Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis.

Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive assessment of their effects on the immune system in comparison to treatment-naïve pwRRMS. Herein, we evaluated the numbers of circulating B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naïve or treated with different DMTs. Compared to treatment-naïve pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4+ and CD8+ T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) ß have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study comprehensively evaluates the magnitude of the effect of different DMTs on blood immune cells providing a better understanding of therapy outcome. Furthermore, the lack of a discernible pattern in the effects of DMTs on blood immune cells suggests that multiple immune cells can independently modulate the disease.

One-year regional brain volume changes as potential predictors of cognitive function in multiple sclerosis: a pilot study.

BACKGROUND: The most reliable magnetic resonance imaging (MRI) marker of cognitive dysfunction in multiple sclerosis (MS) is brain atrophy. However, 1-year volumetric changes prior to cognitive assessment were never studied as potential predictors of cognition, which we aim to assess with this pilot work. METHODS: Twenty-two MS patients were submitted to a baseline measure of 83 regional brain volumes with MRI and re-evaluated 1 year later; they were also tested with the Brief International Cognitive Assessment for MS (BICAMS): sustained attention and processing speed were examined with the Symbol Digit Modalities Test (SDMT), verbal and visuo-spatial learning and memory with the learning trials from the California Verbal Learning Test-II (CVLT) and the Brief Visuo-spatial Memory Test-revised (BVMT), respectively. Controlling for age, sex, and years of education, a multivariate linear regression model was created for each cognitive score at 1-year follow-up in a backward elimination manner, considering cross-sectional regional volumes and 1-year volume changes as potential predictors. RESULTS: Decreases in the volumes of the left amygdala and the right lateral orbitofrontal cortex in the year prior to assessment were identified as possible predictors of worse performance in verbal memory (P = 0.009) and visuo-spatial memory (P = 0.001), respectively, independently of cross-sectional brain regional volumes at time of testing. CONCLUSION: Our work reveals novel 1-year regional brain volume changes as potential predictors of cognitive deficits in MS. This suggests a possible role of these regions in such deficits and might contribute to uncover cognitively deteriorating patients, whose detection is still unsatisfying in clinical practice.

Astrocytes Undergo Metabolic Reprogramming in the Multiple Sclerosis Animal Model.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that presents a largely unknown etiopathology. The presence of reactive astrocytes in MS lesions has been described for a long time; however, the role that these cells play in the pathophysiology of MS is still not fully understood. Recently, we used an MS animal model to perform high-throughput sequencing of astrocytes' transcriptome during disease progression. Our data show that astrocytes isolated from the cerebellum (a brain region typically affected in MS) showed a strong alteration in the genes that encode for proteins related to several metabolic pathways. Specifically, we found a significant increase in glycogen degradation, glycolytic, and TCA cycle enzymes. Together with these alterations, we detected an upregulation of genes that characterize "astrocyte reactivity". Additionally, at each disease time point we also reconstructed the morphology of cerebellum astrocytes in non-induced controls and in EAE animals, near lesion regions and in the normal-appearing white mater (NAWM). We found that near lesions, astrocytes presented increased length and complexity compared to control astrocytes, while no significant alterations were observed in the NAWM. How these metabolic alterations are linked with disease progression is yet to be uncovered. Herein, we bring to the literature the hypothesis of performing metabolic reprogramming as a novel therapeutic approach in MS.

Anthocyanins and reactive oxygen species: a team of rivals regulating plant development?

Anthocyanins are a family of water-soluble vacuolar pigments present in almost all flowering plants. The chemistry, biosynthesis and functions of these flavonoids have been intensively studied, in part due to their benefit for human health. Given that they are efficient antioxidants, intense research has been devoted to studying their possible roles against damage caused by reactive oxygen species (ROS). However, the redox homeostasis established between antioxidants and ROS is important for plant growth and development. On the one hand, high levels of ROS can damage DNA, proteins, and lipids, on the other, they are also required for cell signaling, plant development and stress responses. Thus, a balance is needed in which antioxidants can remove excessive ROS, while not precluding ROS from triggering important cellular signaling cascades. In this article, we discuss how anthocyanins and ROS interact and how a deeper understanding of the balance between them could help improve plant productivity, nutritional value, and resistance to stress, while simultaneously maintaining proper cellular function and plant growth.

Assessment of the treating physicians' first-hand experience with handling and satisfaction of ofatumumab therapy: findings from the PERITIA survey conducted in Europe.

