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Forests around the world are facing climate change. Increased drought stress and severe heat waves in recent decades have negatively impacted on forest health, making them more vulnerable and prone to dieback and mortality phenomena. Although the term vulnerability is used to indicate an increased susceptibility of forests to climate change with a worsening of their vigour status that can compromise their ability to respond to further climate extreme events, there are still uncertainties on how to evaluate it. Indeed, evaluation of forest vulnerability is complex both because of some critical issues in the estimation methods used and because of the multiple factors influencing the response of forests to ongoing climate change. A way to assess the vulnerability to environmental stresses is by combining remote sensing and dendroecological data. However, these two approaches entail multiple uncertainties, including growth/photosynthetic relationships, carbon allocation dynamics, biases of tree-ring data and noisy remote sensing data, which require further clarification for proper monitoring of pre- and post-drought forest trajectories. Our review aims to create an overview of the current literature and knowledge to understand the critical issues, needs and possible solutions that forest vulnerability research is addressing. We focus on Mediterranean forests located in a climate warming hotspot and showing a high vulnerability to increased aridification.

Floodplain forests are sensitive to climate warming and increased drought, as showed by recent oak (Quercus robur) dieback and mortality episodes. However, a comprehensive comparison of coexisting tree species under different climate settings or biomes are lacking. Herein, we compared growth rates, growth responses to climate and drought severity, and modeled climate mediated growth of oak and three coexisting tree species (ash, Fraxinus angustifolia; alder, Alnus glutinosa; elm, Ulmus minor). Two floodplain forests subjected to cooler (temperate climate, Ticino) and warmer (Mediterranean climate, Bosco Pantano) conditions in northern and southern Italy, respectively, were analyzed. Ash seemed to be the most sensitive to drought, particularly at the Mediterranean site where oak and elm growth were also negatively affected by water shortages. Alder appeared to be the least sensitive species in terms of growth variability to drought under both temperate and Mediterranean climate conditions. Furthermore, the growth model revealed the influence of soil moisture in spring and summer on the constrained growth of ash and oak and illustrated how oak growth could be severely reduced during drastic hotter droughts. Alder seemed to be the most drought-resistant species under both environmental conditions. These results could represent the first attempts in documenting the ecological consequences of drought in terms of projected climate trends in less investigated Mediterranean floodplain forests. Furthermore, these results highlight how climate and tree-ring data combined with growth models could be useful tools to detect early warning signals of growth decline and impending dieback in floodplain forests in response to dry spells.

Background & aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compare

Background & Aims: The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy. Methods: Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score. Results: Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5–4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal. Conclusion: Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin – 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration. Lay

In the original publication of this article, after the name of the last author, the wording on behalf of the Italian Liver Transplant Working Group is missing.

Several dieback episodes triggered by droughts are revealing the high vulnerability of Mediterranean forests, manifested as declines in growth, increased defoliation, and rising mortality rates. Understanding forest responses to such climate extreme events is of high priority for predicting their future vegetation dynamics. We examined how remotely sensed measures of vegetation activity (NDVI, Normalized Difference Vegetation Index) and radial growth (BAI, basal area increment) responded to climate extreme events. We considered tree (Pinus sylvestris, Quercus pubescens, Quercus frainetto) and shrub (Juniperus phoenicea) populations from Italy and Spain showing recent dieback phenomena. Two components of drought, namely elevated atmospheric demand (VPD, vapor pressure deficit) and low soil moisture were analyzed in nearby stands showing or not showing dieback symptoms. Dieback stands exhibited lower NDVI values than non-dieback stands. NDVI and BAI were positively related in all sites except for the dieback stand of Q. frainetto that was negatively related. Such NDVI-BAI linkages were related to specific time windows, which could be useful for identifying when climatic conditions have the greatest influence on vegetation. Growth decline occurred in response to increasing VPD, but responses differed among species. J. phoenicea was the most negatively impacted by higher VPD, whereas oaks responded to soil moisture. A high VPD was related to stronger growth reduction in dieback P. sylvestris trees regardless of soil moisture changes. We highlighted that coupling between proxies of forest productivity (NDVI, BAI) allows better understanding and forecasting of drought-induced dieback phenomena in forests and shrublands. Scaling up from tree to stand levels might be feasible when using the maximum growing season NDVI, which can be applied for retrospective modeling of the impact of drought stress on forest productivity and tree growth.

