. The tiltmeter station is set in a natural cavity that is part of a karstic system. From March 2013, a multiparametric logger (temperature, stage, electrical conductivity) was installed in the siphon at the bottom of the cave to discover the underground hydrodynamics. The tilt records include signals induced by hydrologic and tectonic effects. The tiltmeter signals have a clear correlation to the rainfall, the discharge series of the river and the data recorded by multiparametric loggers. Additionally, the data of a permanent GPS station located on the southern slopes of the Cansiglio Massif (CANV) show also a clear correspondence with the river level. The fast water infiltration into the epikarst, closely related to daily rainfall, is distinguished in the tilt records from the characteristic time evolution of the karstic springs, which have an impulsive level increase with successive exponential decay. It demonstrates the usefulness of geodetic measurements to reveal the hydrological response of the karst. One outcome of the work is that the tiltmeters can be used as proxies for the presence of flow channels and the pressure that builds up due to the water flow. With 10 years of data, a new multidisciplinary frontier was opened between the geodetic studies and the karstic hydrogeology to obtain a more complete geologic description of the karst plateau.

Online Material: Seismic‐hazard map, figures of event location and waveforms, phase reading distribution, and background seismic noise; and tables of event parameters, 1D regional model, and earthquake catalog. The Collalto Seismic Network (Rete Sismica di Collalto, or RSC) is the infrastructure used to monitor the natural and induced seismicity of the natural gas storage concession known as Collalto Stoccaggio, which is located in northeastern Italy. This network was realized and is currently managed by the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale (OGS), a public research institute, on behalf of Edison Stoccaggio S.p.A., the storage concession holder. The storage exploits a depleted natural gas reservoir that was converted into a seasonal reservoir in the 1990s. The reservoir is a geologic trap, with porous and permeable rock layers, a few meters thick, sealed by impermeable formations. The production levels are located at 1500–1600 m depth (Picotti, 2007) and extend approximately over a 10 km×4 km wide area (Fig. 1). The gas storage activity affects four municipalities, all of which are located in the province of Treviso: Susegana, Nervesa della Battaglia, S. Pietro di Feletto, and Conegliano. Figure 1. Location of the study area, including the Collalto Seismic Network (RSC). Seismometric stations are indicated by triangles; the 10 RSC stations by white triangles (labels start with ED; all are located within area A); and the stations of the Northeastern Italy Integrated Seismic Network (NEI) by black triangles, respectively. All the stations indicated are managed by the OGS. The two rectangles bordered by thin lines indicate the two target areas, A and B. The irregular area bordered by a thick black line within area A corresponds to the surface projection of the gas storage reservoir. The fault lines indicate the active faults known for the study area according to Poli et al. (2008). Insets (a) and (b) …

Continuous GNSS networks provide unique information about the crustal dis-placements, of use for studies concerning plate motions, tectonic processes, and earthquake cycle understanding. The Istituto Nazionale di Oceanografia e di Geofisca Sperimentale—OGS, since 2002, is responsible for the installation, maintenance, and development of FReDNet (Friuli Regional Deformation Network), the system for crustal deformation monitoring in the Friuli Venezia Giulia Region. The main objective of the network is the detection of tectonic plate movements in this collision area: such movements can give some guidance to quantify the seismic hazard. The infrastructure currently consists of 16 permanent stations located in the Friuli Venezia Giulia and Veneto regions, all equipped with GNSS receiver (Global Navigation Satellite Systems) capable of tracking satellite systems GPS, GLONASS and Galileo. The system includes a central server for collecting, processing and distributing of data and results. FReDNet, furthermore, provides a service for browsing high-precision real-time positioning in the most common differential correction RTK (Real Time Kinematic) modes. The current document will briefly describe the technical implementation of FReDNet in the last years with new stations, new features (high-frequency sampling and monumentation) and upgraded services.

