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Background: The wait for the upcoming disease-modifying therapies (DMT) for Alzheimer's disease in Europe is raising questions about the preparedness of national healthcare systems to conduct accurate diagnoses and effective prescriptions. In this article, we focus on the current situation in Italy. Objective: The primary goal is to propose a profile of the Italian Centers for Cognitive Disorders and Dementias (CCDDs) that could be taken into consideration by regional and autonomous provincial authorities when deciding on the prescribing centers for DMT. Methods: Based on responses to a national survey on CCDDs in Italy, we identified the CCDDs that meet the requirements for effective prescription: 1) Multidisciplinary team; 2) Minimum Core Test for the neuropsychological assessment; 3) PET, CSF, and Brain MRI assessments. Univariate and multivariate comparisons were conducted between CCDDs that met the criteria and the others. Results: Only 10.4% of CCDDs met the requirements for effective DMT prescription, mainly located in Northern Italy. They are also characterized by longer opening hours, a higher number of professionals, a university location, and a higher frequency of conducting genetic tests, and could potentially result in prescribing centers. Conclusions: The findings suggest that the Italian national healthcare system may benefit from further enhancements to facilitate the effective prescription of DMTs. This could involve initiatives to reduce fragmentation, ensure adequate resources and equipment, and secure sufficient funding to support this aspect of healthcare delivery.

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Older individuals often face disabilities or diseases that lower their quality of life (QoL). While inpatient rehabilitation can initially enhance QoL, there is often a lack of continuation at home. Virtual coaches (VCs) as specific embodied conversational agents promise appropriate support for home rehabilitation. They emerge as complementary digital aids to ensure care continuity. This paper presents the results of implementing a full-featured VC for older patients' home rehabilitation in a multi-stage study, summarizing the main results regarding QoL outcomes and user experience tests. The study confirms the intervention as an engaging means for rehabilitation (mostly above user experience thresholds) and improvements of QoL (>10% between experimental and control groups).

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Despite the efforts to identify fluid biomarkers to improve diagnosis of Frontotemporal dementia (FTD), only a few candidates have been described in recent years. In a previous study, we identified three circulating miRNAs (miR-92a-3p, miR-320a and miR-320b) differentially expressed in FTD patients with respect to healthy controls and/or Alzheimer's disease (AD) patients. Now, we investigated whether those changes could be due to miRNAs contained in neuron-derived extracellular vesicles (NDEVs). We also evaluated miRNAs content in total plasma EVs and in CSF samples. The analysis of plasma NDEVs carried out on 40 subjects including controls (n = 13), FTD (n = 13) and AD (n = 14) patients, showed that both miR-92a-3p and miR-320a levels were triplicated in the FTD group if compared with CT and AD patients. Increased levels of the same miRNAs were found also in CSF derived from FTD group compared to CTs. No differences were observed in expression levels of miR-320b among the three groups. Worthy of note, all miRNAs analysed were increased in an FTD cell model, MAPT IVS10 + 16 neurons. Our results suggest that miR-92a and miR-320a in NDEVs could be proposed as FTD biomarkers.

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OBJECTIVE: The Clock Drawing Test (CDT) is a widely used test for cognitive screening as its execution taps into a large number of cognitive functions. Because of the involvement of visuospatial abilities, the CDT is also commonly used to assess hemispatial neglect. In the present study, we introduce a new quantitative scoring method for the CDT that aims to measure the use of space for each half of the clock face and asymmetries of space use. METHOD: Two measures are introduced: the explored space (ES) and used space (US) for each half of the clock, as well as two derived asymmetry indices. Such new measures were applied to CDTs of four groups of participants: right brain-damaged patients without visuospatial neglect, two groups of right brain-damaged patients with varying degrees of visuospatial neglect, and a group of neurologically healthy participants. RESULTS: Analyses showed that only neglect patients explored and used the left clock half significantly less than the right one. This result was also confirmed by the asymmetry indices, where neglect patients showed a stronger rightward bias. For neglect patients, the US asymmetry index correlated with the patients' scores on the neuropsychological tests. The analyses of receiver operating characteristic curves showed that left US and left ES scores had good accuracy in categorizing neglect patients. CONCLUSIONS: The present work provides new quantitative indices of CDT space usage in hemispatial neglect. Cutoffs are provided for clinical practice.

