A Human Digital-Twin-Based Framework Driving Human Centricity towards Industry 5.0.

This work presents a digital-twin-based framework focused on orchestrating human-centered processes toward Industry 5.0. By including workers and their digital replicas in the loop of the digital twin, the proposed framework extends the traditional model of the factory's digital twin, which instead does not adequately consider the human component. The overall goal of the authors is to provide a reference architecture to manufacturing companies for a digital-twin-based platform that promotes harmonization and orchestration between humans and (physical and virtual) machines through the monitoring, simulation, and optimization of their interactions. In addition, the platform enhances the interactions of the stakeholders with the digital twin, considering that the latter cannot always be fully autonomous, and it can require human intervention. The paper also presents an implemented scenario adhering to the proposed framework's specifications, which is also validated with a real case study set in a factory plant that produces wooden furniture, thus demonstrating the validity of the overall proposed approach.

Predictors of adverse events after endoscopic ultrasound-guided through-the-needle biopsy of pancreatic cysts: a recursive partitioning analysis.

BACKGROUND AND STUDY AIMS : Endoscopic ultrasound-guided through-the-needle biopsy (TTNB) of pancreatic cystic lesions (PCLs) is associated with a non-negligible risk for adverse events (AEs). We aimed to identify the hierarchic interaction among independent predictors for TTNB-related AEs and to generate a prognostic model using recursive partitioning analysis (RPA). PATIENTS AND METHODS : Multicenter retrospective analysis of 506 patients with PCLs who underwent TTNB. RPA of predictors for AEs was performed and the model was validated by means of bootstrap resampling. RESULTS : Mean cysts size was 36.7 mm. Most common diagnoses were intraductal papillary mucinous neoplasm (IPMN, 45 %), serous cystadenoma (18.8 %), and mucinous cystadenoma (12.8 %). Fifty-eight (11.5 %) AEs were observed. At multivariate analysis, age (odds ratio [OR] 1.32, 1.09-2.14; p = 0.05), number of TTNB passes (OR from 2.17, 1.32-4.34 to OR 3.16, 2.03-6.34 with the increase of the number of passes), complete aspiration of the cyst (OR 0.56, 0.31-0.95; p = 0.02), and diagnosis of IPMN (OR 4.16, 2.27-7.69; p < 0.001) were found to be independent predictors of AEs, as confirmed by logistic regression and random forest analyses. RPA identified three risk classes: high-risk (IPMN sampled with multiple microforceps passes, 28 % AEs rate), low-risk (1.4 % AE rate, including patients < 64 years with other-than-IPMN diagnosis sampled with ≤ 2 microforceps passes and with complete aspiration of the cyst) and middle-risk class (6.1 % AEs rate, including the remaining patients). CONCLUSION : TTNB should be selectively used in the evaluation of patients with IPMN. The present model could be applied during patient selection as to optimize the benefit/risk of TTNB.

Screening and surveillance of oesophageal varices in patients with HCV-positive liver cirrhosis successfully treated by direct-acting antiviral agents.

BACKGROUND & AIMS: limited evidence is available to guide hepatologists regarding endoscopic surveillance of oesophageal varices (EV) in Hepatitis C Virus (HCV)-positive cirrhotic patients achieving a sustained virologic response. To address these issues, we conducted a long-term prospective study on 427 HCV-positive cirrhotic patients successfully treated by Direct Antiviral Agents (DAAs). METHODS: Patients were divided into two groups according to their baseline Baveno VI status: Group 1 (92, 21.5%, favourable Baveno VI status) and Group 2 (335, 78.5%, unfavourable Baveno VI status). Each patient underwent baseline endoscopy and was endoscopically monitored for a median follow-up of 65.2 months according to Baveno VI recommendations. RESULTS: About 4.3% of Group 1 patients showed baseline EV compared with 30.1% of Group 2 patients (p < .0001). No patients belonging to Group 1 without baseline EV developed EV at follow-up endoscopy compared with 6.5% in Group 2 patients (p = .02); 69/107 (64.5%) patients with baseline EV showed small varices. During the endoscopic follow-up, EV disappeared/improved in 36 (33.6%), were stable in 39 (36.4%) and worsened in 32 (29.9%) patients, all belonging to Group 2 (p = .001). Improvement in Baveno VI status was observed in 118/335 (35.2%, p < .0001) of Group 2 patients and among those without pre-therapy EV, none developed EV throughout the follow-up. CONCLUSIONS: HCV-positive cirrhotic patients cured by DAAs showing baseline favourable Baveno VI status and no worsening during follow-up can safely avoid endoscopic screening and surveillance. Patients having unfavourable Baveno VI status without baseline EV who improve their status may suspend further endoscopic surveillance.