INTRODUCTION Short antiviral therapy has been proposed for patients with chronic hepatitis C, easy genotypes, low fibrosis score, low viral load at baseline, and rapid virological response (RVR). However, this approach is not completely accepted. OBJECTIVES The aims of this study were (a) to evaluate the sustained virological response (SVR) in noncirrhotic patients with genotype 2 or 3, achieving an RVR, randomized to receive pegylated-interferon (IFN) α-2b plus ribavirin for either 16 or 24 weeks and (b) to carry out direct cost analysis comparing patients treated for 16 versus 24 weeks. RESULTS Of the 142 initially evaluated patients, 130 were enrolled according to the selection criteria, but independent of the viral load. According to the intention-to-treat analysis, SVR was achieved in 104 patients (80%). Logistic regression analysis showed that RVR (P

Cyclic nucleotide-gated (CNG) channels are activated by binding of cyclic nucleotides. Although structural studies have identified the channel pore and selectivity filter, conformation changes associated with gating remain poorly understood. Here we combine single-molecule force spectroscopy (SMFS) with mutagenesis, bioinformatics and electrophysiology to study conformational changes associated with gating. By expressing functional channels with SMFS fingerprints in Xenopus laevis oocytes, we were able to investigate gating of CNGA1 in a physiological-like membrane. Force spectra determined that the S4 transmembrane domain is mechanically coupled to S5 in the closed state, but S3 in the open state. We also show there are multiple pathways for the unfolding of the transmembrane domains, probably caused by a different degree of α-helix folding. This approach demonstrates that CNG transmembrane domains have dynamic structure and establishes SMFS as a tool for probing conformational change in ion channels.

International audience; Regression of hepatitis C virus (HCV)-associated lymphoma with interferon (IFN)-based antiviral treatment supports an etiological link between lymphoma and HCV infection. In addition, a favorable impact of antiviral treatment on overall survival of patients with HCV-related lymphoma has been reported. Data on IFN-free regimens combining direct-acting antivirals (DAAs) in HCV-associated lymphoproliferative disorders are scanty. We analyzed the virological and lymphoproliferative disease response (LDR) of 46 patients with indolent B-cell non-Hodgkin lymphomas (NHLs) or chronic lymphocytic leukemia (CLL) and chronic HCV infection treated with DAAs. The histological distribution was 37 marginal zone lymphomas (MZLs), 2 lymphoplasmacytic lymphomas, 2 follicular lymphomas, 4 CLL/small lymphocytic lymphomas (CLL/SLLs), and 1 low-grade NHL not otherwise specified. Thirty-nine patients received a sofosbuvir-based regimen and 7 patients received other DAAs. The median duration of DAA therapy was 12 weeks (range, 6-24 weeks). A sustained virological response at week 12 after finishing DAAs was obtained in 45 patients (98%); the overall LDR rate was 67%, including 12 patients (26%) who achieved a complete response. The LDR rate was 73% among patients with MZL, whereas no response was observed in CLL/SLL patients. Seven patients cleared cryoglobulins out of 15 who were initially positive. After a median follow-up of 8 months, 1-year progression-free and overall survival rates were 75% (95% confidence interval [CI], 51-88] and 98% [95% CI, 86-100], respectively. DAA therapy induces a high LDR rate in HCV-associated indolent lymphomas. These data provide a strong rationale for prospective trials with DAAs in this setting.

The introduction of highly active anti-retroviral therapy (HAART) for Human Immunodeficiency Virus (HIV) infection has significantly improved the life expectancy of HIV positive patients. Hepatitis C virus (HCV) co-infection is common in HIV infected patients and is now a significant cause of morbidity and mortality. Optimal management and treatment of HCV in HIV infected patients is therefore essential. Interferon-alpha (IFN-alpha) and ribavirin is the mainstay of treatment for HCV infection in HIV infected people. The sustained virological response rate (SVR) with combination therapy is lower than that commonly observed in HCV mono-infected patients. This is, at least in part, due to the very high treatment drop out rates. Ribavirin in combination with HAART is associated with particular side effects such as mitochondrial toxicity. Therefore, vigilant monitoring of patients during therapy, in specialist centers is essential. Pegylated interferon (PEG-IFN) plus ribavirin is particularly promising as it is easier to administer and will probably become the treatment of choice for co-infected patients. A SVR is associated with genotype 2 and 3, in addition to a high CD4+ cell count and a low HCV load prior to therapy. The progression of HCV related liver disease in HIV positive patients is faster than in subjects with HCV infection alone. As a result, there is an increasing incidence of cirrhosis and end-stage liver disease in co-infected patients. Liver transplantation is being evaluated in many centers. To date the experiences are very limited but encouraging in term of survival rate.

