Telemedicine and Remote Management of Patients with Heart Failure: From Theory to Daily Practice.

Background: Heart failure (HF) is responsible for a high number of hospitalizations, caused by a progressive worsening quality of life. Telemedicine allows for better management of patients' complex conditions, improving the care released. However, the risk of remaining at a testing stage often limits the integration of remote care in daily pathways for HF patients. The aim of this study is to outline the steps needed to integrate telemedicine activities into ordinary HF clinic practices. This methodology is applied to observe activities and trend improvements over a 12-month routine phase. Method: Three steps have been defined for an efficient introduction of remote care services in ordinary activities, integrating them with traditional in-person care: (i) introduction of temporary telemedicine projects, (ii) systematization of telemedicine pathways, and (iii) evaluation of monitoring phase. Observational data have been collected from structured interviews to show the rate of telemedicine activities achieved in clinical practice over the last year. Results: The methodology has been proposed in the HF clinic of the Italian hospital ASST Bergamo Est. After an initial testing phase, in which usability and user experience have been tested, four different remote activities were added: (i) telemonitoring for patients with an implantable device, (ii) follow-up televisits, (iii) nursing telephone support, and (iv) high-intensity telesurveillance pathways for patients after an HF acute event. During the last year, 218 telemonitoring pathways, 75 televisits, 500 telephone calls, and nine telesurveillance pathways have been performed. Success rates were high, and patients gave positive feedback. Conclusion: By integrating multiple telemedicine activities, it has been possible to better manage complex patients, keep track of disease progression, and improve their participation in care.

Motion acquisition of gait characteristics one week after total hip arthroplasty: a factor analysis.

INTRODUCTION: Clinical gait analysis can be used to evaluate the recovery process of patients undergoing total hip arthroplasty (THA). The postoperative walking patterns of these patients can be significantly influenced by the choice of surgical approach, as each procedure alters distinct anatomical structures. The aim of this study is twofold. The first objective is to develop a gait model to describe the change in ambulation one week after THA. The secondary goal is to describe the differences associated with the surgical approach. MATERIALS AND METHODS: Thirty-six patients undergoing THA with lateral (n = 9), anterior (n = 15), and posterior (n = 12) approaches were included in the study. Walking before and 7 days after surgery was recorded using a markerless motion capture system. Exploratory Factor Analysis (EFA), a data reduction technique, condensed 21 spatiotemporal gait parameters to a smaller set of dominant variables. The EFA-derived gait domains were utilized to study post-surgical gait variations and to compare the post-surgical gait among the three groups. RESULTS: Four distinct gait domains were identified. The most pronounced variation one week after surgery is in the Rhythm (gait cycle time: + 32.9 % ), followed by Postural control (step width: + 27.0 % ), Phases (stance time: + 11.0 % ), and Pace (stride length: -  9.3 % ). In postsurgical walking, Phases is statistically significantly different in patients operated with the posterior approach compared to lateral (p-value = 0.017) and anterior (p-value = 0.002) approaches. Furthermore, stance time in the posterior approach group is significantly lower than in healthy individuals (p-value < 0.001). CONCLUSIONS: This study identified a four-component gait model specific to THA patients. The results showed that patients after THA have longer stride time but shorter stride length, wider base of support, and longer stance time, although the posterior group had a statistically significant shorter stance time than the others. The findings of this research have the potential to simplify the reporting of gait outcomes, reduce redundancy, and inform targeted interventions in regards to specific gait domains.

Definition of a Method for the Evaluation of Telemedicine Platforms in the Italian Context.