User Experience during an Immersive Virtual Reality-Based Cognitive Task: A Comparison between Estonian and Italian Older Adults with MCI.

Mild cognitive impairment (MCI) is an early stage of cognitive abilities loss and puts older adults at higher risk of developing dementia. Virtual reality (VR) could represent a tool for the early assessment of this pathological condition and for administering cognitive training. This work presents a study evaluating the acceptance and the user experience of an immersive VR application representing a supermarket. As the same application had already been assessed in Italy, we aimed to perform the same study in Estonia in order to compare the outcomes in the two populations. Fifteen older adults with MCI were enrolled in one Rehabilitation Center of Estonia and tried the supermarket once. Afterwards, they were administered questionnaires aimed at evaluating their technology acceptance, sense of presence, and cybersickness. Estonian participants reported low side effects and discrete enjoyment, and a sense of presence. Nonetheless, their intention to use the technology decreased after the experience. The comparison between Italian and Estonian older adults showed that cybersickness was comparable, but technology acceptance and sense of presence were significantly lower in the Estonian group. Thus, we argue that: (i) cultural and social backgrounds influence technology acceptance; (ii) technology acceptance was rather mediated by the absence of positive feelings rather than cybersickness.

Long-term follow-up of diabetic and non-diabetic patients with chronic hepatitis C successfully treated with direct-acting antiviral agents.

BACKGROUND AND AIMS: Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs). METHODS: Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established. RESULTS: After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics. CONCLUSIONS: SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.

Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis. We undertook this study to elucidate the interplay between macrophage activation, insulin resistance (IR) in target organs/tissues and hepatic damage. METHODS: In 40 non-diabetic patients with biopsy-proven NAFLD we assessed: i) endogenous glucose production (EGP), glucose clearance and indexes of IR in the adipose tissue (Adipo-IR and Lipo-IR) and in the liver (Hep-IR) by tracer infusion ([6,6-2H2]glucose and [2H5]glycerol); ii) macrophage activity (by soluble sCD163) and iii) hepatic expression of CD163 (hCD163). RESULTS: We found that sCD163 levels paralleled both the plasma free fatty acid (FFA) levels and lipolysis from adipose tissue. Consistently, sCD163 significantly correlated with adipose tissue IR (Adipo-IR: r = 0.32, p = 0.042; Lipo-IR: r = 0.39, p = 0.012). At multiple regression analysis, sCD163 levels were associated with FFA levels (rp = 0.35, p = 0.026). In vitro exposure of human monocyte-derived macrophages to palmitate enhanced sCD163 secretion. Conversely, sCD163 did not correlate with EGP or with Hep-IR. In the liver, hCD163 positively correlated with sCD163 (r = 0.58, p = 0.007) and the degree of steatosis (r = 0.34, p = 0.048), but not with EGP or Hep-IR (r = -0.27 and r = 0.11, respectively, p >0.10, both). CONCLUSIONS: Our findings suggest a link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, possibly in response to FFA overflow and independent of obesity and diabetes. Conversely, our findings do not support a link between activated hepatic macrophages and glucose metabolism (EGP or Hep-IR). The relationship between adipose tissue IR and hepatic macrophages should be considered to define therapeutic targets for NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis in the insulin resistant state. This study provides in vivo support for a possible link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, most likely in response to free fatty acid overflow and independent of obesity and diabetes.

Cabin as a Home: A Novel Comfort Optimization Framework for IoT Equipped Smart Environments and Applications on Cruise Ships.

The international tourism competition poses new challenges to the cruise sector, such as the achievement of the tourists' satisfaction and the increase in on board comfort. Moreover, the growing sophistication of tourists' needs leads to a more user-centric touristic offer. Consequently, a personalized cabin environment, which fits the users' activities and their characteristics, could be a plus value during the cruise vacation. These topics, however, are strictly connected with the diffusion of digital technologies and dynamics, which represent the tools to achieve the goal of a customized on-cruise experience. This paper presents E-Cabin, a novel Internet of Things (IoT) framework architecture that has at its core a reasoning system tuned on data gathered from the environment and from each specific passenger and the activities he/she performs. The framework leverages on knowledge representation with ontologies and consists of a publisher⁻subscriber communication framework that allows all of the IoT applications to use the reasoner and the provided ontologies. The paper demonstrates the proposed system in a demo cruise cabin where, by using the E-Cabin application, it is possible to set various atmospheres based on the users and activities occurring in the cabin.

