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Importance: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol., Objective: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver-related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra-hepatic cancers (EHC)., Data Sources and Study Selection: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta-analysis was performed using random-effects modelling., Results: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random-effect OR 1.12, 95% CI 1.04-1.21, p = .004) and CV mortality (random-effect OR 1.15, 95% CI 1.04-1.26, p = .004), and a marginal trend towards higher rates of developing CKD (random-effect OR 1.06, 95% CI 1.00-1.12, p = .058) and EHC events (random-effect OR 1.11, 95% CI 1.00-1.23, p = .052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta-regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD., Conclusions and Relevance: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

This study investigates the socio-economic and environmental drivers shaping renewable energy demand and supply within a meso-level setting (Italian regions, 2004-2020). Employing a panel vector error correction mechanism (PVECM) and an integrative biplot analysis, the research outcomes reveal a market equilibrium between demand and supply in the short and long run. Human capital accumulation is identified as pivotal in driving the renewable energy transition. Significant regional heterogeneities indicate challenges in achieving convergence towards sustainability and socio-economic development and well-being. Key empirical implications include enhancing education and vocational training to strengthen human capital and implementing tailored regional strategies for sustainable infrastructure development. These findings support policymakers in formulating targeted policies for a resilient, balanced energy future and addressing regional disparities in renewable energy adoption., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mattia De Rosa reports financial support was provided by 10.13039/501100000780European Commission. No conflicts If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Economic inequality does not encounter strong protests even though individuals are generally against it. One potential explanation of this paradox is that individuals do not perceive inequality as caused by intentional agents, which, in line with the Theory of Dyadic Morality (Schein & Gray, 2018), should prevent its assessment as immoral and consequently dampen moral outrage and collective action. Across three studies, we test and confirm this hypothesis. In Studies 1 (N = 395) and 2 (N = 337), the more participants believed that inequality is human driven and caused by intentional agents, the more they moralized inequality, felt outraged and wanted to engage in collective action. This was confirmed in Study 3 (N = 243) through an experimental design. Thus, our research shows that agent perception is crucial in the moralization of economic inequality and, more broadly, that morality can be a powerful motivator and effectively mobilize people to action., (© 2024 British Psychological Society.)

The hydrophobic effect is the main factor that drives the folding of polypeptide chains. In this study, we have examined the influence of the hydrophobic effect in the context of the main mechanical forces approach, mainly in relation to the establishment of specific interplays, such as hydrophobic and CH-π cloud interactions. By adopting three oligopeptides as model systems to assess folding features, we demonstrate herein that these finely tuned interactions dominate over electrostatic interactions, including H-bonds and electrostatic attractions/repulsions. The folding mechanism analysed here demonstrates cooperation at the single-residue level, for which we propose the terminology of "single residues cooperative folding". Overall, hydrophobic and CH-π cloud interactions produce the main output of the hydrophobic effect and govern the folding mechanism, as demonstrated in this study with small polypeptide chains, which in turn represent the main secondary structures in proteins.

Airway epithelium represents a physical barrier against toxic substances and pathogens but also presents pattern recognition receptors on the epithelial cells that detect pathogens leading to molecule release and sending signals that activate both the innate and adaptive immune responses. Thus, impaired airway epithelial function and poor integrity may increase the recurrence of infections. Probiotic use in respiratory diseases as adjuvant of traditional therapy is increasingly widespread. There is growing interest in the use of non-viable heat-killed bacteria, such as tyndallized bacteria (TB), due to safety concerns and to their immunomodulatory properties. This study explores in vitro the effects of a TB blend on the immune activation of airway epithelium. 16HBE bronchial epithelial cells were exposed to different concentrations of TB. Cell viability, TB internalization, TLR2 expression, IL-6, IL-8 and TGF-βl expression/release, E-cadherin expression and wound healing were assessed. We found that TB were tolerated, internalized, increased TLR2, E-cadherin expression, IL-6 release and wound healing but decreased both IL-8 and TGF-βl release. In conclusion, TB activate TLR2 pathway without inducing a relevant pro-inflammatory response and improve barrier function, leading to the concept that TB preserve epithelial homeostasis and could be used as strategy to prevent and to manage respiratory infection, exacerbations included., (© 2024. The Author(s).)

