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Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an immune-mediated, inflammatory, demyelinating disorder with a range of clinical presentations including acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), myelitis, and cerebral cortical encephalitis. Phenotypic expression of MOGAD varies with age. MOG antibody (MOG-Ab) titers at disease onset, as well as longitudinally, may predict clinical disease course. The objectives of this study were to (1) describe a cohort of pediatric and adult patients with MOGAD at a single center and (2) investigate if clinical outcomes correlate with ethnicity and MOG-Ab., Methods: The clinical data of 36 pediatric and adult patients with MOGAD who were evaluated at onset and longitudinally were collected between January 2018 and June 2023 at our center. Inclusion criteria were positive MOG-Ab titers, a presentation consistent with proposed consensus criteria for MOGAD, and at least one initial or follow-up visit at our center. Patients were divided into monophasic and relapsing courses. Demographic data and clinical phenotypes were assessed as possible predictors of relapsing disease., Results: We describe demographic and clinical characteristics of 36 patients with MOGAD. Hispanic adults and children had increased rates of disease relapse compared to other ethnicities. Male sex and pediatric onset disease were also associated with increased risk of relapse. MOG-Ab titers at disease onset were not associated with a particular disease course. In adults, an initial phenotype of unilateral optic neuritis was associated with monophasic disease., Conclusion: Our findings within a diverse population suggest that specific characteristics, both of patients and of disease presentation, may be associated with a monophasic or relapsing course. Additional studies with larger cohorts are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) remains a challenging neurological condition for diagnosis and management and is often detected in late stages, delaying treatment. Artificial intelligence (AI) is emerging as a promising approach to extracting MS information when applied to different patient datasets. Given the critical role of metabolites in MS profiling, metabolomics data may be an ideal platform for the application of AI to predict disease. In the present study, a machine-learning (ML) approach was used for a detailed analysis of metabolite profiles and related pathways in patients with MS and healthy controls (HC). This approach identified unique alterations in biochemical metabolites and their correlation with disease severity parameters. To enhance the efficiency of using metabolic profiles to determine disease severity or the presence of MS, we trained an AI model on a large volume of blood-based metabolomics datasets. We constructed this model using an artificial neural network (ANN) architecture with perceptrons. Data were divided into training, validation, and testing sets to determine model accuracy. After training, accuracy reached 87 %, sensitivity was 82.5 %, specificity was 89 %, and precision was 77.3 %. Thus, the developed model seems highly robust, generalizable with a wide scope and can handle large amounts of data, which could potentially assist neurologists. However, a large multicenter cohort study is necessary for further validation of large-scale datasets to allow the integration of AI in clinical settings for accurate diagnosis and improved MS management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: COVID-19 was a viral infection that led to a global pandemic in March 2020. At the beginning of the pandemic, clinicians encountered the challenge of how immunosuppressive treatments would affect the course of COVID-19 infection in people with autoimmune diseases. Neuromyelitis optica spectrum disorder is an autoimmune astrocytopathy that is caused by an inflammation in the CNS. Major treatments to prevent acute relapses include immunosuppressive drugs. Rituximab is a well-established immunosuppressive agent in NMOSD maintenance therapy. Some reports suggested that treatment with Rituximab might increase the risk of COVID-19 infection and its mortality in NMOSD. On the other hand, dose reduction or extended interval treatment might lead to acute relapses of NMOSD and permanent disability., Methods: In this study, we evaluated the correlation between the dose of rituximab and the relapse rate of NMOSD during an epidemic. This was an observational study on 171 patients among whom 55 cases were seropositive. Some patients received full dose rituximab routinely (1000 mg/dose, every 6 months), but others were treated with half dose (500 mg/dose) during the epidemic. Also, some doses were prescribed with a delay, based on the level of CD19 and CD20., Results: The Pearson correlation coefficient (r) showed a negative and significant relation (r: - 0.19, p: 0.022) between the amount of drug and the number of relapses in the seropositive group, so low dosage of the drug was related to more acute relapses. In seronegative cases, there was not any valuable