Background: The COVID-19 outbreak led to the diffusion of several telemedicine solutions. The choice of the correct platform is crucial for ensuring the release of effective assistance. However, there is a lack of an objective method for the assessment of technical features. Objective: This study proposes a methodology for the evaluation of functional requirements of telemedicine platforms. This approach also permits the comparison of solutions in the Italian market by means of defined parameters, thus directing the choice of health care professionals. Methods: The study is divided into three phases. First, a mapping of the telemedicine platforms operating in Italy is performed. Then, the available platforms are selected based on the offered telemedicine activity. Finally, a method for evaluating the investigated platforms is defined. Results: Thirty-three (n = 33) technological systems were identified through an accurate investigation on the web and interviews with IT companies. Fifteen parameters were defined and organized into three categories: (1) usability of the telemedicine platform, (2) security, and (3) technological and organizational aspects. A score between 1 and 4 was assigned to each parameter, proportionally to the completeness of the platform. In particular, 62.96% of platforms reached an average score between 3.01 and 4 points; 33.33% of them had scores between 2.01 and 3, while the remaining 3.70% of solutions obtained a result between 1.01 and 2. Conclusions: The study provides an evaluation approach that is easily usable by health professionals to select the most suitable platform. The number of solutions and quality of information could be updated to obtain a complete tool.

Tracking and Characterization of Spinal Cord-Injured Patients by Means of RGB-D Sensors.

In physical rehabilitation, motion capture solutions are well-known but not as widespread as they could be. The main limit to their diffusion is not related to cost or usability but to the fact that the data generated when tracking a person must be elaborated according to the specific context and aim. This paper proposes a solution including customized motion capture and data elaboration with the aim of supporting medical personnel in the assessment of spinal cord-injured (SCI) patients using a wheelchair. The configuration of the full-body motion capturing system is based on an asymmetric 3 Microsoft Kinect v2 sensor layout that provides a path of up to 6 m, which is required to properly track the wheelchair. Data elaboration is focused on the automatic recognition of the pushing cycles and on plotting any kinematic parameter that may be interesting in the assessment. Five movements have been considered to evaluate the wheelchair propulsion: the humeral elevation, the horizontal abduction of the humerus, the humeral rotation, the elbow flexion and the trunk extension along the sagittal plane. More than 60 volunteers with a spinal cord injury were enrolled for testing the solution. To evaluate the reliability of the data computed with SCI APPlication (APP) for the pushing cycle analysis, the patients were subdivided in four groups according to the level of the spinal cord injury (i.e., high paraplegia, low paraplegia, C7 tetraplegia and C6 tetraplegia). For each group, the average value and the standard deviation were computed and a comparison with similar acquisitions performed with a high-end solution is shown. The measurements computed by the SCI-APP show a good reliability for analyzing the movements of SCI patients' propulsion wheelchair.

NGF steers microglia toward a neuroprotective phenotype.

Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti-inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways. At the functional level, NGF induces an increase in membrane dynamics and macropinocytosis and, in vivo, it activates an outward rectifying current that appears to modulate glutamatergic neurotransmission in nearby neurons. Since microglia are supposed to be a major player in Aß peptide clearance in the brain, we tested the effects of NGF on its phagocytosis. NGF was shown to promote TrkA-mediated engulfment of Aß by microglia, and to enhance its degradation. Additionally, the proinflammatory activation induced by Aß treatment is counteracted by the concomitant administration of NGF. Moreover, by acting specifically on microglia, NGF protects neurons from the Aß-induced loss of dendritic spines and inhibition of long term potentiation. Finally, in an ex-vivo setup of acute brain slices, we observed a similar increase in Aß engulfment by microglial cells under the influence of NGF. Our work substantiates a role for NGF in the regulation of microglial homeostatic activities and points toward this neurotrophin as a neuroprotective agent in Aß accumulation pathologies, via its anti-inflammatory activity on microglia.

Toxic properties of microsome-associated alpha-synuclein species in mouse primary neurons.