With the aim of providing evidence about doctor-managers' resilience during the Covid-19 pandemic, this study analyzes the characteristics of 114 doctor-managers operating within the Italian National Health Service (NHS). During the emergency, doctor-managers had to show adaptive capacities to deal with unexpected situations and develop new paradigms, procedures, and quick responses to patients' needs. This is in line with resilience, and in this perspective, it is crucial to investigate resilience determinants. The paper, therefore, provides an identikit of the resilient doctor-manager. The research was conducted between November and December 2020. Primary data were collected through an online questionnaire consisting of six sections. Participation was voluntary and anonymous. Data were analyzed using quantitative techniques and employing Stata 16. Confirmatory Factor Analysis was employed to test construct validity and scale reliability. Results show that increasing levels of individual resilience are related to increasing levels of managerial identity. Moreover, physicians' individual resilience has a positive association with commitment, knowledge diffusion, and Evidence-Based Medicine adoption. Finally, physicians' individual resilience has a negative association with their role in the university, their specialty, and their gender. The study suggests some practical implications for healtcare organizations. In general, career paths are decided primarily on competency assessment, while an important role should be devoted to behavioral characteristics. Furthermore, organizations should take care of the levels of individual commitment and encourage professional networking because both help doctor-managers cope with uncertainty. The originality of the study relies on a fresh look at all previous work. There are currently few contributions in the literature to explore and investigate resilience elements in doctor-managers during the pandemic era., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In meta-analysis literature, there are several checklists describing the procedures necessary to evaluate studies from a qualitative point of view, whereas preliminary quantitative and statistical investigations on the "combinability" of trials have been neglected. Covariate balance is an important prerequisite to conduct meta-analysis. We propose a method to identify unbalanced trials with respect to a set of covariates, in presence of covariate imbalance, namely when the randomized controlled trials generate a meta-sample that cannot satisfy the requisite of randomization/combinability in meta-analysis. The method is able to identify the unbalanced trials, through four stages aimed at achieving combinability. The studies responsible for the imbalance are identified, and then they can be eliminated. The proposed procedure is simple and relies on the combined Anderson-Darling test applied to the Empirical Cumulative Distribution Functions of both experimental and control meta-arms. To illustrate the method in practice, two datasets from well-known meta-analyses in the literature are used., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Attanasio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lung cancer frequently affects patients with Chronic Obstructive Pulmonary Disease (COPD). Cigarette smoke (CS) fosters cancer progression by increasing oxidative stress and by modulating epithelial-mesenchymal transition (EMT) processes in cancer cells. Formoterol (FO), a long-acting β2-agonist widely used for the treatment of COPD, exerts antioxidant activities. This study explored in a lung adenocarcinoma cell line (A549) whether FO counteracted the effects of cigarette smoke extract (CSE) relative to oxidative stress, inflammation, EMT processes, and cell migration and proliferation. A549 was stimulated with CSE and FO, ROS were evaluated by flow-cytometry and by nanostructured electrochemical sensor, EMT markers were evaluated by flow-cytometry and Real-Time PCR, IL-8 was evaluated by ELISA, cell migration was assessed by scratch and phalloidin test, and cell proliferation was assessed by clonogenic assay. CSE significantly increased the production of ROS, IL-8 release, cell migration and proliferation, and SNAIL1 expression but significantly decreased E-cadherin expression. FO reverted all these phenomena in CSE-stimulated A549 cells. The present study provides intriguing evidence that FO may exert anti-cancer effects by reverting oxidative stress, inflammation, and EMT markers induced by CS. These findings must be validated in future clinical studies to support FO as a valuable add-on treatment for lung cancer management.