Background Pegylated interferon (PEG-IFN) and ribavirin is the most effective treatment for chronic hepatitis C virus (HCV) hepatitis, but the rate of sustained virological response (SVR) remains approximately 50%, and 15-20% of all treated patients have a virological relapse after completing the treatment. Studies on the SVR have failed to discriminate between non-responders and relapsers. Aims To identify the risk factors for relapse among patients with an end-of-treatment response (ETR). Methods We retrospectively analyzed 281 patients consecutively treated with PEG-IFN and ribavirin with a follow- up period of at least 24 weeks. The baseline details collected on each patient included demographic data, histological features, and biochemical profiles. Results Forty-six patients (16.4%) relapsed during the first 6 months of follow-up after discontinuing the therapy. Relapser patients were significantly older, had more steatosis, fibrosis, and showed significantly lower rapid virological response (RVR) rates compared with SVR patients. By logistic regression analysis, only the absence of RVR was found to be significantly associated with relapses in both subgroups of patients with genotypes 1 and 4 (p.004) and those with genotypes 2 and 3 (p.006). Severe fibrosis was also predictive of relapsing disease, but only for genotypes 2 and 3 patients (p.003). During the treatment, serum HCV-RNA decreased more rapidly in patients with SVR compared to non-responder and relapser patients (p.001). Interestingly, relapser patients exhibited an intermediate serum HCV-RNA decay during the first 4 weeks of therapy. Conclusion Among HCV patients treated with PEG-IFN and ribavirin, the absence of RVR was the most important independent predictor of relapse, independent of the HCV genotype. In the subgroup of genotypes 2 and 3 patients, the severity of fibrosis was also an important factor associated with the relapse rate.

Background / Aims The rapid decline in hepatitis C virus RNA is crucial for determining the outcome of therapy in patients with genotype 1 chronic hepatitis C. However, the variables influencing the early phase of viral decay are still largely unexplored. We aimed to assess which pre-treatment variable may predict rapid virologic response (RVR) and sustained virologic response (SVR). Methods We evaluated 90 consecutive non-diabetic patients with genotype 1 chronic hepatitis C without cirrhosis, treated with peginterferon alpha-2b plus ribavirin. Viral load (COBAS Amplicore, Roche) was measured at 1, 4 and 12 weeks after starting treatment, and then 24 weeks after the end of treatment. Results The overall SVR was 47%. The SVR in patients with RVR was 100%. Age, GGT levels, viral load, steatosis, fibrosis and HOMA-IR were significantly associated with RVR in univariate analysis. After logistic regression, HOMA-IR proved to be the strongest independent predictor of RVR (OR 0.37, 95% CI: 0.16–0.89; p =0.027), whereas fibrosis had a weaker independent association with RVR (OR 0.32, 95% CI: 0.1–1.04; p =0.057). Among the eight pre-treatment variables, both BMI and steatosis were significantly associated with HOMA-IR, either in univariate or in multivariate analyses. Conclusions Our data suggest that insulin resistance is strongly associated with RVR, thus reflecting the important role played by metabolic factors in the early phase of viral kinetics. HOMA-IR would appear to be a useful tool in predicting RVR and should be evaluated at baseline in all chronic hepatitis C patients before initiating antiviral treatment.

Prevalence and impact of occult HBV infection in HIV positive patients is controversial. The aims of this study were to determine the prevalence of occult HBV infection and its impact on histological and virological parameters. 52 HIV/HCV (but HBsAg-negative) co-infected patients, 29 HBsAg and anti-HCV negative chronic hepatitis, and 20 HBsAg positive chronic hepatitis controls were studied. DNA was extracted from frozen biopsies and amplified with primers for S, C and X regions, and for (ccc) HBV-DNA. Sera were tested for HBV-DNA with two quantitative assays (Cobas Amplicor HBV Monitor, and the real-time COBAS (r) Taqman HBV Test, Roche Diagnostics, UK). Occult HBV infection was detected in 7 (13.4%) liver biopsies of the study group, and in none case of the non viral chronic hepatitis group (p=0.04). All serum samples were HBV-DNA negative with Cobas Amplicor HBV monitor assay, while 3 cases were found positive with real time PCR. Statistical analysis didn't show any impact of occult HBV infection on liver histology, CD4+ cells count, HIV and HCV load, and ALT levels. Occult B infection is relatively frequent in HIV/HCV co-infected patients, and is underestimated by common HBV-DNA serological assays. However, it doesn't seem to exert a relevant impact.

