Italfarmaco (Italy)

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease and one of the leading causes of sudden cardiac death in young individuals and athletes. Current treatments focus on preventing arrhythmias and sudden cardiac death, but no effective therapy targeting disease progression is available. Myocardial replacement with fibro-fatty tissue, a hallmark of ACM, is primarily driven by the activation of cardiac fibroadipogenic precursors (cFAPs). Here, we evaluate the efficacy of a pan inhibitor of histone deacetylases (givinostat) in reducing cFAP proliferation and differentiation. These cells were found to be enriched in the hearts of a transgenic ACM murine model (Tg-hQ), which overexpresses the DSG2 p.Q558* mutation, compared to wild-type (WT) controls. We observed that givinostat reduced the proliferation of both Tg-hQ and WT isolated cFAPS. Additionally, cFAPS were induced to differentiate into adipocytes or fibroblasts and treated with givinostat. The drug treatment led to a reduction in the number of adipocytes under pro-adipogenic conditions. RNA sequencing analysis revealed a significant downregulation of key regulators of adipogenic differentiation and lipid metabolism (Pparg, Cebpa and Adipoq). In parallel, cells cultured under pro-fibrotic conditions showed decreased expression of genes encoding components of the extracellular matrix (Col1a1, Col6a1 and Postn) upon givinostat treatment. Overall, these results support the potential of givinostat in modulating cFAP proliferation and differentiation in vitro, warranting further in vivo studies to assess its impact on fibro-fatty tissue replacement in ACM.

Background: The aim of this study was to investigate the effectiveness and safety of the combination of diosmin, extract of Vitis vinifera, Ruscus aculeatus, and Melilotus officinalis (Viviven®), in addition to standard of care, as conservative therapy of hemorrhoidal disease (HD). Methods: Prospective, multicenter, observational cohort study, nested analysis of the VIVI2022/01/VIVALDI study, on adults with symptomatic Goligher grade I–II–III HD. The primary study endpoint was the improvement in the Rørvik hemorrhoidal disease symptoms score (HDSS). Secondary endpoints of effectiveness were bleeding entity, measured through the Giamundo score, quality of life, using the Short Health Scale adapted for HD (SHS-HD), Goligher grading, satisfaction with treatment, and the change in strategy. Patients and all scores were evaluated at baseline (VO) and at day 30 (V2). Results: Thirty-five people, 80% males, median (Q1, Q3) age 50 (37, 59) years, affected by HD since 3 (0, 7) years, were enrolled. The mean (standard deviation) HDSS decreased from 8.29 (4.4) at baseline to 4.09 (3.4) at day 30 (P < 0.001). At day 30, 51.4% of participants had no bleeding versus 5.7% at baseline (P < 0.001), and 34.3% showed a Goligher grade downstaging. The mean (standard deviation) SHS-HD score decreased from 12.2 (4.6) at baseline to 7.89 (3.6) at day 30 (P < 0.001). Treatment was deemed satisfactory by 74.3% of participants, with none discontinuing within day 30. Conclusion: The combination of diosmin, extract of V. vinifera, R. aculeatus, and M. officinalis, was safe and effective. Clinical improvements in signs and symptoms were found in people suffering from Goligher grade I–II–III HD.

This paper discusses the design criteria of low voltage circuits for road tunnels where they can reach considerable lengths. The "comb distribution" applicable in road tunnels is a special distribution compliant with the two criteria of their zoning and subdivision into modules that provide intrinsic resilience to fire exposure in the event of an accident. This distribution provides primary circuits to power the tunnel modules and the fans and to be installed in a protected manner at the bottom with reduced exposure to high temperatures. Each primary circuit in its module feeds a uniform configuration of terminal circuits. This paper highlights how for long circuits the minimum short circuit currents must not only be promptly interrupted by the coordinated protection devices, but cannot assume a value lower than a minimum value adequate to guarantee the admissible voltage drop. The maximum length of a circuit that guarantees a given voltage drop is generally less than and in any case different from the maximum protected length. For this purpose, a parameter is introduced that can be evaluated in a simple way, which is the characteristic current of the minimum prospected short circuit for a conductor of given length, section and cable ampacity. The ratio between the minimum characteristic current and the effective load current of the circuit is an index parameter which, if it remains below the minimum value required by the voltage drop, highlights the inadequacy of the circuit at a preliminary design level.