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking., Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC., Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments., Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases., Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity., Competing Interests: Giuseppe Cabibbo participated in advisory board for Bayer, Eisai, Ipsen, and AstraZeneca. Ciro Celsa received speaker fees from Eisai, Ipsen, and MSD. David James Pinato received lecture fees from BMS, Roche, and EISAI; travel expenses from BMS and Bayer Healthcare; consulting fees from Mina Therapeutics, EISAI, Roche, Da Volterra, Ewopharma, and AstraZeneca; research funding (to the institution) from MSD, GSK, and BMS; grant funding from the Wellcome Trust Strategic Fund (PS3416) and from the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG Grant ID 25697); and support from the NIHR Imperial Biomedical Research Centre, the Imperial Experimental Cancer Medicine Centre (ECMC), and the Imperial College Tissue Bank. Calogero Cammà participated in the advisory board for Bayer, MSD/Merck, Ipsen, AstraZeneca, Roche, and Eisai. The other authors have no disclosure to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Mathematical models can improve the understanding of physiological systems behaviour, which is a fundamental topic in the bioengineering field. Having a reliable model enables researchers to carry out in silico experiments, which require less time and resources compared to their in vivo and in vitro counterparts. This work's objective is to capture the characteristics that a nonlinear dynamical mathematical model should exhibit, in order to describe physiological control systems at different scales. The similarities among various negative feedback physiological systems have been investigated and a unique general framework to describe them has been proposed. Within such a framework, both the existence and stability of equilibrium points are investigated. The model here introduced is based on a closed-loop topology, on which the homeostatic process is based. Finally, to validate the model, three paradigmatic examples of physiological control systems are illustrated and discussed: the ultrasensitivity mechanism for achieving homeostasis in biomolecular circuits, the blood glucose regulation, and the neuromuscular reflex arc (also referred to as muscle stretch reflex). The results show that, by a suitable choice of the modelling functions, the dynamic evolution of the systems under study can be described through the proposed general nonlinear model. Furthermore, the analysis of the equilibrium points and dynamics of the above-mentioned systems are consistent with the literature.

Background: Medical-scientific advances in maternal care gradually improved the health of mothers and new-borns. However, this has contributed to increasing levels of medicalization, defined as the overuse of medical interventions even in low-risk pregnancies and childbirths. In Italy pregnancy and birth still appear to be rather medicalized than in the rest of Europe. Moreover, the uneven distribution of these practice over the territory appears to be evident. The purpose of this article is to both highlight and explain the Italian peculiarity in terms of high medicalization of childbirth and its territorial variability., Theoretical Framework: The extensive literature on medicalization of childbirth was systematized by some scholars who use childbirth as a case study to distinguish four meanings of medicalization, by classifying them into two generations of theories. Alongside this literature several studies attempted to interpret differences in maternity model of care showing the important role played by path dependence., Results: In the European scenario, Italy stands out for its high percentage of cesarean sections, but also for its excessive recourse to antenatal visits during pregnancy and the application of interventions during labor and vaginal births. Going into regional detail, however, Italian situation appears rather uneven: relevant differences emerge in relation to medicalization of both pregnancy and birth., Discussion: The article explores the possibility that areas whit different sociocultural, economic, political and institutional background may have introjected different meanings of medicalization, thus reproducing different maternity models of care. In fact, the simultaneous presence, in Italy, of four different meanings of medicalization seems to be rooted. Even with some similar traits, different conditions and situations emerge in different geographical areas, leading to the prevalence of one meaning rather than another and resulting on different outcomes in terms of medicalization., Conclusion: The data presented in this article seem to deny the existence of a national maternity model of care and. On the contrary, they confirm the idea that medicalization is not necessarily linked to the different health conditions of mothers in different geographical areas and that a path dependent variable is able to explain it., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Spina.)

In this study, we estimate the effect of a negative labour market shock on individuals' levels of stress, anxiety, and depression. We use a dataset collected during the first wave of the Covid-19 pandemic, on a representative sample of citizens from Italy, Spain, and the United Kingdom, interviewed on three occasions. We measure stress, anxiety and depression and labour shocks using validated scales. Our research design is a standard difference-in-differences model: we leverage the differential timing of shocks to identify the impact on mental health. In our estimations, a negative labour shock increases the measure of stress, anxiety, and depression by 16% of a standard deviation computed from the baseline., (© The Author(s) 2023.)

Cannabis is the most widely used illicit drug in Western counties and its abuse is particularly high in male adolescents and young adults. Its main psychotropic component, the cannabinoid delta-9-tetrahydrocannabinol (Δ 9 -THC), interferes in the endogenous endocannabinoid system. This signaling system is involved in the control of many biological activities, including the formation of high-quality male gametes. Direct adverse effects of Δ 9 -THC in male reproduction are well known in both animal models and humans. Nevertheless, the possibility of long-term effects due to epigenetic mechanisms has recently been reported. In this review, we summarize the main advances in the field suggesting the need to pay attention to the possible long-term epigenetic risks for the reproductive health of cannabis users and the health of their offspring.

