Search

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.

Abstract 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.

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.

Interferon-beta (IFN-β) 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-β exerted protection against SARS-CoV-2 in people with MS (pwMS). In this viewpoint, we summarize the evidence on IFN-β 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-β usage for this condition. Finally, we leverage the lessons learned in the pandemic to suggest a role of IFN-β in long-COVID-19 and in special MS subpopulations.

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.

Over recent years, various virtual prototyping technologies have been developed to innovate apparel industry. For each step of the garment design process one can find dedicated tools (from body acquisition to garment modelling and simulation) with the aim of making the process easier and faster. However, most of them are based on expensive solutions both for hardware and software systems. In this paper, we focus the attention on the first step of the made-to-measure garment design, i.e. customer’s measures acquisition. We present a plug-in, named Tailor Tracking, which permits to get the measurements by interacting with the customer’s avatar using hands as in the traditional way. Tailor Tracking has been developed using low cost devices, such as Microsoft Kinect sensor, Leap motion device and Oculus Rift, and open source libraries, such as Visualisation Toolkit (VTK) and Qt. The proposed approach is based on the use of multiple Kinect v2 to simultaneously acquire both customer’s body and motion. This permits to emulate the customer’s postures required to take the correct measurements. In addition, a virtual measuring tape is made available to replicate the one commonly used by the tailor. A men shirt has been considered as case study and a tailor and 14 people with no skills in garment design and different levels of experience in virtual reality technology have been involved to preliminary test Tailor tracking. Finally, tests as well as results reached so far are presented and discussed. Results have been considered quite good; however, some critical measures have been identified as well as future developments. Anyway, Tailor Tracking can represent an alternative solution to the existing approaches that automatically extract anthropometric measures from the customer’s avatar.

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.

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.