α-synuclein (αS) is a small protein that self-aggregates into α-helical oligomer species and subsequently into larger insoluble amyloid fibrils that accumulate in intraneuronal inclusions during the development of Parkinson's disease. Toxicity of αS oligomers and fibrils has been long debated and more recent data are suggesting that both species can induce neurodegeneration. However while most of these data are based on differences in structure between oligomer and aggregates, often preassembled in vitro, the in vivo situation might be more complex and subcellular locations where αS species accumulate, rather than their conformation, might contribute to enhanced toxicity. In line with this observation, we have shown that αS oligomers and aggregates are associated with the endoplasmic reticulum/microsomes (ER/M) membrane in vivo and how accumulation of soluble αS oligomers at the ER/M level precedes neuronal degeneration in a mouse model of α-synucleinopathies. In this paper we took a further step, investigating the biochemical and functional features of αS species associated with the ER/M membrane. We found that by comparison with non-microsomal associated αS (P10), the ER/M-associated αS pool is a unique population of oligomers and aggregates with specific biochemical traits such as increased aggregation, N- and C-terminal truncations and phosphorylation at serine 129. Moreover, when administered to murine primary neurons, ER/M-associated αS species isolated from diseased A53T human αS transgenic mice induced neuronal changes in a time- and dose-dependent manner. In fact the addition of small amounts of ER/M-associated αS species from diseased mice to primary cultures induced the formation of beads-like structures or strings of fibrous αS aggregates along the neurites, occasionally covering the entire process or localizing at the soma level. By comparison treatment with P10 fractions from the same diseased mice resulted in the formation of scarce and small puncta only when administered at high amount. Moreover, increasing the amount of P100/M fractions obtained from diseased and, more surprisingly, from presymptomatic mice induced a significant level of neuronal death that was prevented when neurons were treated with ER/M fractions immunodepleted of αS high molecular weight (HMW) species. These data provide the first evidence of the existence of two different populations of αS HMW species in vivo, putting the spotlight on the association to ER/M membrane as a necessary step for the acquisition of αS toxic features.

The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor.

Nerve growth factor is a therapeutic candidate for Alzheimer's disease. Due to its pain-inducing activity, in current clinical trials nerve growth factor is delivered locally into the brain by neurosurgery, but data on the efficacy of local nerve growth factor delivery in decreasing amyloid-ß deposition are not available. To reduce the nerve growth factor pain-inducing side effects, thus avoiding the need for local brain injection, we developed human painless nerve growth factor (hNGFp), inspired by the human genetic disease hereditary sensory and autonomic neuropathy type V. hNGFp has identical neurotrophic potency as wild-type human nerve growth factor, but a 10-fold lower pain sensitizing activity. In this study we first mimicked, in the 5xFAD mouse model, the intraparenchymal delivery of hNGFp used in clinical trials and found it to be ineffective in decreasing amyloid-ß plaque load. On the contrary, the same dose of hNGFp delivered intranasally, which was widely biodistributed in the brain and did not induce pain, showed a potent anti-amyloidogenic action and rescued synaptic plasticity and memory deficits. We found that hNGFp acts on glial cells, modulating inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. We further established that the rescuing effect by hNGFp is mediated by CXCL12, as pharmacological inhibition of CXCL12 receptor CXCR4 occludes most of hNGFp effects. These findings have significant therapeutic implications: (i) we established that a widespread exposure of the brain is required for nerve growth factor to fully exert its neuroprotective actions; and (ii) we have identified a new anti-neurodegenerative pathway as a broad target for new therapeutic opportunities for neurodegenerative diseases.

Exploring the Environmental Impact of Telemedicine: A Life Cycle Assessment.