A Social Virtual Reality-Based Application for the Physical and Cognitive Training of the Elderly at Home.

Frailty is a clinical condition affecting the elderly population which results in an increased risk of falls. Previous studies demonstrated that falls prevention programs are effective, but they suffer from low adherence, especially when subjects have to train unsupervised in their homes. To try to improve treatment adherence, virtual reality and social media have been proposed as promising strategies for the increase of users' motivation and thus their willingness to practice. In the context of smart homes, this work presents SocialBike, a virtual reality-based application aimed at improving the clinical outcomes of older frail adults in their houses. Indeed, SocialBike is integrated in the "house of the future" framework and proposes a Dual Task training program in which the users are required to cycle on a stationary bike while recognizing target animals or objects appearing along the way. It also implements the possibility of training with other users, thus reducing the risk of social isolation. Within SocialBike, users can choose the multiplayer mode they prefer (i.e., collaborative or competitive), and are allowed to train following their own attitude. SocialBike's validation, refinement, and business model are currently under development, and are briefly discussed as future works.

Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents.

Many studies showed insulin resistance amelioration in HCV-patients achieving Sustained Virologic Response (SVR) but results on glycemic control in diabetic patients are unclear. This study aimed to assess fasting glucose (FG) and glycated hemoglobin (HbA1c) values before and after therapy with direct-acting antivirals (DAAs) in HCV-patients with type 2 diabetes mellitus (T2DM). Of the 122 consecutively recruited patients with chronic hepatitis C and T2DM, 110 patients were treated with DAAs and 12 remained untreated. Clinical, biochemical, virological, and metabolic features were collected both at baseline and at 12 weeks after the end of therapy (EOT) or after a comparable period of time in untreated patients. A total of 101 patients obtained a SVR (Group 1), while nine were relapsers. Group 2 (21 patients) was composed by the nine relapsers and the 12 untreated patients. A significant reduction of mean FG (134.3 ± 41.32 mg/dL vs 152.4 ± 56.40 mg/dL, P = 0.002) and HbA1c values (46.51 ± 16.15 mmoL/moL vs 52.15 ± 15.43 mmoL/moL, P < 0.001) was found in Group 1 but not in Group 2 (140.6 ± 47.87 mg/dL vs. 145.31 ± 30.18 mg/dL, P = 0.707, and 55.31 ± 20.58 mmoL/moL vs. 53.38 ± 9.49 mmoL/moL, P = 0.780). In Group 1, 20.7% of patients could reduce or suspend their antidiabetic therapy compared to none in Group 2 (P = 0.03), despite the significant weight increase observed in Group 1. SVR induced a significant amelioration of glycemic control in diabetic HCV-patients, despite a significant weight increase; larger prospective studies are needed to verify whether these results are maintained over the long-term.

Giok the Alien: An AR-Based Integrated System for the Empowerment of Problem-Solving, Pragmatic, and Social Skills in Pre-School Children.

The use of technology for educational purposes is a consolidated reality, and many new tools are constantly being devised and offered for use with both normally developing children and children with special needs. Nonetheless, a detailed analysis of the processes being stimulated and of the goals being pursued is often lacking or absent. In this work we describe the design, development and preliminary testing of an integrated system which combines the use of smart devices, a physical cube, augmented reality (AR) technology, a smart TV, and a software application especially designed to stimulate cognitive and social functions in pre-school children. The system was tested with three groups of children (25 children in total) during kindergarten activities. The results show that the system is easy to understand, elicits high levels of participation and social interaction, favors strategic behaviors, and can be used by the children with limited need of instruction and support by the adult. The implications for empowerment in typically developing children and the possibilities for use with children who have specific impairments in social communication are discussed.

Characteristics, Usability, and Users Experience of a System Combining Cognitive and Physical Therapy in a Virtual Environment: Positive Bike.