relationship. (p: 0.367)., Conclusion: Lower dose of rituximab, especially in seropositive NMOSD patients, can potentially lead to acute relapses. So, the more frequent evaluation of the CD19, CD20, and, CD27 levels, and the general clinical condition of the patients should be considered., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Any of theauthor is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for Multiple Sclerosis and Related Disorders journal and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a heterogeneous entity with either a monophasic or relapsing course. Well-established predictors of relapsing disease are lacking., Objective: Identifying predictors of relapsing MOGAD, particularly at disease onset., Methods: A multicentre observational retrospective study was conducted to characterise a cohort of Portuguese adult MOGAD patients. Patients were identified from participating centre databases. Clinical and demographic data were collected from medical records. Bivariate analysis was conducted to compare patients with relapsing and monophasic MOGAD. Significant variables were included in a stepwise multiple regression analysis to identify independent predictors of relapse., Results: Eighty-seven MOGAD patients from 8 public hospitals were included. Relapsing MOGAD was found in 35.6% (n = 31). Mean diagnostic delay was 3.2 (±6.2) years and time to relapse was 4.4 (±6.4) years. Multiple logistic regression showed that higher neutrophil count (p < 0.01), presence of oligoclonal bands (p = 0.025) and no bridging corticosteroids (p = 0.038) at first attack were predictive of relapsing MOGAD., Conclusion: Neutrophil count and oligoclonal bands at first attack may facilitate early decision-making regarding maintenance immunotherapy. Bridging corticosteroids may also influence the course of MOGAD. Further studies with prospective design are warranted., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have influenced the results reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

One main problem faced by people with multiple sclerosis (PwMS) is upper limb dysfunction, which can occur in the first decade of the disease and with the highest prevalence of disability in the progressive type of the disease. Then, PwMS may benefit from personalised and intensive treatment as provided by robotic devices. These innovative devices have increasingly been brought into the neurorehabilitation field, due to their ability to provide repetitive and task-oriented training. In this quasi-randomized study, we aim to evaluate the effects of robotic-assisted hand training, using the Hand TutorTM device, on hand functionality, active RoM, and manual dexterity, compared to conventional rehabilitation in PwMS. We enrolled 30 MS patients, who received 20 training sessions, each lasting 45 min with robotic-assisted hand training with Hand Tutor (n 15, experimental group) or conventional rehabilitation therapy (n 15, control group). All patients were evaluated at pre- and post-intervention with clinical scales for upper limb functionality (DASH, BBT, NHPT, and MI). In addition, only patients in the experimental group received an objective kinematic analysis of the hand and wrist movements, delivered by the Hand Tutor glove, both pre- and post-intervention. We found that PwMS in both groups statistically improved their upper limb functions, however the experimental group achieved better results in terms of manual dexterity. This promising rehabilitation training with Hand Tutor glove led to positive effects on upper limbs motor outcomes and kinematic parameters in patients with MS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mirjam Bonanno reports financial support was provided by Research Hospital Bonino Pulejo Centre for Brain Injuries. Mirjam Bonanno reports a relationship with Research Hospital Bonino Pulejo Centre for Brain Injuries that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Persons with multiple sclerosis (PwMS) are at an increased risk for falling, making it necessary to identify useful screening tools. The aims of this study were to 1) determine a cut-off score for the 12-item Multiple Sclerosis Walking Scale (MSWS-12) for identifying PwMS as fallers and 2) evaluate its predictive ability of faller status after controlling for other potential contributing factors., Methods: Participant characteristics, MSWS-12, and falls in the last six months were collected on PwMS (n = 171) during a single session. Fallers (53.8 %; n = 92) were individuals reporting ≥ 1 fall in the past six months. A receiver-operating-characteristic (ROC) curve was performed to estimate the classification accuracy (area under the curve; AUC) of the MSWS-12 at detecting fallers. Optimal cut-off scores were calculated using the Youden Index and Index of Union methods. The dichotomized MSWS-12 cut-off score was then entered into a logistic regression, with faller status as the outcome, and age, gender, body mass index, disease duration, and fatigue as covariates., Results: The MSWS-12 had a fair classification accuracy for identifying fallers (AUC = 0.74), with the cut-off score