BACKGROUND: Real-world evidence on experience and satisfaction of ofatumumab as a treatment option for relapsing multiple sclerosis (RMS) is limited. OBJECTIVE: To present cumulative responses from a questionnaire related to first-hand experience of treating physicians on handling and convenience of ofatumumab therapy along with concerns related to COVID-19. METHODS: PERITIA was a multicentre survey conducted to collect responses from the ASCLEPIOS I/II trial investigators from Europe via an online questionnaire. RESULTS: Forty-six physicians (Germany, n = 14; Spain, n = 12; Portugal, n = 10; Italy, n = 10) completed the survey. Overall, 43% of the physicians considered the benefit-risk ratio of ofatumumab as very good. Over 93% were in favour of ofatumumab self-administration at home and the majority (83%) believed it to be completely true that self-administration of ofatumumab eases the burden for patients in terms of time. All investigators would like to potentially use anti-CD20 therapy as a long-term strategy. Even during the COVID-19 pandemic, physicians were in favour of a self-administration of MS therapy at home over other anti-CD20 therapy infusions. CONCLUSION: European neurologists who were part of this survey considered the benefit-risk-ratio of ofatumumab as favourable and the monthly self-administered subcutaneous injections offering convenience for patients in the clinical practice.

People with Primary Progressive Multiple Sclerosis Have a Lower Number of Central Memory T Cells and HLA-DR+ Tregs.

The importance of circulating immune cells to primary progressive multiple sclerosis (PPMS) pathophysiology is still controversial because most immunotherapies were shown to be ineffective in treating people with PPMS (pwPPMS). Yet, although controversial, data exist describing peripheral immune system alterations in pwPPMS. This study aims to investigate which alterations might be present in pwPPMS free of disease-modifying drugs (DMD) in comparison to age- and sex-matched healthy controls. A multicentric cross-sectional study was performed using 23 pwPPMS and 23 healthy controls. The phenotype of conventional CD4+ and CD8+ T cells, regulatory T cells (Tregs), B cells, natural killer (NK) T cells and NK cells was assessed. Lower numbers of central memory CD4+ and CD8+ T cells and activated HLA-DR+ Tregs were observed in pwPPMS. Regarding NK and NKT cells, pwPPMS presented higher percentages of CD56dimCD57+ NK cells expressing NKp46 and of NKT cells expressing KIR2DL2/3 and NKp30. Higher disease severity scores and an increasing time since diagnosis was correlated with lower numbers of inhibitory NK cells subsets. Our findings contribute to reinforcing the hypotheses that alterations in peripheral immune cells are present in pwPPMS and that changes in NK cell populations are the strongest correlate of disease severity.

Promoter replacement of ANT1 induces anthocyanin accumulation and triggers the shade avoidance response through developmental, physiological and metabolic reprogramming in tomato.

The accumulation of anthocyanins is a well-known response to abiotic stresses in many plant species. However, the effects of anthocyanin accumulation on light absorbance and photosynthesis are unknown . Here, we addressed this question using a promoter replacement line of tomato constitutively expressing a MYB transcription factor (ANTHOCYANIN1, ANT1) that leads to anthocyanin accumulation. ANT1-overexpressing plants displayed traits associated with shade avoidance response: thinner leaves, lower seed germination rate, suppressed side branching, increased chlorophyll concentration, and lower photosynthesis rates than the wild type. Anthocyanin-rich leaves exhibited higher absorbance of light in the blue and red ends of the spectrum, while higher anthocyanin content in leaves provided photoprotection to high irradiance. Analyses of gene expression and primary metabolites content showed that anthocyanin accumulation produces a reconfiguration of transcriptional and metabolic networks that is consistent with, but not identical to those described for the shade avoidance response. Our results provide novel insights about how anthocyanins accumulation affects the trade-off between photoprotection and growth.

Cost-effectiveness Analysis of Ocrelizumab for the Treatment of Relapsing and Primary Progressive Multiple Sclerosis in Portugal.