BACKGROUND: Telemedicine has emerged as a potential solution to mitigate the significant greenhouse gas emissions of the healthcare sector. A comprehensive evaluation is required to quantify the environmental benefits of its implementation. OBJECTIVES: The study aims to compare the environmental sustainability of in-person and virtual examinations for heart failure patients. METHODS: A standard life cycle assessment has been applied to quantify the equivalent CO2 of direct and indirect activities required to release a medical examination (virtual or physical) for a patient in an Italian hospital. Inputs of the analysis include electronic devices of hospital and patients, energy consumption, wastes, internet usage and patient travel. Depending on the type of visit (virtual or physical), inputs have been processed differently, considering actual consumption and utilization. RESULTS: Televisit reduces emissions from 9.77 kgCO2e to 0.41 kgCO2e. Transport and internet data use are key inputs for in-person (i.e., 98%) and telemedicine visits (i.e., 72%), respectively. DISCUSSION: Given the frequent car travels, telemedicine emerges as a tool to improve environmental benefits and reduce time for patients and caregivers.

A Sustainable Approach to Telerehabilitation in Europe: Patients Are Ready, but Caregivers Are Essential.

BACKGROUND: Several studies have demonstrated the effectiveness of telerehabilitation. However, it remains unclear what proportion of people in need of rehabilitation can confidently use telecommunications networks and related devices. OBJECTIVES: The aim of this study is to estimate the proportion of patients who possess either the requisite digital literacy to perform telerehabilitation independently or have a family caregiver capable of providing effective support. METHODS: Synthetic populations with a realistic kinship network (i.e. family trees) representative of European countries are built. Age, sex, and location-specific prevalence rates of rehabilitation needs and digital skills are combined to estimate the percentage of digitally literate patients and patients with digitally literate relatives. RESULTS: In Europe, 86% of people in need of rehabilitation are potentially eligible for telerehabilitation. However, in four out of five cases, eligible patients over the age of 65 require caregiver support. CONCLUSION: Telerehabilitation has the potential to spread in Europe. Caregivers have an essential social role in ensuring sustainable access to telerehabilitation.

Prospective observational study to evaluate treatment satisfaction and effectiveness in patients with relapsing multiple sclerosis starting cladribine tablets (CLADREAL) in Italy.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

Sustainability in Healthcare: Methods and Tools for the Assessment.

BACKGROUND: Healthcare sector has a significant impact on the environment and people well-being. Therefore, it is interesting to understand how healthcare contributes to sustainable development. OBJECTIVE: The study aims to perform a literature review on the methodologies applied to quantify environmental impact in healthcare with an attention to telemedicine activities. METHODS: Scopus and PubMed databases were investigated between 2018 and 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) frameworks was followed for article selection. RESULTS: From initial 183 articles, 50 full-studies were included. Life-cycle assessment method proved to be a standard for assessing the impact of devices used in clinical practice. Indeed, for the investigation of care activities a unique methodology was not defined. The assessment of telemedicine is mainly based on avoided travels, and a standard methodology is still missing. CONCLUSIONS: To move toward a sustainable development other aspects of sustainability should be investigated.

Cladribine Tablets Mode of Action, Learning from the Pandemic: A Narrative Review.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, characterized by chronic, inflammatory, demyelinating, and neurodegenerative processes. MS management relies on disease-modifying drugs that suppress/modulate the immune system. Cladribine tablets (CladT) have been approved by different health authorities for patients with various forms of relapsing MS. The drug has been demonstrated to deplete CD4+ and CD8+ T-cells, with a higher effect described in the former, and to decrease total CD19+, CD20+, and naive B-cell counts. COVID-19 is expected to become endemic, suggesting its potential infection risk for immuno-compromised patients, including MS patients treated with disease-modifying drugs. We report here the available data on disease-modifying drug-treated-MS patients and COVID-19 infection and vaccination, with a focus on CladT. MS patients treated with CladT are not at higher risk of developing severe COVID-19. While anti-SARS-CoV-2 vaccination is recommended in all MS patients with guidelines addressing vaccination timing according to the different disease-modifying drugs, no vaccination timing restrictions seem to be necessary for cladribine, based on its mechanism of action and available evidence. Published data suggest that CladT treatment does not impact the production of anti-SARS-CoV-2 antibodies after COVID-19 vaccination, possibly due to its relative sparing effect on naïve B-cells and the rapid B-cell reconstitution following treatment. Slightly lower specific T-cell responses are likely not impacting the risk of breakthrough COVID-19. It could be stated that cladribine's transient effect on innate immune cells likely contributes to maintaining an adequate first line of defense against the SARS-CoV-2 virus.