Background: Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. Methods: We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008–000625–19, and ClinicalTrials.gov, number NCT01288794. Findings: From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40–0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3–4 non-liver related adverse events. Interpretation: In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. Funding: Italian Medicine Agency.

corporate social responsibility through the lenses of international soft law. An empirical analysis

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Attraverso i materiali d'archivio (Fondazione Mondadori e privato dell'autore) il saggio ricostruisce la nascita del romanzo, opera prima di castellaneta, e le sue traveresie editoriali. I materiali d'archivio sono offetri per la prima volta e riportati integralmente

End-stage liver disease related to HCV infection is the most common indication for liver transplantation both in Europe and in USA (; ). The results of liver transplantation for this indication are negatively affected by the high rate of viral recurrence which, through an accelerated rate of disease progression, significantly impairs patient and graft survival. Given this scenario, post-transplant viral eradication should be identified as a primary goal. At present, a combined regimen with pegylated interferon and ribavirin leads to sustained virological response (SVR) in approximately 30% of transplanted patients, which is significantly lower than in immunocompetent subjects. The main problem lies in the high rate of side effects which leads a significant proportion of patients to not receive appropriate therapy. Moreover, in view of the immunological activity of interferon, transplanted patients are exposed to additional immunological risks. Thus, role and efficacy of antiviral therapy in HCV recurrent hepatitis is still under debate. Nevertheless, a progressive amount of data from field practice are now demonstrating that SVR after post-transplant antiviral treatment is associated with a significant benefit on patient and graft survival and is the most relevant modifier of the natural history of HCV recurrent disease after liver transplantation.

Background: Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses. Methods: Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test. Results: After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected. Conclusions: This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis.

Background: Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses. Methods: Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test. Results: After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected. Conclusions: This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis.

Respirable particles from environmental or occupational air pollution are continuously inhaled and part of them is retained in the lungs over time. Accumulated particles may induce various respiratory diseases (pneumoconiosis, lung granulomatosis, alveolar proteinosis,). Most of these diseases are dose related. Since it is often difficult to obtain a thorough exposure history from the patients, mineralogical analysis of the particles recovered from their lungs can be used to get individual estimates of previous exposures. Compared to the numerous studies about asbestos burden in lungs, systematic data about the non-fibrous mineral particles (NFPs) contained in lung samples (bronchoalveolar lavage fluids (BAL) or lung tissue (LT)) are currently scarce. This is perhaps due to the complexity and diversity of the analytical methods (light and electron microscopy, x-ray diffraction) required to analyse particles in the submicron range and to the lack of specific markers for routine analysis. Other obstacles are the variety of particles to be analysed and the existence of a background burden of NFPs in the lungs of everyone which may interfere with the particles directly related to the exposure or disease under investigation. Our experience with NFPs analysis will be summarized and compared to the data available from the literature. From one to over 20 different particle types can be detected in lung samples by analytical transmission electron microscopy. The most frequent are silica, silicates (including clay minerals), iron compounds and titanium oxide. Particle sizes are log normally distributed. Geometric mean diameter range from 0.21 to 1.13 µm. Considering the influence of particle type on particle size, the following gradation can be established; Ø metallic compounds < Ø non lamellar silicates (silica, feldspar, siliceous flyash,) < Ø lamellar silicates (kaolinite, illite, mica, talc, chlorite). NFPs concentrations range from X*104 to 107 P/ml in BAL and from 109 t, info:eu-repo/semantics/nonPublished

Use of asbestos is now banned in many industrialized countries, but health consequences are still expected for at least two decades. Moreover, exposure to asbestos currently continues in several emerging countries. Asbestos-related diseases are usually the consequence of occupational exposures, but cases occurring from para-occupational, bystander or intra-mural exposures were also reported. In rural areas of several countries, fibres naturally occurring in local soils are responsible for a high incidence of asbestos diseases. Health effects of asbestos include malignant and non-malignant lesions of the lung and pleura, and more rarely peritoneum. It is often necessary to assess past exposures to asbestos for clinical, epidemiological, occupational health or even legal purposes. The difficulties and uncertainties associated with the use of occupational histories, job exposure matrixes or calculations from specific exposure databases have led to investigate the capabilities of fiber analysis in lung samples. Key points related to this topic will be reviewed here. Guidelines about technical aspects of fiber analysis and rules to interpret results were published by a workgroup of the European Respiratory Society (1). Evidence of exposure can be obtained by demonstrating elevated levels of asbestos bodies or fibres by light or electron microscopy in samples of lung tissue, bronchoalveolar lavage fluid or sputum. Relevant data are sought about the fiber types present, their amounts, their sizes, composition and crystalline structure and about their importance as aetiological agent. The measured fiber burdens integrate both phenomena of lung deposition and clearance. Compared to amphibole asbestos, chrysotile has a much lower biopersistance and evaluation of past exposures to this variety of asbestos by analysing lung samples is difficult. Interestingly, chrysotile elementary fibrils are morphologically similar to sepiolite and attapulgite fibrils. There are different dos, info:eu-repo/semantics/nonPublished