OBJECTIVES: Ocrelizumab demonstrated significant clinical benefit for the treatment of relapsing (RMS) and primary progressive (PPMS) multiple sclerosis (MS), an incurable disease characterized by disability progression. This study evaluated the clinical and economic impact of ocrelizumab relative to current clinical practice, including other disease-modifying therapies (DMT), available in Portugal. METHODS: Markov models for MS were adapted to estimate the impact of ocrelizumab across three patient populations: treatment-naïve RMS, previously treated RMS, and PPMS. Health states were defined according to the Expanded Disability Status Scale. For RMS, the model further captured the occurrence of relapses and progression to secondary progressive multiple sclerosis (SPMS). A lifetime time-horizon and Portuguese societal perspective were adopted. RESULTS: For RMS patients, ocrelizumab was estimated to maximize the expected time (years) without progression to SPMS (10.50) relative to natalizumab (10.10), dimethyl fumarate (8.64), teriflunomide (8.39), fingolimod (8.38), interferon ß-1a (8.33) and glatiramer acetate (8.18). As the most effective option, with quality-adjusted life year (QALY) gains between 0.3 and 1.2, ocrelizumab was found to be cost-saving relative to natalizumab and fingolimod, and presented incremental cost-effectiveness ratios (ICER) below €16,720/QALY relative to the remaining DMT. For PPMS patients, the ICER of ocrelizumab versus best supportive care was estimated at €78,858/QALY. CONCLUSIONS: Ocrelizumab provides important health benefits for RMS and PPMS patients, comparing favourably with other widely used therapies. In RMS, ocrelizumab was revealed to be either cost-saving or have costs-per-QALY likely below commonly accepted cost-effectiveness thresholds. In PPMS, ocrelizumab fills a clear clinical gap in the current clinical practice. Overall, ocrelizumab is expected to provide good value for money in addressing the need of MS patients.

A Review on Locomotion Mode Recognition and Prediction When Using Active Orthoses and Exoskeletons.

Understanding how to seamlessly adapt the assistance of lower-limb wearable assistive devices (active orthosis (AOs) and exoskeletons) to human locomotion modes (LMs) is challenging. Several algorithms and sensors have been explored to recognize and predict the users' LMs. Nevertheless, it is not yet clear which are the most used and effective sensor and classifier configurations in AOs/exoskeletons and how these devices' control is adapted according to the decoded LMs. To explore these aspects, we performed a systematic review by electronic search in Scopus and Web of Science databases, including published studies from 1 January 2010 to 31 August 2022. Sixteen studies were included and scored with 84.7 ± 8.7% quality. Decoding focused on level-ground walking along with ascent/descent stairs tasks performed by healthy subjects. Time-domain raw data from inertial measurement unit sensors were the most used data. Different classifiers were employed considering the LMs to decode (accuracy above 90% for all tasks). Five studies have adapted the assistance of AOs/exoskeletons attending to the decoded LM, in which only one study predicted the new LM before its occurrence. Future research is encouraged to develop decoding tools considering data from people with lower-limb impairments walking at self-selected speeds while performing daily LMs with AOs/exoskeletons.

Robotic Biofeedback for Post-Stroke Gait Rehabilitation: A Scoping Review.

This review aims to recommend directions for future research on robotic biofeedback towards prompt post-stroke gait rehabilitation by investigating the technical and clinical specifications of biofeedback systems (BSs), including the complementary use with assistive devices and/or physiotherapist-oriented cues. A literature search was conducted from January 2019 to September 2022 on Cochrane, Embase, PubMed, PEDro, Scopus, and Web of Science databases. Data regarding technical (sensors, biofeedback parameters, actuators, control strategies, assistive devices, physiotherapist-oriented cues) and clinical (participants' characteristics, protocols, outcome measures, BSs' effects) specifications of BSs were extracted from the relevant studies. A total of 31 studies were reviewed, which included 660 stroke survivors. Most studies reported visual biofeedback driven according to the comparison between real-time kinetic or spatiotemporal data from wearable sensors and a threshold. Most studies achieved statistically significant improvements on sensor-based and clinical outcomes between at least two evaluation time points. Future research should study the effectiveness of using multiple wearable sensors and actuators to provide personalized biofeedback to users with multiple sensorimotor deficits. There is space to explore BSs complementing different assistive devices and physiotherapist-oriented cues according to their needs. There is a lack of randomized-controlled studies to explore post-stroke stage, mental and sensory effects of BSs.

A multi-camera and multimodal dataset for posture and gait analysis.

Monitoring gait and posture while using assisting robotic devices is relevant to attain effective assistance and assess the user's progression throughout time. This work presents a multi-camera, multimodal, and detailed dataset involving 14 healthy participants walking with a wheeled robotic walker equipped with a pair of affordable cameras. Depth data were acquired at 30 fps and synchronized with inertial data from Xsens MTw Awinda sensors and kinematic data from the segments of the Xsens biomechanical model, acquired at 60 Hz. Participants walked with the robotic walker at 3 different gait speeds, across 3 different walking scenarios/paths at 3 different locations. In total, this dataset provides approximately 92 minutes of total recording time, which corresponds to nearly 166.000 samples of synchronized data. This dataset may contribute to the scientific research by allowing the development and evaluation of: (i) vision-based pose estimation algorithms, exploring classic or deep learning approaches; (ii) human detection and tracking algorithms; (iii) movement forecasting; and (iv) biomechanical analysis of gait/posture when using a rehabilitation device.