The integration of Machine Learning (ML) into susceptibility mapping and hazard modelling has unveiled complex relationships between landslide predisposing factors and occurrence. However, understanding the practical implications of landslide susceptibility results still crucial. One concern is the conventional treatment of landslide inventory data, where various landslide types are uniformly addressed during model training, proving unrealistic given diverse geological and geomorphological conditions for distinct landslide types. Moreover, each landslide type requires a unique mitigation strategy, and valuable information is lost when treating all landslides uniformly. Another challenge is how susceptibility models typically present probabilities, while practical applications demand clear categories to avoid underestimation or overestimation of risks.This study explores the practical application of landslide susceptibility to linear infrastructure, specifically railway design. The investigation centres on two established models, comparing each other: firstly, the classical statistical-based method, Weight of Evidence (WoE); and secondly, a ML method, the Generalized Additive Model (GAM). WoE was chosen for its clarity, while GAM accommodates continuous variables, offering a nuanced understanding of non-linear relationships. The study area encompasses a new 22.11 km railway stretch in the central Marche Region, Italy. We assessed the susceptibility to five landslide types, as classified in the Italian Landslide Inventory (IFFI). The models (WoE and GAM) are applied using different landslide types as distinct training datasets, resulting in unique susceptibility maps for each type. Additionally, the study evaluates the models using the Area Under the Receiver Operating Characteristic (AUROC) curve, providing insights into their performance. The rockfall susceptibility map demonstrates high reliability (AUROC of 0.942 with WoE and 0.978 with GAM), while slide-type landslides show more modest but fairly good results (AUROC of 0.696 with WoE and 0.784 with GAM).To provide a comprehensive understanding of the study area, overall landslide susceptibility was calculated, corresponding to the probability of failure for any type of landslide. The overall probability was obtained by implementing a complementary probability approach for landslide probability analysis. A method is then proposed to classify the sensitivity of landslide types by considering the difference in their influences, facilitating a clearer understanding of their contributions to the overall susceptibility assessment.The second practical concern involves the accurate definition of hazard classes, pivotal due to its direct impact on risk management, decision-making, and overall infrastructure resilience. The study introduces a novel approach, using mode calculation to consolidate results from various reclassification methods. This strategic use of mode calculation ensures a reliable representation of hazard classes, addressing the limitations of individual methodologies.The results underscore the importance of considering multiple models and methodologies to obtain a comprehensive perspective in decision-making processes. Importantly, the study highlights the use of both classical statistical methods, exemplified by WoE, and ML methods like GAM, showcasing the benefits of a diverse analytical approach in landslide risk assessment for linear infrastructure.

Recurrent bacterial vaginosis (RBV) after antibiotic treatment has relapse rates of 35% within 3 months and 60% within 12 months. A medical device containing polycarbophil, lauryl glucoside, and glycerides (PLGG) inhibits bacterial growth and has mucoadhesive properties. This study examined the efficacy of the device in women with RBV. This post-market clinical follow-up study comprised two phases. The first phase was an interventional, open-label, non-controlled, multicenter study enrolling 56 women. The second phase was an observational 10-month follow-up without treatment. After three cycles of PLGG treatment, recurrence was identified in 8 of 54 evaluable patients (14.81%). A positive effect on lactobacilli in the vaginal secretions was observed in 26 of 39 patients (66.67%). Among 35 patients observed after stopping PLGG treatment, one case of RBV (2.86%) was observed after 4 months, and an additional six cases (17.14%) were observed after 10 ± 2 months. Therefore, no recurrence was evidenced in 12 subjects (34.28%) at the end of the study. The use of PLGG vaginal ovules in the treatment of BV reduces the rate of recurrence and apparently produces a positive effect on the vaginal microbiota.

Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16-17 up to 24-25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16-17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24-25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.