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Optic Aphasia (OA) and Associative Visual Agnosia (AVA) are neuropsychological disorders characterized by impaired naming on visual presentation. From a cognitive point of view, while stimulus identification is largely unimpaired in OA (where access to semantic knowledge is still possible), in AVA it is not. OA has been linked with right hemianopia and disconnection of the occipital right-hemisphere (RH) visual processing from the left hemisphere (LH) language areas.In this paper, we describe the case of AA, an 81-year-old housewife suffering from a deficit in naming visually presented stimuli after left occipital lesion and damage to the interhemispheric splenial pathway. AA has been tested through a set of tasks assessing different levels of visual object processing. We discuss behavioral performance as well as the pattern of lesion and disconnection in relation to a neurocognitive model adapted from Luzzatti and colleagues (1998). Despite the complexity of the neuropsychological picture, behavioral data suggest that semantic access from visual input is possible, while a lesion-based structural disconnectome investigation demonstrated the splenial involvement.Altogether, neuropsychological and neuroanatomical findings support the assumption of visuo-verbal callosal disconnection compatible with a diagnosis of OA.

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BACKGROUND: Tracking gait and balance impairment in time is paramount in the care of older neurological patients. The Minimal Detectable Change (MDC), built upon the Standard Error of the Measurement (SEM), is the smallest modification of a measure exceeding the measurement error. Here, a novel method based on linear mixed-effects models (LMMs) is applied to estimate the standard error of the measurement from data collected before and after rehabilitation and calculate the MDC of gait and balance measures. METHODS: One hundred nine older adults with a gait impairment due to neurological disease (66 stroke patients) completed two assessment sessions before and after inpatient rehabilitation. In each session, two trials of the 10-meter walking test and the Timed Up and Go (TUG) test, instrumented with inertial sensors, have been collected. The 95% MDC was calculated for the gait speed, TUG test duration (TTD) and other measures from the TUG test, including the angular velocity peak (ωpeak) in the TUG test's turning phase. Random intercepts and slopes LMMs with sessions as fixed effects were used to estimate SEM. LMMs assumptions (residuals normality and homoscedasticity) were checked, and the predictor variable ln-transformed if needed. RESULTS: The MDC of gait speed was 0.13 m/s. The TTD MDC, ln-transformed and then expressed as a percentage of the baseline value to meet LMMs' assumptions, was 15%, i.e. TTD should be < 85% of the baseline value to conclude the patient's improvement. ωpeak MDC, also ln-transformed and expressed as the baseline percentage change, was 25%. CONCLUSIONS: LMMs allowed calculating the MDC of gait and balance measures even if the test-retest steady-state assumption did not hold. The MDC of gait speed, TTD and ωpeak from the TUG test with an inertial sensor have been provided. These indices allow monitoring of the gait and balance impairment, which is central for patients with an increased falling risk, such as neurological old persons. TRIAL REGISTRATION: NA.

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PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer. Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations. The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations. In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.

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INTRODUCTION: There is evidence to demonstrate that plasticity is "use-dependent" and that intensive practice may be necessary to modify neural organization. PURPOSE: The main aim of this work is to investigate the REACT usability, an innovative app, to assist People with Parkinson Disease (PwPD) at home. METHODS: A pilot study has been conducted enrolling 20 consecutive PwPD. Before home rehabilitation activities started, each patient received training on the REACT app and how to use the device and the services in daily practice. Motor and cognitive evaluations were administered to assign personalized exercises, tailored to patients' needs and potential. PwPD carried out REACT home program for 1 month, four times a week. The app included motor exercise and tutorial of activities of daily living (ADL) and functional cognitive stimulation. REACT-app usability was evaluated with the System Usability Scale (SUS). RESULTS: The results from SUS questionnaire were, on average, above the threshold of "good usability" (SUS score > 68), as reported in the literature. The 47% of PwPD that used the app rated the usability of the solution as "excellent." Almost all SUS items reached the reference benchmark (except items 4, 5, and 7). No adverse events occurred. CONCLUSIONS: REACT can be considered a useful and safe tool to support the continuity of care and treatment at home, in PwPD. Larger-scale trials are needed to validate the good acceptance and efficacy of home rehabilitation through technology applications.

