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Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and diabetes. A reduction in insulin receptor (IR) expression has been reported in these patients. The aims of this study were to evaluate the effects of a mixture of plant extracts consisting of Berberis aristata, Elaeis guineensis and decaffeinated green coffee by Coffea canephora on the improvement of glycaemic profile, through the modulation of IR levels, and of hepatic steatosis in NAFLD patients. Forty-nine patients with a grade of steatosis S1-S2 were randomly allocated to the treatment with plant extracts or placebo for six months. Hepatic steatosis was evaluated using transient elastography with CAP (controlled attenuation parameter). Glucose, insulin, and IR levels were measured in serum samples. At the end of the study, patients treated with plant extracts displayed a significant reduction of serum glucose (p < 0.001), insulin levels (p < 0.01), homeostatic model assessment for insulin resistance (HOMA-IR) index (p < 0.001), and CAP value (p < 0.01) compared to placebo. Moreover, the IR expression was increased significantly in the plant extracts group compared to the placebo group (p < 0.05). The combination of plant extracts increases serum IR levels, determining amelioration of glycemic profile and improvement of hepatic steatosis in NAFLD patients.

Background and aim The present real‐life multicentre, prospective study aims to investigate the effects of direct‐acting antivirals (DAAs) in HCV patients with a previous successfully treated hepatocellular carcinoma (HCC), in terms of neoplastic recurrence and sustained virological response (SVR) rates. Methods From March 2015 to March 2017, all consecutive HCV patients with a previous successfully treated HCC who underwent DAA therapy were enrolled. Neoplastic recurrence was used as the primary outcome, whereas the secondary outcomes were patient characteristics predicting HCC recurrence. Cumulative probabilities of recurrence were extracted from time‐to‐event curves based on the Kaplan‐Meier method. Hazard ratios with 95% confidence intervals were estimated using univariate and multivariate Cox regressions. Results A total of 101 patients were enrolled: 83% of them were in Child‐Pugh class A, 88% had a history of HCC BCLC stage 0/A and 91.1% achieved SVR. The median time from the last successful HCC treatment to DAA start was 10.1 months [IQR: 5.6‐16.7]. Thirty‐one HCC recurrences were observed from DAA start (median follow‐up: 31.7 months). The incidence rate of recurrence was 20.5/100 person‐years. The 6‐, 12‐ and 24‐months HCC recurrence rates from the last HCC treatment were 1%, 8.9% and 25.6% respectively. DAA treatment failure, higher level of total bilirubin, higher BMI and higher level of AFP were significantly associated with higher risk of HCC recurrence in both univariate and Cox multivariate analysis. Conclusions Our data suggest that the achievement of SVR and the absence of well‐known HCC risk factors reduce  recurrence in patients who have taken DAAs.

Internet of Things (IoT) solutions are a concrete answer to many needs in the healthcare framework since they enable remote support for patients and foster continuity of care. Currently, frail elderly people are among end users who most need and would benefit from IoT solutions from both a social and a healthcare point of view. Indeed, IoT technologies can provide a set of services to monitor the healthcare of the elderly or support them in order to reduce the risk of injuries, and preserve their motor and cognitive abilities. The main feature of IoT solutions for the elderly population is ease of use. Indeed, to fully exploit the potential of an IoT solution, patients should be able to autonomously deal with it. The remote-monitoring validation engineering system (ReMoVES) described here is an IoT solution that caters to the specific needs of frail elderly individuals. Its architecture was designed for use at rehabilitation centers and at patients’ homes. The system is user-friendly and comfortably usable by persons who are not familiar with technology. In addition, exergames enhance patient engagement in order to curb therapy abandonment. Along with the technical presentation of the solution, a real-life scenario application is described referring to sit-to-stand activity.

