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Supplementary Table S3 in our recent publication [...].

BACKGROUND: Cranioplasty (CP) is supposed to improve the functional outcome of severe acquired brain injury (sABI) patients with decompressive craniectomy (DC). However, ongoing controversies exist regarding its indications, optimum materials, timing, complications, and relationships with hydrocephalus (HC). For these reasons, an International Consensus Conference (ICC) on CP in traumatic brain injury (TBI) was held in June 2018 to issue some recommendations. AIM: The aims of this study were: to investigate cross-sectionally before the ICC the prevalence of DC/CP in sABI inpatients admitted to neu- rorehabilitation units in Italy; to assess the perception of Italian clinicians working in the sABI neurorehabilitation settings on the management of inpatients with DC/CP during their rehabilitation stay. DESIGN: Cross-sectional. SETTING AND POPULATION: Physiatrists or neurologists working in 38 Italian rehabilitation centers involved in the care of sABI, giving a pooled sample of 599 inpatients. METHODS: Survey questionnaire consisting of 21 closed-ended questions with multiple-choice answers. Sixteen questions regarded the respondents' opinions and experiences regarding the clinical and management aspects of patients. Survey data were collected via e-mail between April and May 2018. RESULTS: About 1/3 of the 599 inpatients had either a DC (18.9%) or a CP (13.5%). TBI and cerebral hemorrhage were strongly associated with DC/CP, although the association was much stronger for TBI. Significant discrepancies were uncovered between some of the recommendations of the ICC and the corresponding perceptions of the respondents, especially regarding the clinical management of patients (i.e., CP timing). Clear guidelines were perceived as the most crucial factor in improving clinical pathways. CONCLUSIONS: Early collaboration between the neurosurgical and the neurorehabilitation teams is crucial to optimize all clinical and organizational factors, which could expedite CP and minimi

Advanced Therapy Medicinal Products (ATMPs) based on somatic cells expanded in vitro, with or without genetic modification, is a rapidly growing area of drug development, even more so following the marketing approval of several such products. ATMPs are produced according to Good Manufacturing Practice (GMP) in authorized laboratories. Potency assays are a fundamental aspect of the quality control of the end cell products and ideally could become useful biomarkers of efficacy in vivo. Here we summarize the state of the art with regard to potency assays used for the assessment of the quality of the major ATMPs used clinic settings. We also review the data available on biomarkers that may substitute more complex functional potency tests and predict the efficacy in vivo of these cell-based drugs.

BACKGROUND: Gait impairments are common disabling symptoms of Parkinson's disease (PD). Among the approaches for gait rehabilitation, interest in robotic devices has grown in recent years. However, the effectiveness compared to other interventions, the optimum amount of training, the type of device, and which patients might benefit most remains unclear. OBJECTIVE: To conduct a systematic review about the effects on gait of robot-assisted gait training (RAGT) in PD patients and to provide advice for clinical practice. METHODS: A search was performed on PubMed, Scopus, PEDro, Cochrane library, Web of science, and guideline databases, following PRISMA guidelines. We included English articles if they used a robotic system with details about the intervention, the parameters, and the outcome measures. We evaluated the level and quality of evidence. RESULTS: We included twenty papers out of 230 results: two systematic reviews, 9 randomized controlled trials, 4 uncontrolled studies, and 5 descriptive reports. Nine studies used an exoskeleton device and the remainders end-effector robots, with large variability in terms of subjects' disease-related disability. CONCLUSIONS: RAGT showed benefits on gait and no adverse events were recorded. However, it does not seem superior to other interventions, except in patients with more severe symptoms and advanced disease.

BACKGROUND: Many robots are available for gait rehabilitation (BWSTRT and ORET) and their application in persons with SCI allowed an improvement of walking function.OBJECTIVE: The aim of the study is to compare the effects of different robotic exoskeletons gait training in persons with different SCI level and severity.METHODS: Sixty-two studies were included in this systematic review; the study quality was assessed according to GRADE and PEDro's scale.RESULTS: Quality assessment of included studies (n = 62) demonstrated a prevalence of evidence level 2; the quality of the studies was higher for BWSTRT (excellent and good) than for ORET (fair and good). Almost all persons recruited for BWSTRT had an incomplete SCI; both complete and incomplete SCI were recruited for ORET. The SCI lesion level in the persons recruited for BWSTRT are from cervical to sacral; mainly from thoracic to sacral for ORET; a high representation of AIS D lesion resulted both for BWSTRT (30%) and for ORET (45%). The walking performance, tested with 10MWT, 6MWT, TUG and WISCI, improved after exoskeleton training in persons with incomplete SCI lesions, when at least 20 sessions were applied. Persons with complete SCI lesions improved the dexterity in walking with exoskeleton, but did not recover independent walking function; symptoms such as spasticity, pain and cardiovascular endurance improved.CONCLUSION: Different exoskeletons are available for walking rehabilitation in persons with SCI. The choice about the kind of robotic gait training should be addressed on the basis of the lesion severity and the possible comorbidities.