Respirable particles from environmental or occupational air pollution are continuously inhaled and part of them is retained in the lungs over time. Accumulated particles may induce various respiratory diseases (pneumoconiosis, lung granulomatosis, alveolar proteinosis,). Most of these diseases are dose related. Since it is often difficult to obtain a thorough exposure history from the patients, mineralogical analysis of the particles recovered from their lungs can be used to get individual estimates of previous exposures. Compared to the numerous studies about asbestos burden in lungs, systematic data about the non-fibrous mineral particles (NFPs) contained in lung samples (bronchoalveolar lavage fluids (BAL) or lung tissue (LT)) are currently scarce. This is perhaps due to the complexity and diversity of the analytical methods (light and electron microscopy, x-ray diffraction) required to analyse particles in the submicron range and to the lack of specific markers for routine analysis. Other obstacles are the variety of particles to be analysed and the existence of a background burden of NFPs in the lungs of everyone which may interfere with the particles directly related to the exposure or disease under investigation. Our experience with NFPs analysis will be summarized and compared to the data available from the literature. From one to over 20 different particle types can be detected in lung samples by analytical transmission electron microscopy. The most frequent are silica, silicates (including clay minerals), iron compounds and titanium oxide. Particle sizes are log normally distributed. Geometric mean diameter range from 0.21 to 1.13 µm. Considering the influence of particle type on particle size, the following gradation can be established; Ø metallic compounds < Ø non lamellar silicates (silica, feldspar, siliceous flyash,) < Ø lamellar silicates (kaolinite, illite, mica, talc, chlorite). NFPs concentrations range from X*104 to 107 P/ml in BAL and from 109 t, info:eu-repo/semantics/nonPublished

Use of asbestos is now banned in many industrialized countries, but health consequences are still expected for at least two decades. Moreover, exposure to asbestos currently continues in several emerging countries. Asbestos-related diseases are usually the consequence of occupational exposures, but cases occurring from para-occupational, bystander or intra-mural exposures were also reported. In rural areas of several countries, fibres naturally occurring in local soils are responsible for a high incidence of asbestos diseases. Health effects of asbestos include malignant and non-malignant lesions of the lung and pleura, and more rarely peritoneum. It is often necessary to assess past exposures to asbestos for clinical, epidemiological, occupational health or even legal purposes. The difficulties and uncertainties associated with the use of occupational histories, job exposure matrixes or calculations from specific exposure databases have led to investigate the capabilities of fiber analysis in lung samples. Key points related to this topic will be reviewed here. Guidelines about technical aspects of fiber analysis and rules to interpret results were published by a workgroup of the European Respiratory Society (1). Evidence of exposure can be obtained by demonstrating elevated levels of asbestos bodies or fibres by light or electron microscopy in samples of lung tissue, bronchoalveolar lavage fluid or sputum. Relevant data are sought about the fiber types present, their amounts, their sizes, composition and crystalline structure and about their importance as aetiological agent. The measured fiber burdens integrate both phenomena of lung deposition and clearance. Compared to amphibole asbestos, chrysotile has a much lower biopersistance and evaluation of past exposures to this variety of asbestos by analysing lung samples is difficult. Interestingly, chrysotile elementary fibrils are morphologically similar to sepiolite and attapulgite fibrils. There are different dos, info:eu-repo/semantics/nonPublished

Gli orientamenti artistico letterari del cardinale Federico Borromeo (poesia pastorale, petrarchismo spirituale e gusto erudito) si ritrovano nelle linee della produzione lirica lombarda di primo Seicento. Al proposito si analizzano i versi di Luca Pastrovicchi. Sintomatiche anche le poesie del ligure Scipione della Cella (edite a Milano nel 1609), le poesie 'lombarde' di Tommaso Stigliani, la formazione pavese di Girolamo Preti e, infine, gli insegnamenti di Erycius Puteanus, padre del laconismo moderno.

Gli orientamenti artistico letterari del cardinale Federico Borromeo (poesia pastorale, petrarchismo spirituale e gusto erudito) si ritrovano nelle linee della produzione lirica lombarda di primo Seicento. Al proposito si analizzano i versi di Luca Pastrovicchi. Sintomatiche anche le poesie del ligure Scipione della Cella (edite a Milano nel 1609), le poesie 'lombarde' di Tommaso Stigliani, la formazione pavese di Girolamo Preti e, infine, gli insegnamenti di Erycius Puteanus, padre del laconismo moderno.