This study aimed to describe the incidence and characteristics of dog-bite injury hospitalizations (DBIH) in the largest administrative region of Italy (Sicily) over the 10-year period: 2012-2021. Four hundred and forty-nine cases were analyzed. Patients were divided into seven age groups: preschoolers (0-5 years), school-age children (6-12 years), teenagers (13-19 years), young adults (20-39 years), middle-aged adults (40-59 years), old adults (60-74 years), and the elderly (≥75 years). Association among categorical variables (age, gender, principal injury location) was evaluated using chi-square tests, and mean differences for normally distributed variables were assessed using one-way analysis of variance. Finally, a Poisson regression general linear model (GLM) analysis was used to model incidence data. The results revealed that the incidence of DBIH per 100,000 population increased from 0.648 in 2012 (95%CI 0.565-0.731) to 1.162 in 2021 (95%CI 1.078-1.247, P < 0.01). Incidence for both male and female victims also increased over the studied period ( P < 0.05). We found an increasing trend of incidence in young and middle-aged adults ( P < 0.05 and P < 0.005 respectively). Moreover, the most frequently injured age group by dogs was the preschooler group and, whilst we found a lower risk of being injured for males older than 20 years, no difference with females was observed. The location of lesions depended on the age group ( P < 0.001). The number of days of DBIH increased significantly with age ( P < 0.01). The increase of DBIH represents a public health problem that requires the development of preventive approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alberghina, Virga, Sottile, Buffa and Panzera.)

The trend towards digitalisation and technological innovation has reshaped the cultural and creative industries (CCIs) by changing the existing funding models and structures. The aim of this article is to explore the impact of cultural dimensions and policies on the adoption of reward-based crowdfunding as a new form of finance for firms in the CCIs in 12 different European countries during the 2015-2019 period. Our results show that national cultural dimensions and policies significantly affect the demand for cultural and creative crowdfunding. Specifically, the adoption of crowdfunding is broader in individualistic countries and in societies characterised by higher uncertainty avoidance, indulgence, short-term orientation, and lower levels of discrimination between genders. Furthermore, we find that the liberal welfare state model, characterised by limited government interference, market orientation, privatisation and a focus on self-responsibility, and the Southern European welfare model, based on a weak and inefficient state, increase the adoption of crowdfunding in the CCIs. The presence of a central ministry with cultural competence also increases the adoption of crowdfunding in the CCIs. Our findings show a U-shaped relationship between European grants and the demand for crowdfunding, mainly driven by a high or low European involvement within these sectors. We also identify a moderation effect of EU grants on the relationship between cultural dimensions and crowdfunding adoption, suggesting that the magnitude of this relationship depends on the amount of EU grants awarded in a specific country. As a robustness check, we run a set of Poisson regressions with correlated random effects (CREs), confirming our main results., Competing Interests: Conflict of interestAuthors declare that they have no conflict of interest., (© The Author(s) 2022.)

In this paper, we propose a new approach based on the fitting of a generalized linear regression model in order to detect points of change in the variance of a multivariate-covariance Gaussian variable, where the variance function is piecewise constant. By applying this new approach to multivariate waveforms, our method provides simultaneous detection of change points in functional time series. The proposed approach can be used as a new picking algorithm in order to automatically identify the arrival times of P- and S-waves in different seismograms that are recording the same seismic event. A seismogram is a record of ground motion at a measuring station as a function of time, and it typically records motions along three orthogonal axes (X, Y, and Z), with the Z-axis being perpendicular to the Earth's surface and the X- and Y-axes being parallel to the surface and generally oriented in North-South and East-West directions, respectively. The proposed method was tested on a dataset of simulated waveforms in order to capture changes in the performance according to the waveform characteristics. In an application to real seismic data, our results demonstrated the ability of the multivariate algorithm to pick the arrival times in quite noisy waveforms coming from seismic events with low magnitudes.