Deep Learning-Based Energy Expenditure Estimation in Assisted and Non-Assisted Gait Using Inertial, EMG, and Heart Rate Wearable Sensors.

Energy expenditure is a key rehabilitation outcome and is starting to be used in robotics-based rehabilitation through human-in-the-loop control to tailor robot assistance towards reducing patients' energy effort. However, it is usually assessed by indirect calorimetry which entails a certain degree of invasiveness and provides delayed data, which is not suitable for controlling robotic devices. This work proposes a deep learning-based tool for steady-state energy expenditure estimation based on more ergonomic sensors than indirect calorimetry. The study innovates by estimating the energy expenditure in assisted and non-assisted conditions and in slow gait speeds similarly to impaired subjects. This work explores and benchmarks the long short-term memory (LSTM) and convolutional neural network (CNN) as deep learning regressors. As inputs, we fused inertial data, electromyography, and heart rate signals measured by on-body sensors from eight healthy volunteers walking with and without assistance from an ankle-foot exoskeleton at 0.22, 0.33, and 0.44 m/s. LSTM and CNN were compared against indirect calorimetry using a leave-one-subject-out cross-validation technique. Results showed the suitability of this tool, especially CNN, that demonstrated root-mean-squared errors of 0.36 W/kg and high correlation (ρ > 0.85) between target and estimation (R¯2 = 0.79). CNN was able to discriminate the energy expenditure between assisted and non-assisted gait, basal, and walking energy expenditure, throughout three slow gait speeds. CNN regressor driven by kinematic and physiological data was shown to be a more ergonomic technique for estimating the energy expenditure, contributing to the clinical assessment in slow and robotic-assisted gait and future research concerning human-in-the-loop control.

Comparative effectiveness of preventive treatment with dimethyl fumarate-loaded solid lipid nanoparticles and oral dimethyl fumarate in a mouse model of multiple sclerosis.

BACKGROUND: Orally administered dimethyl fumarate (DMF) presents gastrointestinal adverse effects, such as pain and diarrhea, in addition to flushing and lymphopenia. OBJECTIVE: Solid lipid nanoparticles (SLNs) with DMF were developed for subcutaneous administration. METHODS: DMF-incorporated SLNs and free DMF were tested in mice induced with experimental autoimmune encephalomyelitis (EAE). RESULTS: Preventive treatment of free or incorporated DMF were able to reduce the EAE clinical scores, increase the weight of the animals, reduce the lesion area (demyelination and infiltration), reduce microglial fluorescence intensity and reduce the number of microglial cells and astrocytes, when compared to untreated EAE animals. Groups that received DMF had reduced numbers of T cells, B cells and natural killer (NK) cells in the blood, when compared to the non-induced group. CONCLUSIONS: DMF incorporated in SLNs was as effective as free DMF in reducing the clinical scores of the animals, but with reduced administrations when given subcutaneously. In addition, SLN-DMF preventive treatment partially prevented a reduction in the percentages of T and B cells, in the blood, when compared to preventive treatment with free DMF (oral), which suggests reduction of lymphopenia.

Low Memory T Cells Blood Counts and High Naïve Regulatory T Cells Percentage at Relapsing Remitting Multiple Sclerosis Diagnosis.