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Introduction: Anodal transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost and environment-friendly brain neuromodulation technique that increases cortical excitability. In post-stroke aphasia, the role of the right hemisphere in language recovery remains debated. In this preliminary study, we aimed to investigate the efficacy of excitatory tDCS on the right hemisphere in chronic aphasic patients. Methods: We applied anodal tDCS to the right homologous region of Broca's area in four chronic aphasic patients while performing a one-month naming rehabilitation treatment. Longitudinal data on language assessment and naming performance were collected. Resting-state fMRI images were acquired before and after treatment to measure changes in functional connectivity. Results: Results showed enhanced positive functional connectivity of the right Broca homologous with the left middle frontal and middle temporal gyri. Every patient showed improvements in language functions, but no major changes in naming performance. Conclusion: These preliminary findings suggest that tDCS applied over the unaffected hemisphere may result in longitudinal inter-hemispheric functional neuroplastic changes that could specifically improve language recovery and could potentially be included in therapeutic neurorehabilitative plans.

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BACKGROUND: Chronic pain is one of the most common and critical long-term effects of breast cancer. Digital health technologies enhance the management of chronic pain by monitoring physical and psychological health status and supporting pain self-management and patient treatment decisions throughout the clinical pathway. OBJECTIVE: This pilot study aims to evaluate patients' experiences, including usability, with a novel digital integrated health ecosystem for chronic pain named PainRELife. The sample included patients with breast cancer during survivorship. The PainRELife ecosystem comprises a cloud technology platform interconnected with electronic health records and patients' devices to gather integrated health care data. METHODS: We enrolled 25 patients with breast cancer (mean age 47.12 years) experiencing pain. They were instructed to use the PainRELife mobile app for 3 months consecutively. The Mobile Application Rating Scale (MARS) was used to evaluate usability. Furthermore, pain self-efficacy and participation in treatment decisions were evaluated. The study received ethical approval (R1597/21-IEO 1701) from the Ethical Committee of the European Institute of Oncology. RESULTS: The MARS subscale scores were medium to high (range: 3.31-4.18), and the total app quality score was 3.90. Patients with breast cancer reported reduced pain intensity at 3 months, from a mean of 5 at T0 to a mean of 3.72 at T2 (P=.04). The total number of times the app was accessed was positively correlated with pain intensity at 3 months (P=.03). The engagement (P=.03), information (P=.04), and subjective quality (P=.007) subscales were positively correlated with shared decision-making. Furthermore, participants with a lower pain self-efficacy at T2 (mean 40.83) used the mobile app more than participants with a higher pain self-efficacy (mean 48.46; P=.057). CONCLUSIONS: The data collected in this study highlight that digital health technologies, when developed using a patient-driven approach, might be valuable tools for increasing participation in clinical care by patients with breast cancer, permitting them to achieve a series of key clinical outcomes and improving quality of life. Digital integrated health ecosystems might be important tools for improving ongoing monitoring of physical status, psychological burden, and socioeconomic issues during the cancer survivorship trajectory. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/41216.

