The paper summarizes the design, implementation and validation of the Computer Based Interlocking (ACC) designed by Ansaldo Trasporti under the supervision of the Italian Railways. Particularly, details are provided on the methodology that has been adopted to set the safety requirements and to give preliminary safety demonstrations.During the development of the ACC design, new drafts of European Standards have been circulated on the design and validation of railway signalling systems.Safety assessment activities compliant with the new European Standards have been started and integrated within the ACC safety process.The failure models presented in this paper have demonstrated that the ACC design requirements assure the system compliance with the required safety integrity levels. They also have allowed for the identification of the parameters to be measured by fault injection tests in an exhaustive experimental evaluation environment, which will be developed in the subsequent phases of the validation process. 21

The Omicron variant of SARS-CoV-2 (Spike mutant B.1.1.529) carrying more than 30-point mutations in its structure, of which 15 are localized in the receptor-binding domain (RBD), allows to hypothesize a relevant change in interactivity with ACE2. In previous reports we hypothesized that the worse outcome of the COVID-19 disease in diabetes mellitus condition could be related to the non-enzymatic glycation of ACE2 receptor and an in silico evaluation led to the demonstration that the number of interactions is decreased in comparison to the unmodified model, possibly shifting the virus attack through different, multiple alternative entry routes. Given the evidenced features of this variant, we aimed to investigate with a computational approach the characteristics of Omicron SARS-CoV-2 with respect to its binding to human ACE-2 receptor, in a particular population, namely people affected by diabetes mellitus, at risk for unfavorable outcomes of the COVID-19. The computational analysis, considering the case in which all the lysine residues in the system are subjected to non-enzymatic glycation, confirmed that lysine glycation causes a general loss of interactivity between wild-type (WT)-Spike-RBD and ACE2. In the Omicron variant, Lys417 mutates into an asparagine, preventing the possible non-enzymatic glycation of this residue. Therefore, if non-enzymatic glycation seemed to cause a shift in the way in which the virus enters the cell from the ACE2-mediated mechanism to other pathways, in the case of the Omicron variant the ACE2-mediated approach of the virus seems to remain an important event to take into account. Indeed, interaction profile analysis, together with molecular mechanics–generalized Born surface area (MM-GBSA) calculations, suggests that the Omicron-Spike-RBD maintains a higher affinity for ACE2 subsequently to non-enzymatic glycation with respect to WT-Spike-RBD. The finding of the present computational study may suggest a different clinical relevance of the Omicron variant for the diabetes mellitus field, also in the possible direction of a lower severity of the disease.

Aims The aim of the present study was to evaluate, by means of a meta-analysis approach, whether new available data, appeared on qualified literature, can support the effectiveness of an association of HbA1c variability with the risk of macro- and/or micro-vascular complications in type 2 diabetes mellitus (T2DM). Methods The meta-analysis was conducted according to PRISMA Statement guidelines and considered published studies on T2DM, presenting HbA1c variability as standard deviation (SD) or its derived coefficient of variation (CV). Literature search was performed on PubMed in the time range 2015–July 2022, with no restrictions of language. Results Twenty-three selected studies fulfilled the aims of the present investigation. Overall, the analysis of the risk as hazard ratios (HR) indicated a significant association between the HbA1c variability, expressed either as SD or CV, and the complications, except for neuropathy. Macro-vascular complications were all significantly associated with HbA1c variability, with HR 1.40 (95%CI 1.31–1.50, p < 0.0001) for stroke, 1.30 (95%CI 1.25–1.36, p < 0.0001) for transient ischaemic attack/coronary heart disease/myocardial infarction, and 1.32 (95%CI 1.13–1.56, p = 0.0007) for peripheral arterial disease. Micro-vascular complications yielded HR 1.29 (95%CI 1.22–1.36, p < 0.0001) for nephropathy, 1.03 (95%CI 0.99–1.08, p = 0.14) for neuropathy, and 1.15 (95%CI 1.08–1.24, p < 0.0001) for retinopathy. For all-cause mortality, HR was 1.33 (95%CI 1.27–1.39, p < 0.0001), and for cardiovascular mortality 1.25 (95%CI 1.17–1.34, p < 0.0001). Conclusions Our meta-analysis on HbA1c variability performed on the most recent published data since 2015 indicates positive association between HbA1c variability and macro-/micro-vascular complications, as well as mortality events, in T2DM, suggesting that this long-term glycaemic parameter merits further attention as a predictive, independent risk factor for T2DM population.