Monitoring is a critical component in fog environments: it promptly provides insights about the behavior of systems, reveals Service Level Agreements (SLAs) violations, enables the autonomous orchestration of services and platforms, calls for the intervention of operators, and triggers self-healing actions. In such environments, monitoring solutions have to cope with the heterogeneity of the devices and platforms present in the Fog, the limited resources available at the edge of the network, and the high dynamism of the whole Cloud-To-Thing continuum. This paper addresses the challenge of accurately and efficiently monitoring the Fog with a self-Adaptive peer-To-peer (P2P) monitoring solution that can opportunistically adjust its behavior according to the collected data exploiting a lightweight rule-based expert system.Empirical results show that adaptation can improve monitoring accuracy, while reducing network and power consumption at the cost of higher memory consumption.

Background: The recovery of walking after stroke is a priority goal for recovering autonomy. In the last years robotic systems employed for Robotic Assisted Gait Training (RAGT) were developed. However, literature and clinical practice did not offer standardized RAGT protocol or pattern of evaluation scales. Objective: This systematic review aimed to summarize the available evidence on the use of RAGT in post-stroke, following the CICERONE Consensus indications. Methods: The literature search was conducted on PubMed, Cochrane Library and PEDro, including studies with the following criteria: 1) adult post-stroke survivors with gait disability in acute/subacute/chronic phase; 2) RAGT as intervention; 3) any comparators; 4) outcome regarding impairment, activity, and participation; 5) both primary studies and reviews. Results: Sixty-one articles were selected. Data about characteristics of patients, level of disability, robotic devices used, RAGT protocols, outcome measures, and level of evidence were extracted. Conclusion: It is possible to identify robotic devices that are more suitable for specific phase disease and level of disability, but we identified significant variability in dose and protocols. RAGT as an add-on treatment seemed to be prevalent. Further studies are needed to investigate the outcomes achieved as a function of RAGT doses delivered.

Research reports a relationship between impulsive behaviors and unhealthy eating behaviors. Serious games, combining educational contents with gamification, can increase engagement in therapeutic activities and behavioral training programs. In this context, we have developed a Serious Game to promote healthy eating style in children and adolescents in which impulsivity is a predominant feature, specifically individuals with attention deficit hyperactivity disorder. An initial analysis of the usability of the Serious Game was performed on a sample of 12 participants by means of quantitative and qualitative measures. Participants' feedback, which was overall positive, was helpful for defining the required improvements. Once implemented, the serious game will be then proposed to children and their families and included in home-based educational interventions.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of comorbidities and death worldwide. Pulmonary Rehabilitation (PR) is a comprehensive intervention proven effective in improving COPD patients’ quality of life. However, its benefits often decrease with time because of low motivation, lack of direct surveillance, and low self-awareness. In this scenario, digital technologies can play a key role by allowing more engaging protocols and enabling home-based programs. The cooperation between clinical and technology experts is crucial to develop protocols that are effective and well-accepted by patients. This work aimed at developing and testing a hybrid PR program for patients with COPD based on digital applications that allow the personalization of the intervention, and support the delivery of healthcare services also in the context of continuity of care. Our protocol proved able to improve the patients’ condition, as traditional programs do, paving the way for the adoption of such technologies in the clinical practice.