In the northern part of Friuli Venezia Giulia Region (Italy), in the Carnic Alps, above the Cercevesa stream, an active mass movement has been recently identified and classified as Deep Seated Gravitational Slope Deformation (DSGSD). The phenomenon covers an area of about 0.5 km2 and involves limestones overlying sandstones and mudstones. The most evident morphological feature of the Cercevesa DSGSD is a double-crested ridge on the top of the slope. The first measurements, recorded since June 2008, show a constant opening rate of about 58 cm/yr, a really rare value for gravitational phenomena in the Alps. To detect the triggering factor, geomorphological data, meteorological time series (rainfall, snowfall and temperature) and seismological data have been analyzed. The comparative analysis highlighted that the persistent rainfall of mid-November 1990 can be identified as the root cause of the phenomenon.

We used optical tweezers, video imaging, immunocytochemistry and a variety of inhibitors to analyze the role of Rac1 in the motility and force generation of lamellipodia and filopodia from developing growth cones of isolated Dorsal Root Ganglia neurons. When the activity of Rac1 was inhibited by the drug EHop-016, the period of lamellipodia protrusion/retraction cycles increased and the lamellipodia retrograde flow rate decreased; moreover, the axial force exerted by lamellipodia was reduced dramatically. Inhibition of Arp2/3 by a moderate amount of the drug CK-548 caused a transient retraction of lamellipodia followed by a complete recovery of their usual motility. This recovery was abolished by the concomitant inhibition of Rac1. The filopodia length increased upon inhibition of both Rac1 and Arp2/3, but the speed of filopodia protrusion increased when Rac1 was inhibited and decreased instead when Arp2/3 was inhibited. These results suggest that Rac1 acts as a switch that activates upon inhibition of Arp2/3. Rac1 also controls the filopodia dynamics necessary to explore the environment.

Underground caves bear a natural hazard due to their possible evolution into a sink hole. Mapping of all existing caves could be useful for general civil usages as natural deposits or tourism and sports. Natural caves exist globally and are typical in karst areas. We investigate the resolution power of modern gravity campaigns to systematically detect all void caves of a minimum size in a given area. Both aerogravity and terrestrial acquisitions are considered. Positioning of the gravity station is fastest with GNSS methods the performance of which is investigated. The estimates are based on a benchmark cave of which the geometry is known precisely through a laser-scan survey. The cave is the Grotta Gigante cave in NE Italy in the classic karst. The gravity acquisition is discussed, where heights have been acquired with dual-frequency geodetic GNSS receivers and Total Station. Height acquisitions with non-geodetic low-cost receivers are shown to be useful, although the error on the gravity field is larger. The cave produces a signal of −1.5 × 10−5 m/s2, with a clear elliptic geometry. We analyze feasibility of airborne gravity acquisitions for the purpose of systematically mapping void caves. It is found that observations from fixed wing aircraft cannot resolve the caves, but observations from slower and low-flying helicopters or drones do. In order to detect the presence of caves the size of the benchmark cave, systematic terrestrial acquisitions require a density of three stations on square 500 by 500 m2 tiles. The question has a large impact on civil and environmental purposes, since it will allow planning of urban development at a safe distance from subsurface caves. The survey shows that a systematic coverage of the karst would have the benefit to recover the position of all of the greater existing void caves.