of ≥ 46 % having 76.1 % sensitivity and 64.6 % specificity. The MSWS-12 cut-off score remained a significant predictor of faller status in the adjusted model (adjusted odds ratio [aOR]: 3.77, 95 % CI: 1.75, 8.15, P = .001), along with higher fatigue (aOR: 1.11, 95 % CI: 1.02, 1.20, P = .015)., Conclusion: PwMS with MSWS-12 scores ≥ 46 % were more likely to be fallers than those with lower scores. When used in conjunction with a clinician's judgement and other assessments, the MSWS-12 may be a useful screening tool for identifying PwMS who are fallers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There are plausible mechanisms, yet mixed evidence, that higher polyunsaturated fatty acids (PUFAs) levels reduces the risk of multiple sclerosis (MS). Prior studies relied on dietary surveys to estimate levels., Objective: We tested associations between plasma levels of n-3 and n-6 PUFAs and likelihood of MS onset or clinically isolated syndrome (CIS) using data from the MS Sunshine Study, a case-control study conducted in the United States., Methods: Case participants (n = 589) aged ≥ 18 years and matched control participants (n = 630) were recruited between 2011 and 2015. Plasma phospholipid fatty acid profiling was conducted by gas-liquid chromatography. We used logistic regression to report odds ratios, testing for interactions, adjusting for covariates and correcting for multiple comparisons., Results: There was a 6 % lower probability of MS/CIS per unit increase in total n-6 PUFA level, expressed as a percentage of total plasma phospholipid fatty acids (odds ratio = 0.94; 95 % confidence interval = 0.90,0.98; p = 0.012). We found no statistically significant association between individual or total plasma levels of n-3 PUFAs and probability of MS/CIS; however, plasma levels of n-3 PUFAs were low across the cohort. No other individual or aggregate PUFA levels were significantly associated with MS/CIS., Conclusion: A higher total n-6 PUFA level may be beneficial in terms of MS susceptibility. Further research is needed to determine whether n-3 PUFAs may be beneficial only above a threshold that is achievable by supplementation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Optic neuritis is a common clinical presentation in patients suffering from multiple sclerosis (MS). Even though optic neuritis is not part of the MS diagnostic criteria, the diagnosis and consideration of differential diagnoses are important in clinical routine. For the evaluation of the optic nerves with MRI, T2-weighted images with fat suppression, known as short tau inversion recovery sequences (STIR), are often used. Besides that, double inversion recovery (DIR) sequences are being used increasingly in MS patients, especially to determine cortical lesions. The Aim of this study was to evaluate the 3D-DIR for the detection of lesions in the optic nerves in MS patients., Methods: MR examinations of 45 MS-patients containing both STIR and DIR images were independently assessed by two neuroradiologic experienced radiologists, blinded to clinical data. A third neuroradiologic, an experienced radiologist, evaluated the images together, also considering clinical data. These results were considered ground truth and statistically compared to the results of the single readings. To objectify our findings, ROI measurements of affected and unaffected optic nerve segments were made, and a contrast ratio (CR) was calculated., Result: DIR images are statistically equivalent to STIR images concerning the detection of lesions in the optic nerve (p < 0.001). The sensitivity of DIR images (84.7 %) and STIR images (77 %), as well as the specificity (92.2 % and 91.2 %), are comparable. The interrater reliability was substantial for both sequences (κ = 0,73) as well as separated for the STIR images (κ = 0.744) and the DIR images (κ = 0.707). The objective analysis revealed significantly higher CRs in DIR images (p < 0.001)., Conclusion: 3D DIR images showed similar sensitivity and specificity for detecting optic nerve lesions in comparison to dedicated 2D images of the optic nerve. When 3D DIR images are part of the routine scan protocol for evaluating MS patients, additional 2D imaging of the optic nerve is no longer necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Neuromyelitis Optica Spectrum Disorders (NMOSD) is a neuroinflammatory condition characterized by optic neuritis and transverse myelitis. While the current approach to NMOSD focuses on relapse-associated worsening (RAW), recent evidence indicates Relapse-Independent Disease Activity (RIDA) in patients., Method: Databases including Embase, PubMed, Scopus, and Web of Sciences were systematically searched up to December 2023. No restrictions were applied. Inclusion criteria focused on studies reporting evidence of RIDA in NMOSD patients. Data extraction involved details such as study title, author, participant characteristics, treatment, evaluation methods, positive findings according to RIDA, and prevalence of findings in NMOSD patients. This study is conducted following the PRISMA guidelines with a registered protocol on PROSPERO (ID = CRD42023492352)., Result: Of 802 studies, 38 were included in the systematic review, covering 1881 NMOSD patients. AQP4-IGg status was positive in 90.6 % of the patients. Ocular findings indicative of RIDA were reported in 23 studies, including thinning of GCIPL, RNFL, GCC, and GCL layers, foveal and macular shape and volume abnormalities, vessel loss, and visual evoked potentials (VEPs) abnormalities. MRI findings supporting the RIDA were reported in 13 studies, including new lesion incidence and brain and spinal cord atrophy. Serum and CSF RIDA-supporting findings were reported in five studies, including elevation in sGFAP and sNFL. Biopsies and autopsies suggested inflammatory processes in relapse-free patients in 2 studies. The predominant manifestation of RIDA in NMOSD was identified in the visual system, suggesting the impaired retinal glial cells like Müller cells during the relapse-free period in NMOSD., Interpretation: Our systematic review provides valuable insights into RIDA in NMOSD. Establishing guidelines for the diagnosis and treatment of RIDA is crucial. Further studies are needed to provide robust evidence on RIDA in NMOSD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: To investigate the reliability of balance tests administered using a tele-assessment method in patients with multiple sclerosis (MS)., Methods: The participants were assessed both online and face-to-face. The assessments were performed synchronously by two physiotherapists. The first method to used to evaluate the participants was determined through randomization. The Berg Balance Scale (BBS), Dynamic Gait Index (DGI), and Timed Up and Go (TUG) were used in the evaluations. Three days were left between the assessment methods. Online platforms were used for tele-assessment. The agreement between and correlation of face-to-face and tele-assessments was analyzed by applying intra-class correlation coefficients (ICC), limits of agreement, and Pearson's correlation coefficient., Results: This study included 39 individuals with MS with an EDSS score of 3.03 ± 1.41. Intra-rater reliability of the tele-assessment was excellent (ICC BBS = 0.96; ICC DGI = 0.97; ICC TUG = 0.97). Very high correlations were observed in all BBS, DGI, and TUG measurements between face-to-face and tele-assessment methods according to the first and second assessors (r BBS1 = 0.92; r BBS2 = 0.93; r DGI1 = 0.94; r DGI2 = 0.95; r TUG1 = 0.94; r TUG2 = 0.95, respectively). The inter-rater reliability of tele-assessments (ICC BBS = 0.97; ICC DGI = 0.97; ICC TUG = 1.00) achieved excellent reliability., Conclusion: BBS, DGI, and TUG are reliable and agreed tests that can be used with tele-assessments, offering similar data to face-to-face methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis is a common inflammatory neurological disease among young adults and is the tenth leading cause of the global burden of disease. Existing common treatments such as pharmacological and palliative therapies do not control the neurodegenerative process or cure multiple sclerosis. Numerous epidemiological surveys, randomised controlled trials, and systematic reviews with meta-analyses support the effects of physical activity on health-related outcomes among patients with multiple sclerosis. Moreover, bibliometric analysis can provide a broad evidence synthesis beyond systematic reviews and meta-analyses, allowing researchers and other stakeholders to obtain a one-stop overview of this research field. Therefore, this bibliometric analysis aims to provide insight into the knowledge structure of the field of physical activity for multiple sclerosis over the past three decades, and to predict emerging research trends., Methods: This study strictly complied with step-by-step guidelines of bibliometric analysis, combining performance analysis and science mapping. Four indexes from the Web of Science Core Collection were selected as data sources, and articles and review articles in the field of physical activity for multiple sclerosis from 1994 to 2023 were included in this analysis. Mircrosoft Excel, RStudio, VOSviewer 1.6.20, and CiteSpace 6.3.R1 (64-bit) Advanced were used to perform performance analysis and science mapping., Results: Over the past three decades, this field published a total of 1,271 documents, with the scientific output showing a rapid upward trend over the past two decades. Robbert W Motl was the most prolific author in this field, with a total of 300 publications. The USA contributed nearly half of the publications in this field (549 documents), and the University of Illinois System was the institution with the highest number of publications (222 documents). Multiple Sclerosis and Related Disorders was the journal that published the highest number of documents in this field (117 documents), while more than a third of this field's publications were included in the category: Clinical Neurology (438 documents). The Reference co-citation analysis identified three main research trends, including shifts in research methodology, changes in health outcomes in randomised controlled trials, and shifts in different types of