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Parkinson's Disease's (PD) neuropsychological profile is often characterized by altered performance in executive functions (EF) tasks, with a remarkable impact on patients' quality of life. To date, the available neuroimaging literature lacks conclusive evidence about neural patterns underlying EF deficits in PD. Here, we aimed to synthesize the results of PET/fMRI studies examining the differences in brain activation between PD patients and controls during EF tasks, focusing on the three main EF sub-components: cognitive flexibility, working memory, and response inhibition. We conducted a coordinate-based meta-analysis to assess the converging alterations in brain activity in PD patients compared to controls. We assessed the association between aberrant patterns of activity and the EF sub-domains. We found a significant association between hypoactivation patterns in PD converging at the level of the right inferior frontal gyrus in response inhibition tasks, whereas hypoactivation in the left inferior frontal gyrus was found in association with the cognitive flexibility domain. Our results confirm the existence of neural alterations in PD patients in relation to specific EF sub-domains.

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Chronic pain is a condition in which the use of digital health technologies, ecological momentary assessments, and digital communication tools may boost patient's engagement and coping. Here we present the results of the PainRE-Life a project, financed by the Lombardy Region (Italy), aimed to develop a dynamic and integrated technology ecosystem based on big data management and analysis to allow care continuity in patients with pain, and able to act as a decision aid for patients and caregivers.

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Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection.

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Background: Balance, i.e., the ability not to fall, is often poor in neurological patients and this impairment increases their risk of falling. The Mini-Balance Evaluation System Test (Mini-BESTest), a rating scale, the Timed Up and Go (TUG) test, and gait measures are commonly used to quantify balance. This study assesses the criterion validity of these measures as balance measures. Methods: The probability of being a faller within nine months was used as the balance criterion. The Mini-BESTest, TUG (instrumented with inertial sensors), and walking test were administered before and after inpatient rehabilitation. Multiple and LASSO logistic regressions were used for the analysis. The diagnostic accuracy of the model was assessed with the area under the curve (AUC) of the receiver operating characteristic curve. Mobility measure validity was compared with the Akaike Information Criterion (AIC). Results: Two hundred and fourteen neurological patients (stroke, peripheral neuropathy, or parkinsonism) were recruited. In total, 82 patients fell at least once in the nine-month follow-up. The Mini-BESTest (AUC = 0.69; 95%CI: 0.62-0.76), the duration of the TUG turning phase (AUC = 0.69; 0.62-0.76), and other TUG measures were significant faller predictors in regression models. However, only the turning duration (AIC = 274.0) and Mini-BESTest (AIC = 276.1) substantially improved the prediction of a baseline model, which only included fall risk factors from the medical history (AIC = 281.7). The LASSO procedure selected gender, disease chronicity, urinary incontinence, the Mini-BESTest, and turning duration as optimal faller predictors. Conclusion: The TUG turning duration and the Mini-BESTest predict the chance of being a faller. Their criterion validity as balance measures in neurological patients is substantial.

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The neurofibromatosis-1 gene (NF1) was initially characterized because its germline mutation is responsible for an inherited syndromic disease predisposing tumor development, in particular neurofibromas but also various malignancies. Recently, large-scale tumor sequencing efforts have demonstrated NF1 as one of the most frequently mutated genes in human cancer, being mutated in approximately 5-10% of all tumors, especially in malignant peripheral nerve sheath tumors and different skin tumors. NF1 acts as a tumor suppressor gene that encodes neurofibromin, a large protein that controls neoplastic transformation through several molecular mechanisms. On the other hand, neurofibromin loss due to NF1 biallelic inactivation induces tumorigenic hyperactivation of Ras and mTOR signaling pathways. Moreover, neurofibromin controls actin cytoskeleton structure and the metaphase-anaphase transition. Consequently, neurofibromin deficiency favors cell mobility and proliferation as well as chromosomal instability and aneuploidy, respectively. Growing evidence supports the role of oxidative stress in NF1-related tumorigenesis. Neurofibromin loss induces oxidative stress both directly and through Ras and mTOR signaling activation. Notably, innovative therapeutic approaches explore drug combinations that further increase reactive oxygen species to boost the oxidative unbalance of NF1-altered cancer cells. In our paper, we review NF1-related tumors and their pathogenesis, highlighting the twofold contribution of oxidative stress, both tumorigenic and therapeutic.