The present work reports preliminary results in a group of post-COVID patients participating in a pulmonary rehabilitation program with an Immersive Virtual Reality system. 22 participants performed endurance training for 3 weeks, cycling in an Immersive Virtual Park while wearing a Head-Mounted Display. Motivation, positive and negative emotions, and flow status are assessed at the beginning (t0) and end (t1) of the rehabilitation program. All the variables related to motivation (Intrinsic Motivation, Identified Regulation, and External Regulation) obtain higher average scores after the rehabilitation program (respectively, p = 0.003, p = 0.006, p = 0.015), showing that the experience is perceived as fun, motivating, and as a choice and not an obligation. Similarly, the flow state increases with the experience (p = 0.024). At the same time, amotivation decreases during the 3 weeks of treatment (p < 0.001). During the PR program, no difference emerges between positive and negative affects, but positive affects are reported more often than negative ones. These preliminary results suggest that training with the Immersive Virtual Park is perceived as a highly positive experience and can support the patient’s motivation for long-term rehabilitation.

Atherosclerosis is a chronic and progressive inflammatory process beginning early in life with late clinical manifestation. This slow pathological trend underlines the importance to early identify high-risk patients and to treat intensively risk factors to prevent the onset and/or the progression of atherosclerotic lesions. In addition to the common Cardiovascular (CV) risk factors, new markers able to increase the risk of CV disease have been identified. Among them, high levels of Lipoprotein(a)—Lp(a)—lead to very high risk of future CV diseases; this relationship has been well demonstrated in epidemiological, mendelian randomization and genome-wide association studies as well as in meta-analyses. Recently, new aspects have been identified, such as its association with aortic stenosis. Although till recent years it has been considered an unmodifiable risk factor, specific drugs have been developed with a strong efficacy in reducing the circulating levels of Lp(a) and their capacity to reduce subsequent CV events is under testing in ongoing trials. In this paper we will review all these aspects: from the synthesis, clearance and measurement of Lp(a), through the findings that examine its association with CV diseases and aortic stenosis to the new therapeutic options that will be available in the next years.

Purpose: To investigate the acceptability and user experience of an in-hospital endurance training program based on the Virtual Park, a semi-immersive Virtual Reality (VR) system for patients with Chronic Obstructive Pulmonary Disease (COPD). Materials and methods Patients performed 20 min of cycling two times/day for around ten days. The evaluation included adherence, exercise capacity, physical performance, and user experience. Results: Fourteen patients (6 F/8 M; age = 71.29 ± 6.93 years) with mild/moderate COPD participated. The adherence rate was satisfying: 85.71% of patients attended the program without adverse events; the individual attendance rate (86.85% ± 27.43) was also high. The exercise capacity assessed before and after the training significantly improved in our group (6MWT pre-post: t(11)= −5.040, p < 0.05), as happens in standard PR programs. The physical performance metrics of each session indicate that all participants could sustain the proposed training protocol over the whole period. Patients judged the VR experience positively (User Experience Questionnaire = 1.84 ± 0.22) and were highly engaged in the activity for the whole period (Short Flow State Scale pre-post: 4.61 ± 0.27/4.40 ± 0.36). Conclusions: Our preliminary results open the possibility for further investigations on long-term motivation and clinical effectiveness of more immersive VR interventions for COPD.

INTRODUCTION: There is growing evidence on the efficacy of gait robotic rehabilitation in patients with multiple sclerosis (MS), but most of the studies have focused on gait parameters. Moreover, clear indications on the clinical use of robotics still lack. As part of the CICERONE Italian Consensus on Robotic Rehabilitation, the aim of this systematic review was to investigate the existing evidence concerning the role of lower limb robotic rehabilitation in improving functional recovery in patients with MS. EVIDENCE ACQUISITION: We searched for and systematically reviewed evidence-based studies on gait robotic rehabilitation in MS, between January 1st, 2010 and December 31st, 2020, in the following databases: Cochrane Library, PEDro, PubMed and Google Scholar. The study quality was assessed by the 16-item assessment of multiple systematic reviews 2 (AMSTAR 2) and the 10-item PEDro scale for the other research studies. EVIDENCE SYNTHESIS: After an accurate screening, only 17 papers were included in the review, and most of them (13 RCT) had a level II evidence. Most of the studies used the Lokomat as a grounded robotic device, two investigated the efficacy of end-effectors and two powered exoskeletons. Generally speaking, robotic treatment has beneficial effects on gait speed, endurance and balance with comparable outcomes to those of conventional treatments. However, in more severe patients (EDSS >6), robotics leads to better functional outcomes. Notably, after gait training with robotics (especially when coupled to virtual reality) MS patients also reach better non-motor outcomes, including spasticity, fatigue, pain, psychological well-being and quality of life. Unfortunately, no clinical indications emerge on the treatment protocols. CONCLUSIONS: The present comprehensive systematic review highlights the potential beneficial role on functional outcomes of the lower limb robotic devices in people with MS. Future studies are warranted to evaluate the role of robot