Tracking SARS-CoV-2 variants along with vaccinations are fundamental for severe COVID-19 disease prevention. A study was performed that focused on 43 patients with the SARS-CoV-2 infection who were admitted to the Emergency Department. RT-PCR-positive nasopharyngeal samples were sequenced using the MiSeq II system for variant detection. The main reason for Emergency Department admission was COVID-19 (67%), followed by other causes (33%); 51% patients were unvaccinated or vaccinated with a single dose and 49% had completed the vaccination course with two or three doses. Among the vaccinated group, 38% were admitted for COVID-19, versus 94.5% of the unvaccinated group. After admission, 50% of the vaccinated group and 36% of the unvaccinated group were discharged and allowed to go home, and 80% of the unvaccinated had no major comorbidities; 63% needed hospital admission and 5% required a stay in the Intensive Care Unit. Of these, 37% were vaccinated with 3 doses, 11% with two doses, 4% with a single dose, and 48% were unvaccinated. The 70% of the vaccinated patients who were admitted to hospital presented major comorbidities versus 38% of the unvaccinated group. Two unvaccinated patients that needed intensive care had relevant comorbidities and died. Genome sequencing showed the circulation of three omicron and two pure sub-lineages of omicron, including 22 BA.1, 12 BA.1.1, and 7 BA.2. Data showed the SARS-CoV-2 national and international migration patterns and how vaccination was useful for severe COVID-19 disease prevention.

The propagation of bankruptcy-induced shocks across domestic and global economies is sometimes very dramatic; this phenomenon can be modelled as a dynamical process in economic networks. Economic networks are usually scale-free, and scale-free networks are known to be vulnerable with respect to targeted attacks, i.e., attacks directed towards the biggest nodes of the network. Here we address the following question: to what extent does the scale-free nature of economic networks and the vulnerability of the biggest nodes affect the propagation of economic shocks? We model the dynamics of bankruptcies as the propagation of financial contagion across the banking sector over a scale-free network of banks, and perform Monte-Carlo simulations based on synthetic networks. In addition, we analyze the public data regarding the bankruptcy of US banks from the Federal Deposit Insurance Corporation. The dynamics of the shock propagation is characterized in terms of the Bank Failures Diffusion Index, i.e., the average number of new bankruptcies triggered by the bankruptcy of a single bank, and in terms of the Shannon entropy of the whole network. The simulation results are in-line with the empirical findings, and indicate the important role of the biggest banks in the dynamics of economic shocks.

The present paper is a review of the empirical studies on consumer acceptance of novel protein sources in Italy. The authors uncovered the most recent scientific contributions regarding novel plant-based products, and insect-based foodstuffs as well as cultivated meat, in the attempt of framing the main socio-economic drivers and challenges for each product with respect to consumers' perception and acceptance. Novel plant-based foods and edible insects represent the most viable alternatives in the nearest future, as already available (or very close to being) to the Italian consumer and more appealing to vegetarians and vegans. Nevertheless, some intrinsic characteristics of these products have yet to be accepted. The cultivated meat represents an animal source of protein, hence undesirable for some segments of consumers, although described as a good potential substitute for conventional meat. Nevertheless, institutional, technological and cultural barriers are yet to be solved before paving the way for its presence on Italian supermarket shelves., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes., Data Synthesis: A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms. A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%-23%;I 2  = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%-31%;I 2  = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH., Conclusion: This study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Since 2020, the COVID-19 pandemic represented an important worldwide burden. Well-structured surveillance by reliable and timely genomic data collection is crucial. In this study, a genomic monitoring analysis of all SARS-CoV-2 positive samples retrieved at the Fondazione Policlinico Universitario Campus Bio-Medico, in Rome, Italy, between December 2021 and June 2022, was performed. Two hundred and seventy-four SARS-CoV-2-positive samples were submitted to viral genomic sequencing by Illumina MiSeqII. Consensus sequences were generated by de novo assembling using the iVar tool and deposited on the GISAID database. Lineage assignment was performed using the Pangolin lineage classification. Sequences were aligned using ViralMSA and maximum-likelihood phylogenetic analysis was performed by IQ-TREE2. TreeTime tool was used to obtain dated trees. Our genomic monitoring revealed that starting from December 2021, all Omicron sub-lineages (BA.1, BA.2, BA.3, BA.4, and BA.5) were circulating, although BA.1 was still the one with the highest prevalence thought time in this early period. Phylogeny revealed that Omicron isolates were scattered throughout the trees, suggesting multiple independent viral introductions following national and international human mobility. This data represents a sort of thermometer of what happened from July 2021 to June 2022 in Italy. Genomic monitoring of the circulating variants should be encouraged considering that SARS-CoV-2 variants or sub-variants emerged stochastically and unexpectedly., Competing Interests: The authors declare no competing interests.