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BACKGROUND: Alzheimer disease (AD) and Parkinson disease (PD) are the 2 most common neurodegenerative diseases affecting millions of people worldwide. The Personalized Integrated Care Promoting Quality of Life for Older People (PC4L) project proposes an integrated, scalable, and interactive care ecosystem that can be easily adapted to the needs of several neurodegenerative and chronic diseases, care institutions, and end user requirements. OBJECTIVE: The study protocol developed within the framework of the PC4L project aims to iteratively test the integrated platform and its modules, and focuses primarily on assessing the impact of the proposed solution (ie, the PC4L platform) on patients' quality of life, as well as its usability and feasibility on a large-scale sample size in 3 different scenarios (home, neurorehabilitation, and day care centers). METHODS: A prospective multicenter clinical study is conducted in 5 European countries (Germany, Italy, Portugal, Romania, and Spain) at 6 different pilot centers, for 3 months, in patients with PD, Parkinsonism, AD, and other dementias (ODs). Patients were randomized in a ratio of 1:1 to the intervention group (use of the PC4L system) or the control group (no intervention). The PC4L system consists mainly of a wristband for monitoring parameters such as steps and levels of physical activity, and the PC4L app, which includes different engaging functionalities. Both groups are assessed through baseline and end-of-study clinical evaluations, including assessment of quality of life through the EQ-5D-3L scale. RESULTS: The study protocol is part of a project approved and funded by the European Commission Horizon 2020 (grant agreement number 875221). The ethics committees of all involved centers reviewed and approved the study protocol. The study began with the recruitment phase in September 2022, and enrollment ended in February 2023. Recruitment is now closed (April 2023). The results of this study are expected to be published in summer 2023. A total of 558 patients, 279 per study group, were recruited. The results will allow to clarify the impact of PC4L on quality of life, will assess the empowerment of patients and the medical resources use, as well as the usability of the final version of the PC4L system. It will also provide information on the support of the system as a tool to facilitate the decision-making process. CONCLUSIONS: The PC4L project intends to test a technology-based, integrated, scalable, and interactive care platform on patients with neurodegenerative diseases and proposes a good coordinated care model between all involved actors. Future developments of the PC4L solution may involve caregivers and socio-health professionals in the decision-making process in order to facilitate efficient communication between all stakeholders and ensure reliable and protected access to data within Europe. TRIAL REGISTRATION: ClinicalTrials.gov NCT05538455; https://clinicaltrials.gov/study/NCT05538455. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47916.

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The number of people with dementia is increasing worldwide. Two main approaches have been adopted to identify subjects with Alzheimer's disease (AD): the neuropsychological evaluation and the identification of biomarkers of AD. The first method is less invasive and easier to perform. This study assesses the psychometric properties of COGITAB, a novel web application d esigned to be sensitive to the subtle cognitive changes distinctive of the early Mild Cognitive Impairment (MCI) and the preclinical phase of AD. We enrolled 518 healthy controls, classified according to several risk factors and the presence of a family history of dementia. The participants were given COGITAB after a neuropsychological screening. The COGITAB Total Score (TS) was significantly affected by age and years of education. Acquired risk factors and family history of dementia significantly impacted only the COGITAB total execution time (TET), not the TS. This study provides normative data for a newly developed web application. Control subjects with acquired risk factors performed slower, giving an important role to the TET recording. Further studies should examine the ability of this new technology to discriminate between healthy subjects and subjects with initial cognitive decline, even when not detected by standard neuropsychological assessments.