Introduction: Stroke is the third leading cause of adult disability worldwide, and lower extremity motor impairment is one of the major determinants of long-term disability. although robotic therapy is becoming more and more utilized in research protocols for lower limb stroke rehabilitation, the gap between research evidence and its use in clinical practice is still significant. The aim of this study was to determine the scope, quality, and consistency of guidelines for robotic lower limb rehabilitation after stroke, in order to provide clinical recommendations. EVidEncE acQuisition: We systematically reviewed stroke rehabilitation guideline recommendations between January 1, 2010 and october 31, 2020. We explored electronic databases (n.=4), guideline repositories and professional rehabilitation networks (n.=12). two independent reviewers used the appraisal of Guidelines for research and Evaluation (aGrEE) ii instrument, and brief syntheses were used to evaluate and compare the different recommendations, considering only the most recent version. EVIDENCE SYNTHESIS: From the 1219 papers screened, ten eligible guidelines were identified from seven different regions/countries. Four of the included guidelines focused on stroke management, the other six on stroke rehabilitation. robotic rehabilitation is generally recommended to improve lower limb motor function, including gait and strength. unfortunately, there is still no consensus about the timing, frequency, training session duration and the exact characteristics of subjects who could benefit from robotics. conclusions: our systematic review shows that the introduction of robotic rehabilitation in standard treatment protocols seems to be the future of stroke rehabilitation. however, robot assisted gait training (raGt) for stroke needs to be improved with new solutions and in clinical practice guidelines, especially in terms of applicability.

In literature a lot has been done to investigate the possible advantages of integrating the virtual and physical world, combining the benefits of both and improving the overall user experience. Plenty of tangible user interfaces were designed, to facilitate the development of cognitive skills, motor skills, social skills, or more concrete notions such as STEM concepts for children. Also, thanks to the flexibility provided by digital systems, it is recently growing a sub-research field that specifically addressed people with a cognitive disability. In this scenario, immersive multi-sensory environments are gaining more and more interest as a support tool for learning and therapeutic methods. In this paper, we present Smart Buckets, an interactive interface integrated into "Magika", a multi-sensory system; the result of co-design with therapists specialized in the treatment and education of children with a cognitive disability. The paper illustrates the multi-step co-design process used to produce this idea as a tailored support for their therapeutic activities. Finally, it highlights the importance of adding a new customizable tangible interaction combined within the multi-sensory experience of Magika system.

The post-COVID syndrome is emerging as a new chronic condition, characterized by symptoms of breathlessness, fatigue, and decline of neurocognitive functions. Rehabilitation programs that include physical training seem to be beneficial to reduce such symptoms and improve patients’ quality of life. Given this, and considering the limitations imposed by the pandemic on rehabilitation services, it emerged the need to integrate telerehabilitation programs into clinical practice. Some telerehabilitation solutions, also based on virtual reality (VR), are available in the market. Still, they mainly focus on rehabilitation of upper limbs, balance, and cognitive training, while exercises like cycling or walking are usually not considered. The presented work aims to fill this gap by integrating a VR application to provide cardio-respiratory fitness training to post-COVID patients in an existing telerehabilitation platform. The ARTEDIA application allows patients to perform a cycling exercise and a concurrent cognitive task. Patients can cycle in a virtual park while performing a “go/no-go” task by selecting only specific targets appearing along the way. The difficulty of the practice can be adjusted by the therapists, while the physiological response is continuously monitored through wearable sensors to ensure safety. The application has been integrated into the VRRS system by Khymeia. In the next months, a study to assess the feasibility of a complete telerehabilitation program based on physical and cognitive training will take place. Such a program will combine the existing VRRS exercises and the cardio-respiratory fitness exercise provided by the ARTEDIA application. Feasibility, acceptance, and usability will be assessed from both the patients’ and the therapists’ sides.