Objective: The aim of this study is to assess the peripheral immune system of newly diagnosed patients with relapsing remitting multiple sclerosis (RRMS) and compare it to healthy controls (HC). Methods: This cross-sectional study involves 30 treatment-naïve newly diagnosed patients with RRMS and 33 sex- and age-matched HC. Peripheral blood mononuclear cells were analyzed regarding: i) thymic function surrogates [T cell receptor excision circles (TRECs) and recent thymic emigrants (RTEs)]; ii) naïve and memory CD4+ and CD8+ T cells subsets; iii) T helper (Th) phenotype and chemokine receptors expression on CD8+ T cells subsets; iv) regulatory T cell (Tregs) phenotype; and exclude expression of activating/inhibitory receptors by natural killer (NK) and NKT cells. Analyses were controlled for age, sex, and human cytomegalovirus (HCMV) IgG seroprevalence. Results: Newly diagnosed patients with RRMS and HC have equivalent thymic function as determined by similar numbers of RTEs and levels of sjTRECs, DJßTRECs, and sj/DJßTREC ratio. In the CD8+ T cells compartment, patients with RRMS have a higher naive to memory ratio and lower memory cell counts in blood, specifically of effector memory and TemRA CD8+ T cells. Interestingly, higher numbers and percentages of central memory CD8+ T cells are associated with increasing time from the relapse. Among CD4+ T cells, lower blood counts of effector memory cells are found in patients upon controlling for sex, age, and anti-HCMV IgG seroprevalence. Higher numbers of CD4+ T cells (both naïve and memory) and of Th2 cells are associated with increasing time from the relapse; lower numbers of Th17 cells are associated with higher MS severity scores (MSSS). Patients with RRMS have a higher percentage of naïve Tregs compared with HC, and lower percentages of these cells are associated with higher MSSS. Percentages of immature CD56bright NK cells expressing the inhibitory receptor KLRG1 and of mature CD56dimCD57+ NK cells expressing NKp30 are higher in patients. No major alterations are observed on NKT cells. Conclusion: Characterization of the peripheral immune system of treatment-naïve newly diagnosed patients with RRMS unveiled immune features present at clinical onset including lower memory T cells blood counts, particularly among CD8+ T cells, higher percentage of naïve Tregs and altered percentages of NK cells subsets expressing inhibitory or activating receptors. These findings might set the basis to better understand disease pathogenesis.

Lipocalin-2 does not influence EAE clinical score but it increases inflammation in central nervous system.

The contribution of lipocalin-2 (LCN2) to multiple sclerosis (MS) is controversial. Herein, we induced experimental autoimmune encephalomyelitis (EAE) in LCN2-null and wild-type (Wt) mice. While we did not find differences between genotypes regarding clinical score, LCN2-null EAE mice presented decreased expression of interferon gamma and diminished demyelination in the cerebellum. Both genotypes presented similar alterations in the thymocyte and splenocyte populations. In MS patients, higher LCN2 CSF levels at diagnosis could be associated with faster disease progression, however further studies are needed to confirm these results, since this association was lost after controlling for the patients age, presence of oligoclonal bands and gender. Overall, our results support a harmful role for LCN2 in the disease context.

Defining the prodromal phase of multiple sclerosis based on healthcare access in a Portuguese population - ProdMS study.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. Prodromal symptoms and higher healthcare use have been suggested in patients who later develop MS. OBJECTIVES: Assess the healthcare utilization pattern of relapsing-remitting MS (RRMS) patients in the five years prior to MS diagnosis. METHODS: Retrospective, multicentric study. Demographic and clinical data, drug prescriptions and diagnostic tests were collected from electronic health records five-years previous to MS diagnosis and compared with national data. RESULTS: Included 168 patients, 112 (66.7%) female, median age 34±11 years. The mean number of healthcare use per patient per year was 3.14±2,69, most of them in primary healthcare (47%). Most frequent symptoms were musculoskeletal (22%), gastrointestinal (17%), sensitive (14%) and sensory organs (14%). Median number of diagnostic tests per patient was 6 (IQR 7), and drug prescriptions per patient was 6 (IQR 9). Most frequently prescribed drugs were analgesic/anti-inflammatories, antibiotics and anxiolytics and there was a high request rate of MRIs. CONCLUSION: RRMS patients had a high frequency of healthcare utilization when compared to national data. This supports the current evidence showing a prodromal phase in MS.

Always-On Sub-Microwatt Spiking Neural Network Based on Spike-Driven Clock- and Power-Gating for an Ultra-Low-Power Intelligent Device.

This paper presents a novel spiking neural network (SNN) classifier architecture for enabling always-on artificial intelligent (AI) functions, such as keyword spotting (KWS) and visual wake-up, in ultra-low-power internet-of-things (IoT) devices. Such always-on hardware tends to dominate the power efficiency of an IoT device and therefore it is paramount to minimize its power dissipation. A key observation is that the input signal to always-on hardware is typically sparse in time. This is a great opportunity that a SNN classifier can leverage because the switching activity and the power consumption of SNN hardware can scale with spike rate. To leverage this scalability, the proposed SNN classifier architecture employs event-driven architecture, especially fine-grained clock generation and gating and fine-grained power gating, to obtain very low static power dissipation. The prototype is fabricated in 65 nm CMOS and occupies an area of 1.99 mm2. At 0.52 V supply voltage, it consumes 75 nW at no input activity and less than 300 nW at 100% input activity. It still maintains competitive inference accuracy for KWS and other always-on classification workloads. The prototype achieved a power consumption reduction of over three orders of magnitude compared to the state-of-the-art for SNN hardware and of about 2.3X compared to the state-of-the-art KWS hardware.