In contemporary society, following the sudden changes that occur, different forms of addiction are becoming popular. Of note are the new addictions and concepts of poly-dependencies that involve common behaviors and trap people who suffering from them in a vicious circle. The main goal of this study is to investigate the possible mediating role that self-esteem had between trait anxiety and two specific new addictions: compulsive buying behavior and eating disorders. Furthermore, it was verified through a multigroup analysis that trait anxiety had a greater effect on eating disorders in a group of compulsive consumers. Three-hundred and fifty-two participants (67.9% women) were enrolled to participate in this study. The results showed that there was a direct effect of trait anxiety on eating disorders and on compulsive buying behavior; self-esteem mediated the effect of trait anxiety on eating disorders and compulsive buying behavior with specific differences; multi-group analysis showed differences in anxiety’s effect on eating disorders between compulsive and non-compulsive consumers; the group of compulsive consumers revealed a significant and stronger effect of trait anxiety on eating disorders in all domains identified. Further research is recommended to better understand the predictors of these disorders and to contribute to a more effective preventive intervention.

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.

Background Lysine demethylase enzymes (KDMs) are an emerging class of therapeutic targets, that catalyse the removal of methyl marks from histone lysine residues regulating chromatin structure and gene expression. KDM4A isoform plays an important role in the epigenetic dysregulation in various cancers and is linked to aggressive disease and poor clinical outcomes. Despite several efforts, the KDM4 family lacks successful specific molecular inhibitors. Results Herein, starting from a structure-based fragments virtual screening campaign we developed a synergic framework as a guide to rationally design efficient KDM4A inhibitors. Commercial libraries were used to create a fragments collection and perform a virtual screening campaign combining docking and pharmacophore approaches. The most promising compounds were tested in-vitro by a Homogeneous Time-Resolved Fluorescence-based assay developed for identifying selective substrate-competitive inhibitors by means of inhibition of H3K9me3 peptide demethylation. 2-(methylcarbamoyl)isonicotinic acid was identified as a preliminary active fragment, displaying inhibition of KDM4A enzymatic activity. Its chemical exploration was deeply investigated by computational and experimental approaches which allowed a rational fragment growing process. The in-silico studies guided the development of derivatives designed as expansion of the primary fragment hit and provided further knowledge on the structure–activity relationship. Conclusions Our study describes useful insights into key ligand-KDM4A protein interaction and provides structural features for the development of successful selective KDM4A inhibitors.

Background The overuse of antimicrobials favors the dissemination of antimicrobial resistance, as well as invasive fungal diseases and Clostridium difficile infections (CDI). In this study, we assessed the impact of a mixed educational and semi-restrictive antimicrobial stewardship (AMS) project in a large teaching hospital in Italy. Methods The AMS project was conducted from May 2014 to April 2016. It consisted of two initiatives in two consecutive periods: (1) educational activities; (2) semi-restrictive control of antimicrobial prescribing through a computerized software. The primary endpoint was consumption of antibacterials and antifungals. Secondary endpoints were incidence of CDI, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI, and Candida BSI. Results During the study period, a statistically significant reduction in consumption was observed for antibacterials (−1.45 defined daily doses (DDD)/1000 patient-days monthly, 95% confidence intervals [CI] −2.38 to −0.52, p 0.004), mainly driven by reductions in the use of fluoroquinolones, third/fourth generation cephalosporins, and carbapenems. No decrease in consumption of antifungals was observed (−0.04 DDD/1000 patient-days monthly, 95% CI −0.34 to +0.25, p 0.750). A statistically significant trend towards reduction was observed for incidence of CRKP BSI (incidence rate ratio 0.96, 95% CI 0.92–0.99, p 0.013). No statistically significant variations in trends were observed for CDI, MRSA BSI, and Candida BSI. Conclusions The mixed AMS project was effective in reducing the use of major antibacterials and the incidence of CRKP BSI. Further research is needed to assess the extent of long-term benefits of semi-restrictive approaches.