Usability of a continuous oxygen saturation device for home telemonitoring.

Background: The emergency for the COVID-19 pandemic has led to greater use of home telemonitoring devices. The aim of this study was to assess the usability of continuous home-monitoring care with an oxygen saturation device on post-COVID-19 patients. Method: The system consists of a digital continuous pulse oximeter and a smartphone with an App, which were provided to patients. A survey composed of a standard Post-Study System Usability Questionnaire, and a satisfaction questionnaire was exploited to conduct a usability and feasibility analysis of the service. Results: A total of 29 patients (17.2% female) with a mean age of 65 ± 11.5 years were enrolled: 20 patients were smartphone users (69%) with a mean age of 60.2 ± 9.5 years, and 9 patients (31%) did not own a smartphone (mean age 76.8 ± 5.9). The monitoring period was 1 month: a total of 444 recordings were conducted, 15 recordings per patient averagely. In total, 82% of the recordings performed did not require any intervention, while 18% led to the production of a report and subsequent intervention by a nurse who verified, together with the specialist, the need to intervene (i.e. the patient accessed the clinic for medical control and/or modification of oxygen therapy). A total of 17 patients compiled a usability questionnaire. The service was perceived as useful and well-structured, although it often required caregiver support. Conclusions: Using continuous home-monitoring care with an oxygen saturation device seems feasible and useful for patients who could be followed at home avoiding going back to the hospital every time a trend oximetry is needed. Further improvements in connections, data flow processes, and simplifications, based on patients' feedback, are needed to scale up the service.

The value of Interferon ß in multiple sclerosis and novel opportunities for its anti-viral activity: a narrative literature review.

Interferon-beta (IFN-ß) for Multiple Sclerosis (MS) is turning 30. The COVID-19 pandemic rejuvenated the interest in interferon biology in health and disease, opening translational opportunities beyond neuroinflammation. The antiviral properties of this molecule are in accord with the hypothesis of a viral etiology of MS, for which a credible culprit has been identified in the Epstein-Barr Virus. Likely, IFNs are crucial in the acute phase of SARS-CoV-2 infection, as demonstrated by inherited and acquired impairments of the interferon response that predispose to a severe COVID-19 course. Accordingly, IFN-ß exerted protection against SARS-CoV-2 in people with MS (pwMS). In this viewpoint, we summarize the evidence on IFN-ß mechanisms of action in MS with a focus on its antiviral properties, especially against EBV. We synopsize the role of IFNs in COVID-19 and the opportunities and challenges of IFN-ß usage for this condition. Finally, we leverage the lessons learned in the pandemic to suggest a role of IFN-ß in long-COVID-19 and in special MS subpopulations.

Reduced levels of NGF shift astrocytes toward a neurotoxic phenotype.