We estimate the effects of a chronic disease management program (CDMP) which adapts various supply-side interventions to specific demand-side conditions (disease-staging) for patients with chronic kidney disease (CKD). Using a unique dataset on the entire population of the Emilia-Romagna region of Italy with hospital-diagnosed CKD, we estimate the causal effects of the CDMP on adherence indicators and health outcomes. As CKD is a progressive disease with clearly-defined disease stages and a treatment regimen that can be titrated by disease severity, we calculate dynamic, severity-specific, indicators of adherence as well as several long-term health outcomes. Our empirical work produces statistically significant and sizeable causal effects on many adherence and health outcome indicators across all CKD patients. More interestingly, we show that the CDMP produces larger effects on patients with early-stage CKD, which is at odds with some of the literature on CDMP that advocates intensifying interventions for high-cost (or late-stage) patients. Our results suggest that it may be more efficient to target early-stage patients to slow the deterioration of their health capital. The results contribute to a small, recent literature in health economics that focuses on the marginal effectiveness of CDMPs after controlling either for supply- or demand-side sources of heterogeneity., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The current Covid-19 pandemic is severely affecting public health and global economies. In this context, accurately predicting its evolution is essential for planning and providing resources effectively. This paper aims at capturing the dynamics of the positivity rate (PPR) of the novel coronavirus using the Heterogeneous Autoregressive (HAR) model. The use of this model is motivated by two main empirical features arising from the analysis of PPR time series: the changing long-run level and the persistent autocorrelation structure. Compared to the most frequently used Autoregressive Integrated Moving Average (ARIMA) models, the HAR is able to reproduce the strong persistence of the data by using components aggregated at different interval sizes, remaining parsimonious and easy to estimate. The relative merits of the proposed approach are assessed by performing a forecasting study on the Italian dataset. As a robustness check, the analysis of the positivity rate is also conducted by considering the case of the United States. The ability of the HAR-type models to predict the PPR at different horizons is evaluated through several loss functions, comparing the results with those generated by ARIMA models. The Model Confidence Set is used to test the significance of differences in the predictive performances of the models under analysis. Our findings suggest that HAR-type models significantly outperform ARIMA specifications in terms of forecasting accuracy. We also find that the PPR could represent an important metric for monitoring the evolution of hospitalizations, as the peak of patients in intensive care units occurs within 12-16 days after the peak in the positivity rate. This can help governments in planning socio-economic and health policies in advance., Competing Interests: The author has no conflicts of interest to disclose., (© 2022 Elsevier Ltd. All rights reserved.)

Since the start of the 21st century, the world has not confronted a more serious threat to global public health than the COVID-19 pandemic. While governments initially took radical actions in response to the pandemic to avoid catastrophic collapse of their health care systems, government policies have also had numerous knock-on socioeconomic, political, behavioral and economic effects. Researchers, thus, have a unique opportunity to forward our collective understanding of the modern world and to respond to the emergency situation in a way that optimizes resources and maximizes results. The PERISCOPE project, funded by the European Commission, brings together a large number of research institutions to collect data and carry out research to understand all the impacts of the pandemic, and create predictive models that can be used to optimize intervention strategies and better face possible future health emergencies. One of the main tangible outcomes of this project is the PERISCOPE Atlas: an interactive tool that allows to visualize and analyze COVID-19-related health, economic and sociopolitical data, featuring a WebGIS and several dashboards. This paper describes the first release of the Atlas, listing the data sources used, the main functionalities and the future development.