Spinal muscular atrophy (SMA) is a progressive disorder caused by SMN1 mutations. While therapies have changed its course, current motor scales often miss aspects. This study aimed to validate the Italian SMA Independence Scale (SMAIS-ULM) for reliability, applicability, and expansion across diverse SMA phenotypes. Patients with genetically confirmed 5qSMA were recruited from 12 Italian centers. Analyses included Intraclass Correlation Coefficients (ICCs) for test–retest reliability, the Kruskal–Wallis for group comparisons, and the Spearman correlations with functional measures. Ceiling/floor effects were defined as ≥ 85% of a group reaching the maximum or minimum score. The study analyzed 472 completed questionnaires: 263 from caregivers (mean age 26.4 ± 17.6; 29 SMA I, 123 SMA II, 104 SMA III, 7 presymptomatic) and 209 from patients (mean age 33.1 ± 16.4; 3 SMA I, 101 SMA II, 104 SMA III; 1 SMA IV), including 195 matched caregiver-patient pairs. ICC was conducted in 29 caregivers and 31 patients; values ranged from 0.97 to 1.00. SMAIS-ULM scores differed by SMA type, with SMA III/presymptomatic subjects scoring higher than SMA I/II ( p  < 0.001) and walkers scoring higher than sitters/non-sitters ( p  < 0.001). Floor effects were found in 18.9% of non-sitters and 50% of walkers, with comparable patterns in patient responses. Strong correlations with functional measures were found, with no significant differences between caregiver and patient reports. Conclusion : The findings confirm the reliability and validity of the SMAIS-ULM as an effective tool for measuring functional independence in individuals with SMA, both from the caregiver and patient perspectives. What is Known: • Disease-modifying therapies have modified natural history of all SMA types. • Patient-reported tools are increasingly used to assess daily task assistance, independence and participation. What is New: • SMAIS-ULM proved applicable across a wide functional spectrum in SMA, with strong score variation by type and function in Type II/III SMA. • Ambulant individuals often had ceiling effect but ~50% of them showed limited independence, supporting the scale’s value in a discriminating among patients who have maintained ambulation.

Background and purpose Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease‐modifying treatments have reported their efficacy and safety, long‐term natural history data are lacking for comparison. The aim of this prospective study was to report 4‐year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number. Methods The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number. Results In SMA type II (n = 226), the 4‐year mean change was −2.20 points. The largest mean changes were observed in sitters aged 5–14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4‐year mean change was −2.75 points. The largest mean changes were in those aged 7–15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4‐year changes. Conclusions Our findings provide natural history reference data for comparison with long‐term follow‐up of clinical trials or real‐world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

Onasemnogene abeparvovec (OA) is an AAV9-based gene therapy for spinal muscular atrophy type I (SMA I). Real-world outcomes show increased response variability compared to clinical trials, and follow-up data beyond 12-18 months are limited. The aim of this 24-month prospective observational study is to comprehensively describe the clinical outcomes of an Italian cohort of SMA I patients treated with OA. Based on recent literature, patients' treatment status was categorized as: monotherapy (OA only), bridge therapy (transition to OA within 3 months of starting nusinersen or risdiplam), or switch therapy (transition to OA after > 3 months of 1st treatment). Linear mixed-effects models examined predictors of improvement (CHOP-INTEND), adjusting for baseline motor function, SMN2 copy number, age, and prior treatment. Descriptive analyses were used to show changes in motor, respiratory, and nutritional milestones. The cohort included 64 patients: 27 monotherapy, 9 bridge, and 28 switch. All patients showed significant improvement over 24 months (β = 20.40 points/year, p < 0.001). Patients who switched showed slower improvement (β = -3.76, p = 0.038) compared to monotherapy, while those who bridged showed no difference. Older age at treatment was associated with slower improvement (β = -1.48 points/year per month, p = 0.002). Of 49 non-sitters at baseline, 39 (80%) achieved sitting and 5 (10%) achieved walking. No new safety signals emerged in the second year of follow-up. Age and baseline motor functional status significantly influence outcomes; however, substantial confounding, particularly the initial treatment, limits the ability to isolate individual effects. Longer follow-up is essential for evaluating therapeutic responses in heterogeneous SMA I populations.