Nerve growth factor (NGF) is critical for neuronal physiology during development and adulthood. Despite the well-recognized effect of NGF on neurons, less is known about whether NGF can actually affect other cell types in the central nervous system (CNS). In this work, we show that astrocytes are susceptible to changes in ambient levels of NGF. First, we observe that interfering with NGF signaling in vivo via the constitutive expression of an antiNGF antibody induces astrocytic atrophy. A similar asthenic phenotype is encountered in an uncleavable proNGF transgenic mouse model (TgproNGF#72), effectively increasing the brain proNGF levels. To examine whether this effect on astrocytes is cell-autonomous, we cultured wild-type primary astrocytes in the presence of antiNGF antibodies, uncovering that a short incubation period is sufficient to potently and rapidly trigger calcium oscillations. Acute induction of calcium oscillations by antiNGF antibodies is followed by progressive morphological changes similar to those observed in antiNGF AD11 mice. Conversely, incubation with mature NGF has no effect on either calcium activity nor on astrocytic morphology. At longer timescales, transcriptomic analysis revealed that NGF-deprived astrocytes acquire a proinflammatory profile. In particular, antiNGF-treated astrocytes show upregulation of neurotoxic transcripts and downregulation of neuroprotective mRNAs. Consistent with that data, culturing wild-type neurons in the presence of NGF-deprived astrocytes leads to neuronal cell death. Finally, we report that in both awake and anesthetized mice, astrocytes in layer I of the motor cortex respond with an increase in calcium activity to acute NGF inhibition using either NGF-neutralizing antibodies or a TrkA-Fc NGF scavenger. Moreover, in vivo calcium imaging in the cortex of the 5xFAD neurodegeneration mouse model shows an increased level of spontaneous calcium activity in astrocytes, which is significantly reduced after acute administration of NGF. In conclusion, we unveil a novel neurotoxic mechanism driven by astrocytes, triggered by their sensing and reacting to changes in the levels of ambient NGF.

A virtual environment to evaluate the arm volume for lymphedema affected patients.

BACKGROUND AND OBJECTIVE: The paper presents a novel procedure based on 3D scanning and 3D modelling to automatically assess linear and volumetric measurements of an arm and to be further applied to patients affected by post breast cancer lymphedema. The aim is the creation of a virtual platform easily usable by medical personnel to get more objective evaluations during the lymphedema treatment. METHODS: The procedure is based on the 3D scanning of the arm using the Occipital Structure Sensor and an ad-hoc developed application, named Lym 3DLab. Lym 3DLab emulates the traditional measurement methods, which consist in taking manual circumference measurements or using the water displacement method. These measurements are also used to design the compression stockings, the typical orthopaedic device used for lymphedema treatment. A validation test has been performed to compare the measurements computed by Lym 3DLab with both water displacement and manual circumference measurements. Eight volunteers have been involved who are not affected by lymphedema. Furthermore, a specific usability test has been performed to evaluate the 3D scanning procedure by involving four physiotherapists. RESULTS: The comparison between the volumes has highlighted how all the 3D acquired models have their volumes inside a range of acceptability. This range has been defined by considering the sensitivity error of the tape measure used to measure the water displacement. The comparison between the perimeters of cross sections computed with Lym 3DLab and the circumference measurements has shown results that are very accurate with an average difference of 2 mm. The measure errors have been considered negligible by the medical personnel who have evaluated the proposed procedure more accurate than the traditional ones. The test with physiotherapists has shown a high level of usability of the whole virtual environment, but the 3D scanning procedure requires an appropriate training of the personnel to make the 3D acquisition as fast and efficient as possible. CONCLUSIONS: The achieved results and the physiotherapists' feedback allow planning a future test with patients affected by lymphedema in collaboration with the hospital. A further test has been planned to use the computed measurements to design orthopaedic compression stockings.

A digital patient for computer-aided prosthesis design.

This article concerns the design of lower limb prosthesis, both below and above knee. It describes a new computer-based design framework and a digital model of the patient around which the prosthesis is designed and tested in a completely virtual environment. The virtual model of the patient is the backbone of the whole system, and it is based on a biomechanical general-purpose model customized with the patient's characteristics (e.g. anthropometric measures). The software platform adopts computer-aided and knowledge-guided approaches with the goal of replacing the current development process, mainly hand made, with a virtual one. It provides the prosthetics with a set of tools to design, configure and test the prosthesis and comprehends two main environments: the prosthesis modelling laboratory and the virtual testing laboratory. The first permits the three-dimensional model of the prosthesis to be configured and generated, while the second allows the prosthetics to virtually set up the artificial leg and simulate the patient's postures and movements, validating its functionality and configuration. General architecture and modelling/simulation tools for the platform are described as well as main aspects and results of the experimentation.