Objectives: Early chimerism analysis is important to assess engraftment in allogeneic hematopoietic stem cell transplantations., Methods: We retrospectively investigated the impact of T-cell chimerism at day 30 in bone marrow on acute graft-versus-host disease (aGVHD), relapse, and overall survival in 142 adult allo-transplanted patients., Results: The majority of patients (89%) received myeloablative conditioning and 90% have undergone T-cell replete donor graft. At day 30, 103 patients showed T-complete chimerism with prevalence in haploidentical transplants, whereas 39 cases had CD3+ mixed chimerism, including 30 patients transplanted with HLA identical donors, and 21 with T-cell donors<90%. T-cell chimerism at day 30 was weakly inversely related to aGVHD grades II-IV (p = .078) with no cases of grades III-IV aGVHD in patients with CD3+ <95%. Mixed T-cell chimerism did not impact on relapse (p = .448) and five of the seven patients who relapsed had T-cell chimerism ≤90%. Older age and active disease at transplant had a statistically significant negative effect on overall survival (p = .01 and p = .0001, respectively), whereas mixed CD3+ chimerism did not., Conclusions: T lymphocyte chimerism analysis at day +30 in bone marrow could identify allo-transplanted patients at major risk of aGVHD grades III-IV (CD3+ donors >95%) mainly post-myeloablative conditioning regimen., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We propose an endemic-epidemic model: a negative binomial space-time autoregression, which can be employed to monitor the contagion dynamics of the COVID-19 pandemic, both in time and in space. The model is exemplified through an empirical analysis of the provinces of northern Italy, heavily affected by the pandemic and characterized by similar non-pharmaceutical policy interventions., (© 2021 Elsevier B.V. All rights reserved.)

We compare the expected all-cause mortality with the observed one for different age classes during the pandemic in Lombardy, which was the epicenter of the epidemic in Italy. The first case in Italy was found in Lombardy in early 2020, and the first wave was mainly centered in Lombardy. The other three waves, in Autumn 2020, March 2021 and Summer 2021 are also characterized by a high number of cases in absolute terms. A generalized linear mixed model is introduced to model weekly mortality from 2011 to 2019, taking into account seasonal patterns and year-specific trends. Based on the 2019 year-specific conditional best linear unbiased predictions, a significant excess of mortality is estimated in 2020, leading to approximately 35000 more deaths than expected, mainly arising during the first wave. In 2021, instead, the excess mortality is not significantly different from zero, for the 85+ and 15-64 age classes, and significant reductions with respect to the 2020 estimated excess mortality are estimated for other age classes., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies., Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences., Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases., Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC., Competing Interests: Giuseppe Cabibbo participated in advisory board for Bayer, Eisai, and Ipsen. Maria Reig is a consultant at Bayer-Shering Pharma, BMS, Roche, Ipsen, AstraZeneca, Lilly, and BTG; attended paid conferences at Bayer-Shering Pharma, BMS, Gilead, and Lilly; received research grants from Bayer-Shering Pharma and Ipsen. Ciro Celsa received speaker fees from Eisai. Amit Singal served on advisory boards or as consultant for Genentech, Bayer, Eisai, Exelixis, Bristol Myers Squibb, and AstraZeneca. Jordi Bruix is a consultant at AbbVie, Adaptimmune, Arqule, Astra-Medimmune, Basilea, Bayer-Shering Pharma, Bio-Alliance, BMS, BTG-Biocompatibles, Eisai, Gilead, Incyte, Ipsen, Kowa, Lilly, MSD, Nerviano, Novartis, Polaris, Quirem, Roche, Sirtex, Sanofi, and Terumo; received research grants from Bayer and BTG; received educational grants from Bayer and BTG; attended paid conferences at Bayer, BTG, Astra-Zeneca, and Ipsen; gave paid talks at Bayer-Shering Pharma, BTG-Biocompatibles, Eisai, Terumo, Sirtex, and Ipsen. Calogero Cammà participated in the advisory board for Bayer, MSD/Merck, Ipsen, and Eisai. The other authors have no disclosure to declare., (Copyright © 2021 by S. Karger AG, Basel.)