Virtual Reality (VR) has proven effective in improving rehabilitation by providing engaging and customized inter-ventions. The application of VR in pulmonary rehabilitation is still limited, although it may increase patients' exercise tolerance. Studies on other target groups prove that VR can modify exercise performance and reduce perceived effort. Despite encouraging, the methodological differences among studies prevent reaching definitive conclusions on whether VR can influence exercise tolerance and which factors are more impactful. Our work aims to define and validate an experimental protocol for quantitative evaluation of the effects of VR on perceived effort. Secondary goals are to investigate whether a higher degree of immersion or interaction induces a lower perceived exertion. The experimental protocol consists of cycling at light/moderate intensity under four conditions: no VR, non-immersive VR, immersive VR with and without a dual-task. Heart rate, breathing response (breathing rate, tidal volume, and minute ventilation), cycling cadence, and rate of perceived exertion (RPE) are measured. Thirteen healthy adults (25.08pm 5.50 years) participated in the study. Results show that the protocol is sustainable and suitable for the aims set. All participants maintained the predefined exercise intensity and the desired cadence. RPE was not influenced by any VR factor (p = 0.224), although showing a tendency to decrease in the case of immersive VR (RPE = 11). In the future, a broader sample will allow drawing more definitive results. Further investigations include more factors in the analysis and replicate the study to healthy elderly and respiratory patients.

Technological advances, lower cost, and greater availability of extended reality (XR) have led to more widespread applications and uptake of these technologies. Simulated environments can be used to study, measure, and influence human behavior in a variety of situations, and there are many examples of application in education, training, and rehabilitation, among others. However, the quality of the user experience and effectiveness of these applications are influenced by a variety of factors including the design of, and interaction with, the technology. This chapter presents an overview of human factors/ergonomics (HF/E) issues associated with XR with reference to user experience models defined in early virtual reality research. Using case examples that show how multisensory and multimodal interaction techniques can enhance the realism and efficacy of the user experience, and how XR technology can be used to deliver engaging and effective rehabilitation programs for older users, the importance of HF/E considerations are highlighted. Recommendations for future research include: the need for deeper understanding regarding optimum design of simulation content and multimodal user interaction; cost/benefit analysis taking into account user characteristics and the context of use; a provision of guidelines to aid technology producers during the design process for development of new XR applications; and standardized protocols for the evaluation of user experiences.

Disabilities related to motor and/or cognitive impairment may impact driving abilities. The project Rip@rto aims at supporting INAIL personnel during the evaluation of the residual capabilities of people with disability who apply for a driving license. The newly designed simulator presents new features compared to the current state of art. It will provide a realistic 3D environment and a mechatronic platform to improve the realism of the driving experience. The simulator will also allow collecting objective (mental workload) and subjective (stress, risk perception, user-experience) data to support the operator's decision.

Endothelial dysfunction (ED) is frequently found in patients with heart failure (HF). Among several pharmacological agents reported to improve endothelial function, levosimendan seems to be a promising one, even though, to date, only two previously published studies have evaluated its effects on ED in these patients. The aim of our pilot study was to further investigate the role of periodic levosimendan infusion on endothelial function in patients affected by advanced HF. In this cross-sectional study, three different groups were enrolled: 20 patients with advanced HF treated with periodic levosimendan (LEVO), 20 patients with HF on optimal medical therapy (OMT), and 20 healthy subjects (control group). ED was evaluated through flow-mediated dilation (FMD) at the level of the brachial artery. The three groups presented similar ages with significant differences in gender distribution, systolic blood pressure, and chronic kidney disease (eGFR < 30 mL/min). In HF patients, ischaemic aetiology was more prevalent in the LEVO group than in the OMT group (60 vs. 40%, p < 0.001). The New York Heart Association (NYHA) functional class was worse in the LEVO group, as well as in NT-proBNP (5636.7 ± 6164.6 ng/dL and 1243.7 ± 1487.2 ng/dL, in the LEVO and OMT groups, respectively, p = 0.005). The FMD was significantly higher in the healthy control group compared to that of the OMT group (15.7 ± 6.4 vs. 9.1 ± 6.0%, p = 0.007) while it showed an intermediate value in LEVO patients (12.4 ± 7.1%) (ANOVA p = 0.010). In conclusion, levosimendan therapy seems to ameliorate endothelial dysfunction related to heart failure. Longitudinal studies in patients on periodic therapy are needed in order to confirm the long-term effects of levosimendan on ED.

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.