We present the architecture and usability evaluation of virtual reality system-"Positive Bike"-designed for improving cognitive and motor conditions in frail elderly patients. The system consists of a cycle-ergometer integrated in an immersive virtual reality system (CAVE) which allows combining motor and cognitive exercises according to a "dual-task" paradigm. We tested the usability and user's experience of the prototype in a pilot evaluation study that involved five elderly patients. The prototype was tested in one-session training to understand the limitations and areas for improvement of our system. The evaluation consisted in (i) usability assessment using the system usability scale; (ii) evaluation of user's engagement using the flow state scale; and (iii) expert evaluation involving interviews with domain experts. Results showed a good usability, both for system usability scale and the semi-structured interview. The level of flow (i.e., enjoyment with the task at hand) measured using the short flow state scale, was also high. Analysis of semi-structured interview carried out with domain experts provided further indications to improve the system. Overall, these findings show that, despite some limitations, the system is usable and provides an enjoyable user's experience.

Negativization of viremia prior to liver transplant reduces early allograft dysfunction in hepatitis C-positive recipients.

Although early allograft dysfunction (EAD) negatively impacts survival from the first months following liver transplantation (LT), direct-acting antiviral agents (DAAs) have revolutionized hepatitis C virus (HCV) therapy. We investigated the EAD definition best predicting 90-day graft loss and identified EAD risk factors in HCV-positive recipients. From November 2002 to June 2016, 603 HCV-positive patients (hepatocellular carcinoma, 53.4%) underwent a first LT with HCV-negative donors. The median recipient Model for End-Stage Liver Disease (MELD) score was 15, and the median donor age was 63 years. At LT, 77 (12.8%) patients were HCV RNA negative; negativization was achieved and maintained by pre-LT antiviral therapy (61 patients) or pre-LT plus a pre-emptive post-LT course (16 patients); 60 (77.9%) patients received DAAs and 17 (22.1%) interferon. We compared 3 different EAD definitions: (1) bilirubin ≥ 10 mg/dL or international normalized ratio ≥ 1.6 on day 7 after LT or aspartate aminotransferase or alanine aminotransferase > 2000 IU/L within 7 days of LT; (2) bilirubin > 10 mg/dL on days 2-7 after LT; and (3) MELD ≥ 19 on day 5 after LT. EAD defined by MELD ≥ 19 on day 5 after LT had the lowest negative (0.1) and the highest positive (1.9) likelihood ratio to predict 90-day graft loss. At 90 days after LT, 9.2% of recipients with EAD lost their graft as opposed to 0.7% of those without EAD (P < 0.001). At multivariate analysis, considering variables available at LT, MELD at LT of >25 (OR = 7.4) or 15-25 (OR = 3.2), graft macrovesicular steatosis ≥ 30% (OR = 6.7), HCV RNA positive at LT (OR = 2.7), donor age > 70 years (OR = 2.0), earlier LT era (OR = 1.8), and cold ischemia time ≥ 8 hours (OR = 1.8) were significant risk factors for EAD. In conclusion, in HCV-positive patients, MELD ≥ 19 on day 5 after LT best predicts 90-day graft loss. Preventing graft infection by pre-/peri-LT antiviral therapy reduces EAD incidence and could be most beneficial in high-MELD patients and recipients of suboptimal grafts. Liver Transplantation 23 915-924 2017 AASLD.

Impact of viral eradication with sofosbuvir-based therapy on the outcome of post-transplant hepatitis C with severe fibrosis.

BACKGROUND & AIMS: Several studies have shown that new direct-acting antivirals maintain their efficacy in liver transplant (LT) recipients with severe hepatitis C virus (HCV) recurrence. We determined the clinical impact of sofosbuvir/ribavirin in LT through the changes in liver function and fibrosis state at 24 and 48 weeks after treatment. METHODS: Between June 2014 and July 2015, 126 patients (30 F3, 96 F4 Metavir stage) were enrolled to receive sofosbuvir + ribavirin (24 weeks, 118 patients) or sofosbuvir + simeprevir + ribavirin (12 weeks, 8 patients); treatment was initiated at a median time of 4.3 years from LT. Median follow-up after therapy completion was 461 days. RESULTS: All 30 F3 patients achieved a sustained virological response at week 24 after treatment (SVR24) and showed a distinct amelioration of the AST-to-platelet ratio index (APRI), FIB-4 and liver stiffness at elastography by week 24 post-therapy, which were maintained at week 48. Of the 96 F4 cirrhotic patients, 72 (75%) achieved SVR24 accompanied by significant improvement of liver function, which was maintained at week 48 (Child B-C 22% baseline, 11% week 24, 7% week 48); APRI, FIB-4 and liver stiffness further improved significantly between weeks 24 and 48 of follow-up. Among the 77 responders (27 F3, 50 F4) who underwent elastography at baseline and at the end of follow-up, 39 (50.6%; 18 F3, 21 F4) exhibited a regression in fibrosis stage. CONCLUSION: At about 1 year from the completion of successful sofosbuvir-based therapy, patients with post-LT HCV and severe fibrosis experienced a long-term liver function improvement accompanied by a regression of fibrosis stage in half of them.