The study aims at demonstrating how social communication has changed in terms of flows and content in the different phases of the COVID-19 pandemic to get to the fact that public administrations have embarked on a path of rapprochement with the citizen that starts from the methods of communication and interaction. This article presents an exploratory and multidisciplinary study conducted through the analysis of the Facebook page of the Italian municipalities with the highest Covid19-induced mortality rates (Piacenza, Bergamo, Lodi, Cremona, Brescia, Pavia, Parma, Mantova, Alessandria, Lecco and Sondrio). Fanpage Karma has been used to conduct the investigation and get the analytics. Local governments are implementing a process of gradual approach to the needs of the citizen and learning new ways of communication. In the conclusion of our study - conducted at the time of the pandemic - we can affirm that local governments are in an early stage of the process both for the acquisition of skills for social communication and for the definition of a communication strategy to strengthen their social identity aware of the fact that the agile and lean communication makes the citizen much more informed and involved in city life than traditional communication. This paper analyses a social network like Facebook as a not common tool for local government's communication in a period of severe emergency. A multidisciplinary approach is adopted as a distinctive factor. The focus is on the contribution of social communication on citizens' engagement., (© 2020 John Wiley & Sons Ltd.)

Background: In the UK, it is recommended that hospital patients have their nutritional status assessed within 24 h of admission using the Malnutrition Universal Screening Tool (MUST). The present study aimed to examine the association between nurse staffing levels and missed nutritional status assessments., Methods: A single-centre, retrospective, observational study was employed using routinely collected MUST assessments from 32 general adult hospital wards over 2 years, matched to ward nurse staffing levels. We used mixed-effects logistic regression to control for ward characteristics and patient factors., Results: Of 43 451 instances where staffing levels could be linked to a patient for whom an assessment was due, 21.4% had no MUST score recorded within 24 h of admission. Missed assessments varied between wards (8-100%). There was no overall association between registered nurse staffing levels and missed assessments; although higher admissions per registered nurse were associated with more missed assessments [odds ratio (OR) = 1.09, P = 0.005]. Higher healthcare assistant staffing was associated with lower rates of missed assessments (OR = 0.80, P < 0.001). There was a significant interaction between registered nurses and healthcare assistants staffing levels (OR = 0.97, P = 0.011)., Conclusions: Despite a written hospital policy requiring a nutritional assessment within 24 h of admission, missed assessments were common. The observed results show that compliance with the policy for routine MUST assessments within 24 h of hospital admission is sensitive to staffing levels and workload. This has implications for planning nurse staffing., (© 2021 The British Dietetic Association Ltd.)

Background& Aims: Time to progression (TTP) and progression-free survival (PFS) are commonly used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of TTP and PFS with overall survival (OS) in studies of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (u-HCC) by innovative methods., Methods: A search of databases for studies of TACE for u-HCC reporting both OS and TTP or PFS was performed. Individual patient data were extracted from TTP/PFS and OS Kaplan-Meier curves of TACE arms. Pooled median TTP and OS were obtained from random-effect model. The surrogate relationships of hazard ratios (HRs) and median TTP for OS were evaluated by the coefficient of determination R 2 ., Results: We identified 13 studies comparing TACE vs systemic therapy or vs TACE plus systemic therapy and including 1932 TACE-treated patients. Pooled median OS was 11.2 months (95% confidence interval [95%CI] 7.9-17.8), and pooled median TTP was 5.4 months (95%CI 3.8-8.0). Heterogeneity among studies was highly significant for both outcomes. The correlation between HR TTP and HR OS was moderate (R 2  = 0.65. 95%CI 0.08-0.81). R 2 value was 0.04 (95%CI 0.00-0.35) between median TTP and median OS., Conclusion: In studies of TACE for u-HCC, the surrogate relationship of radiology-based endpoints with OS is moderate. Multiple endpoints including hepatic decompensation, macrovascular invasion and extrahepatic spread are needed for future trials comparing systemic therapies or combination of TACE with systemic therapies vs TACE alone., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events., Methods: We performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3-F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19-63 months)., Results: Based on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00-1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02-1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11-2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02)., Conclusions: In patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world., (© 2021 Author(s).)

The availability of intensive care beds during the COVID-19 epidemic is crucial to guarantee the best possible treatment to severely affected patients. In this work we show a simple strategy for short-term prediction of COVID-19 intensive care unit (ICU) beds, that has proved very effective during the Italian outbreak in February to May 2020. Our approach is based on an optimal ensemble of two simple methods: a generalized linear mixed regression model, which pools information over different areas, and an area-specific nonstationary integer autoregressive methodology. Optimal weights are estimated using a leave-last-out rationale. The approach has been set up and validated during the first epidemic wave in Italy. A report of its performance for predicting ICU occupancy at regional level is included., (© 2020 Wiley-VCH GmbH.)