Introduction When Italy was placed under lockdown to contain the COVID-19 pandemic from 9 March to 18 May 2020, alternative approaches to delivering care—such as telemedicine—were promoted for patients with chronic diseases like diabetes mellitus (DM). The aim of this study was to analyze patients’ perception of, and satisfaction with the telehealth services offered during the COVID-19 emergency at an outpatient diabetes care unit in Italy. Methods A cross-sectional survey was conducted on 250 patients with type 2 diabetes mellitus who regularly attended our diabetes care unit. Data were collected by means of telephone interviews, asking patients how they perceived the telehealth services, and their satisfaction with the televisit and computer-based care. A standardized questionnaire was administered: there were questions answered using a five-point Likert scale, and one open-ended question. Patients’ demographic, anthropometric and biological data were collected from their medical records. Correlations between patients’ characteristics, their perception of telemedicine, and their satisfaction with the televisit were examined. Spearman’s rank-order correlation coefficient ρ (rho) and Kendall’s rank correlation coefficient τ (tau) were used as nonparametric measures of the strength of the association between the scores obtained for the two ordinal variables, Perception and Satisfaction, and between other clinical parameters. Principal component analysis (PCA) was also used to assess overall links between the variables. Results Almost half of the interviewees expressed a strongly positive perception of the medical services received, and more than 60% were very satisfied with the telehealth service provided during the COVID-19 emergency. There was a strong correlation between patients’ perception and satisfaction ratings (p<0.0001). Duration of disease showed a significant positive correlation with patients’ satisfaction with their medical care. By means of PCA, it was found that BMI correlated inversely with both perception and satisfaction. Following a qualitative analysis of patients’ answers to the open-ended question, contact with their specialist was important to them: it was reassuring and a source of scientifically correct information about their disease and the association between COVID-19 and diabetes. Conclusions Based on our telephone interviews, patients appreciated the telehealth approach and were satisfied with it, regardless of the characteristics of their disease. Telemedicine proved essential to avoid interrupting the continuity of care, and therefore had not only clinical, but also psycho-social repercussions.

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Background. Type 2 diabetes mellitus (T2DM) is an important risk factor for peripheral artery disease (PAD). Measuring the Ankle-Brachial Index (ABI) in patients with diabetes is a simple way to screen for PAD. In the last decade, pathological ABI values (≤ 0.9; ≥1.3) were found associated with a higher cardiovascular (CV) risk and mortality. The role of classic risk factors for PAD in patients with diabetes is still unclear, and there is no specific PAD risk scoring system for these patients. The main goals of this study were to establish the prevalence of PAD in a T2DM population, and assess the relationship between PAD and the CV risk calculated with the CUORE Project score (CPS) (https://www.cuore.iss.it/). The association between the ABI, the main risk factors for PAD and T2DM complications was also investigated. Methods. Two hundred patients attending the Diabetes Clinic run by the ULSS 6 District Health Unit in Padua (north-east Italy) were consecutively enrolled, and their left and right ABI were measured. Twenty-seven patients with a history of CV events were excluded for the purpose of calculating the CPS, which was thus recorded for a total of 173 patients. Results. The prevalence of PAD in this study population was 17%. The CV risk calculated with the CPS tended to be higher (p = 0.0712) in the group with a pathological ABI than in the group with a normal ABI (0.91–1.29). The distribution of patients in the different CV risk classes did not differ significantly (p = 0.2208) between the two groups (pathological vs normal ABI). Glycated hemoglobin (r = -0.1591; p = 0.0244), total cholesterol (r = -0.1958; p = 0.0054), LDL cholesterol (r = -0.1708; p = 0.0156) and systolic blood pressure (r = -0.1523; p = 0.0313) correlated significantly and inversely with the left ABI. The frequency of diabetic retinopathy differed significant (p = 0.0316) between the two groups (pathological vs normal ABI), and was higher in the group with a pathological ABI. Conclusions. The data collected reveal a high prevalence of PAD in patients with T2DM, consistently with studies conducted in other countries. The CPS confirmed that patients with a pathological ABI have tendency to a higher CV risk. Overall, the present results point to the importance of an accurate CV assessment – also measuring individuals’ ABI and calculating their CPS - to better pinpoint those at high risk of PAD, especially among patients with T2DM.

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