An Ontology-Based Decision Support System for Tailored Clinical Nutrition Recommendations for Patients With Chronic Obstructive Pulmonary Disease: Development and Acceptability Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic condition among the main causes of morbidity and mortality worldwide, representing a burden on health care systems. Scientific literature highlights that nutrition is pivotal in respiratory inflammatory processes connected to COPD, including exacerbations. Patients with COPD have an increased risk of developing nutrition-related comorbidities, such as diabetes, cardiovascular diseases, and malnutrition. Moreover, these patients often manifest sarcopenia and cachexia. Therefore, an adequate nutritional assessment and therapy are essential to help individuals with COPD in managing the progress of the disease. However, the role of nutrition in pulmonary rehabilitation (PR) programs is often underestimated due to a lack of resources and dedicated services, mostly because pneumologists may lack the specialized training for such a discipline. OBJECTIVE: This work proposes a novel knowledge-based decision support system to support pneumologists in considering nutritional aspects in PR. The system provides clinicians with patient-tailored dietary recommendations leveraging expert knowledge. METHODS: The expert knowledge-acquired from experts and clinical literature-was formalized in domain ontologies and rules, which were developed leveraging the support of Italian clinicians with expertise in the rehabilitation of patients with COPD. Thus, by following an agile ontology engineering methodology, the relevant formal ontologies were developed to act as a backbone for an application targeted at pneumologists. The recommendations provided by the decision support system were validated by a group of nutrition experts, whereas the acceptability of such an application in the context of PR was evaluated by pneumologists. RESULTS: A total of 7 dieticians (mean age 46.60, SD 13.35 years) were interviewed to assess their level of agreement with the decision support system's recommendations by evaluating 5 patients' health conditions. The preliminary results indicate that the system performed more than adequately (with an overall average score of 4.23, SD 0.52 out of 5 points), providing meaningful and safe recommendations in compliance with clinical practice. With regard to the acceptability of the system by lung specialists (mean age 44.71, SD 11.94 years), the usefulness and relevance of the proposed solution were extremely positive-the scores on each of the perceived usefulness subscales of the technology acceptance model 3 were 4.86 (SD 0.38) out of 5 points, whereas the score on the intention to use subscale was 4.14 (SD 0.38) out of 5 points. CONCLUSIONS: Although designed for the Italian clinical context, the proposed system can be adapted for any other national clinical context by modifying the domain ontologies, thus providing a multidisciplinary approach to the management of patients with COPD.

A Knowledge-based Decision Support System for recommending safe recipes to individuals with dysphagia.

BACKGROUND: Dysphagia is a disorder that can be associated to several pathological conditions, including neuromuscular diseases, with significant impact on quality of life. Dysphagia often leads to malnutrition, as a consequence of the dietary changes made by patients or their caregivers, who may deliberately decide to reduce or avoid specific food consistencies (because they are not perceived as safe), and the lack of knowledge in how to process foods are critics. Such dietary changes often result in unbalanced nutrients intake, which can have significant consequences for frail patients. This paper presents the development of a prototypical novel ontology-based Decision Support System (DSS) to support neuromuscular patients with dysphagia (following a per-oral nutrition) and their caregivers in preparing nutritionally balanced and safe meals. METHOD: After reviewing scientific literature, we developed in collaboration with Ear-Nose-Throat (ENT) specialists, neurologists, and dieticians the DSS formalizes expert knowledge to suggest recipes that are considered safe according to patient's consistency limitations and dysphagia severity and also nutritionally well-balanced. RESULTS: The prototype can be accessed via digital applications both by physicians to generate and verify the recommendations, and by the patients and their caregivers to follow the step-by-step procedures to autonomously prepare and process one or more recipe. The system is evaluated with 9 clinicians to assess the quality of the DSS's suggested recipes and its acceptance in clinical practice. CONCLUSIONS: Preliminary results suggest a global positive outcome for the recipes inferred by the DSS and a good usability of the system.