Malignant transformation of oral leukoplakia: a multicentric retrospective study in Brazilian population / Transformación maligna de la leucoplasia oral: un estudio retrospectivo multicéntrico en población brasileña

Background: Among the oral potentially malignant disorders, leukoplakia stands out as the most prevalent. Thepurpose of this study was to analyse the clinical-pathological features of oral leukoplakia in groups of patientsfrom three major pathology centers in two different regions of Brazil, in order to determine which factors wouldbe associated to the clinical risk of malignant transformation.Material and Methods: A total of 148 patients was analyzed, and data regarding gender, age, site, classification ofthe clinical subtype, harmful habits such as use of tobacco and alcohol, time of evolution and presence of dyspla-sia were collected. The association between risk factors and malignant transformation was investigated using thechi-square test and Fischer's exact test for correlation of variables. A significance level of 5% (p≤0.05) was used.Results: The mean age of the patients was 60 years, and 56% were female. Most of the lesions (34,5%) were lo-cated in the lateral and ventral regions of the tongue. Of the 148 patients, ninety had clinical follow-up. Malignanttransformation occurred in 13 patients (8.8%), with an average of 44 months of follow up.Conclusions: Non-smoker, nonhomogeneous clinical presentation, location at the tongue, and the presence of highdegree of dysplasia were statistically relevant factors associated with a higher risk of transformation transformation.(AU)

Multiple Sclerosis Patient Management During the COVID-19 Pandemic: Practical Recommendations From the Portuguese Multiple Sclerosis Study Group (GEEM).

The spread of the COVID-19 pandemic has imposed significant challenges on healthcare provision, requiring changes in the conventional patient management, particularly in chronic diseases like multiple sclerosis (MS). To increase patient safety and reduce the risk of infection, while ensuring an appropriate and regular follow-up, tele-medicine gained prominence as a valid alternative to face-to-face appointments. However, the urgency of the implementation and the lack of experience in most MS centers led to "ad hoc" and extremely diverse approaches, which now merit to be standardized and refined. Indeed, while tele-consultation cannot fully replace face-to-face visits, it certainly can, and will, be incorporated as part of the routine care of MS patients in the near future. Bearing this in mind, the Portuguese Multiple Sclerosis Study Group (GEEM) has developed a set of recommendations for the usage of tele-medicine in the management of MS patients, both during the pandemic and in the future. The consensus was obtained through a two-step modified Delphi methodology, resulting in 15 recommendations, which are detailed in the manuscript.

TyPed study: Natalizumab for the treatment of pediatric-onset multiple sclerosis in Portugal.

BACKGROUND: A significant proportion of pediatric-onset multiple sclerosis (POMS) patients do not respond to first-line disease-modifying therapies. Clinical trials showed that natalizumab is effective and safe in adults, but there are limited clinical trial data for children. Natalizumab is currently prescribed off-label for POMS. We aimed to characterize the effectiveness, safety and tolerability of natalizumab in all POMS cases treated in Portugal (from 2007 to 2018). METHODS: Data from clinical records were retrospectively collected for all POMS cases treated with natalizumab in Portugal. RESULTS: Twenty-one patients were included, 14 (67%) of which were female. The median age at POMS diagnosis was 13 years old. The median duration of treatment with natalizumab was 2 years and 3 months. Median Expanded Disability Status Scale score decreased from 1.5 to 1.0 after 24 months. The Annualized Relapse Rate decreased from 1.31 events/patient/year before treatment with natalizumab to 0 after 12 months of treatment and to 0.04 after 24 months. No gadolinium-enhancing lesions or new or enlarged T2 hyperintense lesions were observed in 8/8 patients (100%) after 12 months, and 4/5 (80%) after 24 months. There was one possible serious adverse event, which did not require dose adjustment. Five patients discontinued treatment due to positive anti-JCV (JC virus) antibody JC serostatus. CONCLUSION: Natalizumab may be an effective and safe disease-modifying therapy for POMS. Our results are in line with data published for the adult population, as well as with similar observational studies in pediatric populations in other regions.