PURPOSE An elevated frequency of the CCR5-Delta32 mutation in German patients with hepatitis C with viremia has been reported. The aim of the present study was to verify whether this mutation occurs in an Italian population with hepatitis C and whether it is an adverse host factor indicative of severity of liver disease and response to antiviral therapy. STUDY The authors amplified 189-bp (wild-type) and 157-bp (Delta32 deletion) fragments of the CCR5 gene by polymerase chain reaction in 130 patients with chronic hepatitis C. Comparisons were drawn with 110 blood donors and 135 patients with primary biliary cirrhosis. RESULTS Four (3.1%) patients with chronic hepatitis C and 1 blood donor (0.9%) were CCR5-Delta32 homozygous, whereas there was no CCR5-Delta32 homozygosity among primary biliary cirrhosis patients; the wild-type gene was present in a similar percentage in the 3 groups of patients without any significant difference (83.1% vs 90.4% vs 83.6%, respectively). Among the patients with chronic hepatitis C, no significant correlation was found between CCR5-Delta32 homozygosity and the following parameters: histologic grade/stage, hepatitis C virus genotype, viral load, serum aspartate aminotransferase, serum alanine aminotransferase, and serum gamma-glutamyltransferase. Ninety-five patients received a standard antiviral protocol with pegylated interferon (PEG Intron)+ribavirin; a sustained response was achieved in 59 patients (62.1%), and the remainder did not respond or experienced a relapse. Response to treatment was not influenced by CCR5-Delta32 deletion. CONCLUSION No greater frequency of CCR5-Delta32 homozygosity was seen in an Italian population of patients with chronic hepatitis C. This mutation does not seem to influence either the overall severity of liver disease or the response to viral therapy.

Objectives The aims of this study were to evaluate the prevalence and impact of Chlamydia pneumoniae infection in HIV-positive patients and to establish the relationship between C. pneumoniae infection and lipid profile. Methods Detection of C. pneumoniae was by polymerase chain reaction (PCR) on Peripheral Blood Mononuclear Cells (PBMCs) collected from 97 HIV-positive patients. Samples were collected after overnight fast in EDTA-treated tubes. On the same day, patients were also tested for routine chemistry, HIV viral load, CD3, CD8 and CD4 cell counts and lipid profile [cholesterol, high-density lipoproteins (HDLs), low-density lipoproteins (LDLs) and triglycerides]. Results The overall prevalence of C. pneumoniae was 39%. The prevalence of C. pneumoniae was inversely related to the CD4 lymphocyte count (P=0.03). In the naive group, C. pneumoniae-positive patients had both significantly higher HIV load (71 021±15 327 vs. 14 753±14 924 HIV-1 RNA copies/mL; P=0.03) and lower CD4 cell count (348.0±165.4 vs. 541.7±294.8; P=0.04) than C. pneumoniae-negative patients. Moreover, treatment-naive patients with C. pneumoniae infection had significantly higher mean levels of cholesterol (185.3±56.2 vs. 124.8±45.9 mg/dL; P=0.01), triglycerides (117.2±74.7 vs. 68±27.6 mg/dL; P=0.04) and LDL (122.4±60.1 vs. 55.6±58 mg/dL; P=0.05) than C. pneumoniae-negative patients. Conclusions These data indicate that, in HIV-positive subjects, C. pneumoniae infection is relatively frequent and is associated with both low CD4 cell count and high HIV load. Furthermore, C. pneumoniae appears to be associated with hyperlipidaemia and might therefore represent a further risk factor for cardiovascolar disease in HIV-positive patients.

Background: the frequency and the impact of occult HBV infection in patients with chronic hepatitis C infection is still a matter of some controversy. Objectives: our aim was to evaluate the prevalence of occult HBV infection and assess its impact on liver biochemistry, HCV viral titre, liver histology and on outcome of therapy in patients with chronic hepatitis C. Study design: paired liver biopsies and serum samples were collected from 51 patients (84% IVDUS) with HBsAg negative chronic hepatitis C, and tested for HBV-DNA with nested PCR. Liver biopsies were further studied histologically, with morphometric analyses and immunostaining techniques. Twenty-five were treated with alpha Interferon and ribavirin and followed for at least 18 months. Results: HBV DNA was detected in 29.4% of liver tissue specimens and in only one (1.9%) serum sample. Three liver specimens were positive for surface gene, nine for core gene, three for both and none for the X gene. No significant difference in mean transaminase values, HCV viral titre, HCV genotype, or grading and staging and morphometric analysis was observed in patients with or without HBV DNA. Moreover, all 51 liver specimens were negative for both HBsAg and HBcAg. Sustained response to combination therapy was achieved in 40% of patients with and in 53% of patients without HBV DNA in the liver specimens (P=NS). Conclusions: HBV DNA is frequently found in the liver of patients with chronic hepatitis C. However, the lack of any significant impact on HCV viral titre, liver enzymes, histological parameters and response to therapy, suggests that in most cases HBV DNA detected in the liver by PCR may be either an integrated or low level replicative form.