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BACKGROUND: Chronic pain (CP) and its management are critical issues in the care pathway of patients with breast cancer. Considering the complexity of CP experience in cancer, the international scientific community has advocated identifying cutting-edge approaches for CP management. Recent advances in the field of health technology enable the adoption of a novel approach to care management by developing integrated ecosystems and mobile health apps. OBJECTIVE: The primary end point of this pilot study is to evaluate patients' usability experience at 3 months of a new digital and integrated technological ecosystem, PainRELife, for CP in a sample of patients with breast cancer. The PainRELife ecosystem is composed of 3 main technological assets integrated into a single digital ecosystem: Fast Healthcare Interoperability Resources-based cloud platform (Nu platform) that enables care pathway definition and data collection; a big data infrastructure connected to the Fast Healthcare Interoperability Resources server that analyzes data and implements dynamic dashboards for aggregate data visualization; and an ecosystem of personalized applications for patient-reported outcomes collection, digital delivery of interventions and tailored information, and decision support of patients and caregivers (PainRELife app). METHODS: This is an observational, prospective pilot study. Twenty patients with early breast cancer and chronic pain will be enrolled at the European Institute of Oncology at the Division of Medical Senology and the Division of Pain Therapy and Palliative Care. Each patient will use the PainRELife mobile app for 3 months, during which data extracted from the questionnaires will be sent to the Nu Platform that health care professionals will manage. This pilot study is nested in a large-scale project named "PainRELife," which aims to develop a cloud technology platform to interoperate with institutional systems and patients' devices to collect integrated health care data. The study received approval from the Ethical Committee of the European Cancer Institute in December 2021 (number R1597/21-IEO 1701). RESULTS: The recruitment process started in May 2022 and ended in October 2022. CONCLUSIONS: The new integrated technological ecosystems might be considered an encouraging affordance to enhance a patient-centered approach to managing patients with cancer. This pilot study will inform about which features the health technological ecosystems should have to be used by cancer patients to manage CP. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41216.

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BACKGROUND: In the last few years, new noninvasive strategies have emerged as rehabilitative treatments for patients with stroke. Action observation treatment (AOT) is a rehabilitation approach based on the properties of the mirror neuron system with a positive impact on modifying cortical activation patterns and improving the upper limb kinematics. AOT involves the dynamic process of observing purposeful actions with the intention of imitating and then practicing those actions. In recent years, several clinical studies suggested the effectiveness of AOT in patients with stroke to improve motor recovery and autonomy in activities of daily living. However, a deeper knowledge of the behavior of the sensorimotor cortex during AOT seems to be essential. OBJECTIVE: The aim of this clinical trial, conducted in 2 neurorehabilitation centers and in patients' homes, is to investigate the effectiveness of AOT in patients with stroke, confirming the translational power of a tailored treatment. Particular emphasis will be placed on the predictive value of neurophysiological biomarkers. In addition, the feasibility and impact of a home-based AOT program will be investigated. METHODS: A 3-arm, assessor-blinded, randomized controlled trial will be performed by enrolling patients with stroke in the chronic stage. A total of 60 participants will be randomly allocated to receive 15 sessions of AOT with different protocols (AOT at the hospital, AOT at home, and sham AOT), 3 sessions per week. The primary outcome will be assessed using the Fugl-Meyer Assessment-Upper Extremity scores. Secondary outcomes will be clinical, biomechanical, and neurophysiological assessment. RESULTS: The study protocol is part of a project (project code GR-2016-02361678) approved and funded by the Italian Ministry of Health. The study began with the recruitment phase in January 2022, and enrollment was expected to end in October 2022. Recruitment is now closed (December 2022). The results of this study are expected to be published in spring 2023. Upon completion of the analyses, we will examine the preliminary effectiveness of the intervention and neurophysiological outcomes. CONCLUSIONS: This study will be used to evaluate the effectiveness of 2 different AOT scenarios (ie, AOT at the hospital and AOT at home) in patients with chronic stroke and to assess the predictive value of neurophysiological biomarkers. Specifically, we will attempt to induce the functional modification of the cortical components by exploiting the features of the mirror neuron system, demonstrating relevant clinical, kinematic, and neurophysiological changes after AOT. With our study, we also want to provide, for the first time in Italy, the AOT home-based program while assessing its feasibility and impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT04047134; https://clinicaltrials.gov/ct2/show/NCT04047134. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42094.