Type 1 diabetes mellitus is the result of an autoimmune process characterized by pancreatic beta cell destruction. It has been reported that chronic hepatitis C infection is associated with type 2 diabetes mellitus, but not with type 1. Although the prevalence of markers of pancreatic autoimmunity in hepatitis C virus-positive patients is not significantly different to that reported in the general population, it increases during alpha-interferon therapy from 3 to 7%, probably due to the immunostimulatory effects of this cytokine. To date, 31 case reports of type 1 diabetes mellitus related to interferon treatment have been published. Type 1 diabetes mellitus occurs more frequently in patients treated for chronic hepatitis C than for other conditions and is irreversible in most cases. In 50% of these patients, markers of pancreatic autoimmunity predated treatment, the majority of cases having a genetic predisposition. Thus, in predisposed individuals, alpha-interferon can either induce or accelerate a diabetogenic process already underway. We suggest that islet cell autoantibodies and glutamic acid decarboxylase autoantibodies should be investigated before and during interferon treatment in order to identify subjects at high risk of developing type 1 diabetes mellitus.

Although hepatitis C virus (HCV) is a recognized cause of circulating cryoglobulins, the role of human immunodeficiency virus (HIV) in the pathogenesis of cryoglobulinemia has not been investigated extensively. To evaluate the prevalence of circulating cryoglobulins and to assess the relationship with clinical and virological parameters, 162 HIV-positive subjects (84 anti-HCV(+)) were tested for cryoglobulins, C3, C4, RF, autoantibodies, HIV-viral titer, and CD4(+) count. Anti-HCV-positive subjects were tested for HCV-RNA, HCV-viral titer, and HCV genotype. All patients were examined for the presence of signs or symptoms of vasculitis and tested for cryoglobulins using a standard biochemical assay. Cryoglobulins were found in 30 (18.5%) cases. Of the 30 positive cases, 29 (96.7%) were anti-HCV-positive and 28 (93.3%) HCV-RNA-positive. The presence of cryoglobulins was significantly associated (P < 0.01) with HCV-RNA positivity (OR = 27), liver cirrhosis (OR = 16), decreased levels of C3 (OR = 8.6), C4 (OR = 13.6), increased levels of IgG and IgM (OR = 6.1 and 7.9, respectively), and RF positivity (OR = 6.3), but was unrelated to CD4(+) cell count, HIV viral load, diagnosis of AIDS, HCV viral load and the presence of autoantibodies. Interestingly, the presence of cryoglobulins was not significantly associated with signs and symptoms commonly associated with cryoglobulinemia. In conclusion, HIV infection does not seem to play a significant role in the production of circulating cryoglobulins, which strongly correlates with HCV co-infection and liver cirrhosis. Typical signs and symptoms of cryoglobulinemia do not correlate with the detection of circulating cryoglobulins in HIV and HCV patients.

Differentiating neurons process the mechanical stimulus by exerting the protrusive forces through lamellipodia and filopodia. We used optical tweezers, video imaging and immunocytochemistry to analyze the role of non-muscle myosin-II on the protrusive force exerted by lamellipodia and filopodia from developing growth cones (GCs) of isolated Dorsal Root Ganglia (DRG) neurons. When the activity of myosin-II was inhibited by 30 μM Blebbistatin protrusion/retraction cycles of lamellipodia slowed down and during retraction lamellipodia could not lift up axially as in control condition. Inhibition of actin polymerization with 25 nM Cytochalasin-D and of microtubule polymerization with 500 nM Nocodazole slowed down the protrusion/retraction cycles, but only Cytochalasin-D decreased lamellipodia axial motion. The force exerted by lamellipodia treated with Blebbistatin decreased by 50%, but, surprisingly, the force exerted by filopodia increased by 20-50%. The concomitant disruption of microtubules caused by Nocodazole abolished the increase of the force exerted by filopodia treated with Blebbistatin. These results suggest that; i- Myosin-II controls the force exerted by lamellipodia and filopodia; ii- contractions of the actomyosin complex formed by filaments of actin and myosin have an active role in ruffle formation; iii- myosin-II is an essential component of the structural stability of GCs architecture.