physical activity interventions. Combining the results from reference co-citation analysis and citation burst analysis, the combination of behaviour change technique and telerehabilitation may be the emerging research trend., Conclusion: This bibliometric analysis identifies rapid growth in the field of physical activity for multiple sclerosis over the past two decades. Moreover, the combination of performance analysis and science mapping provides insight into knowledge structure in this field and informed future research trends for researchers and the relevant stakeholders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Immunosuppressive therapies as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are widely prescribed as first-line treatment to prevent relapses in NMOSD. However, the rate of response to these traditional therapies is unknown in Argentina. We aimed to describe and compare treatment failure rates in NMOSD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177)., Methods: A retrospective cohort study was conducted in NMOSD patients included in RelevarEM (a nationwide, longitudinal, observational, non-mandatory registry of MS and NMOSD in Argentina). NMOSD patients were defined based on validate diagnostic criteria. Only NMOSD patients who received AZA or MMF for at least 6 months or RTX for at least 1 month were included. Patients who were receiving AZA, MMF, or RTX and then switched to another 1 of these 3 therapies were included if the above-mentioned criteria for each drug were fulfilled. Data on patient demographics, clinical, neuroradiological findings, and treatments administered were collected. Treatment failure was defined as any new attack/relapse that occurred despite immunosuppressive treatment., Results: We included 139 NMOSD patients who were receiving AZA (n = 105), MMF (n = 5) or RTX (n = 29) with a mean follow-up time of 41.3 ± 11.4 months and median of EDSS at treatment initiation of 3. We observed a reduction in the annualized relapse rate from pre-treatment to post-treatment of 51.1 %, 48.4 %, and 79.1 % respectively with a Hazard Risk relative to RTX (95 % CI) of 1.67 (1.34-3.54, p = 0.01) for AZA and 2.01 (1.86-4.43, p = 0.008) for MMF. AZA, MMF and RTX failure was observed in 45/105 (42.8 %), 2/5 (40 %) and 3/29 (10.3 %) patients, respectively., Conclusions: Treatment failure rates were higher for AZA and MMF than RTX in Argentinean NMOSD patients in a real-world setting. High-efficacy treatment increases the opportunity to prevent attacks of NMOSD., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Medical research offers potential for disease prediction, like Multiple Sclerosis (MS). This neurological disorder damages nerve cell sheaths, with treatments focusing on symptom relief. Manual MS detection is time-consuming and error prone. Though MS lesion detection has been studied, limited attention has been paid to clinical analysis and computational risk factor prediction. Artificial intelligence (AI) techniques and Machine Learning (ML) methods offer accurate and effective alternatives to mapping MS progression. However, there are challenges in accessing clinical data and interdisciplinary collaboration. By analyzing 103 papers, we recognize the trends, strengths and weaknesses of AI, ML, and statistical methods applied to MS diagnosis. AI/ML-based approaches are suggested to identify MS risk factors, select significant MS features, and improve the diagnostic accuracy, such as Rule-based Fuzzy Logic (RBFL), Adaptive Fuzzy Inference System (ANFIS), Artificial Neural Network methods (ANN), Support Vector Machine (SVM), and Bayesian Networks (BNs). Meanwhile, applications of the Expanded Disability Status Scale (EDSS) and Magnetic Resonance Imaging (MRI) can enhance MS diagnostic accuracy. By examining established risk factors like obesity, smoking, and education, some research tackled the issue of disease progression. The performance metrics varied across different aspects of MS studies: Diagnosis: Sensitivity ranged from 60 % to 98 %, specificity from 60 % to 98 %, and accuracy from 61 % to 97 %. Prediction: Sensitivity ranged from 76 % to 98 %, specificity from 65 % to 98 %, and accuracy from 62 % to 99 %. Segmentation: Accuracy ranged up to 96.7 %. Classification: Sensitivity ranged from 78 % to 97.34 %, specificity from 65 % to 99.32 %, and accuracy from 71 % to 97.94 %. Furthermore, the literature shows that combining techniques can improve efficiency, exploiting their strengths for better overall performance., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is a neuroinflammatory condition with a prevalence of about 309.2 per 100,000 people in the United States. We aim to identify MS-related mortality trends in the USA from 1999 to 2020, stratified by age, sex, race, and geography, and its correlation with sunlight., Methods: Death certificates from the CDC-WONDER database were examined for adults aged ≥25 years. Crude rates (CR) and age-adjusted mortality rates (AAMRs) per 1,000,000 persons and annual percent change (APC) were calculated. We also retrieved data for daily sunlight from 1999 to 2011., Results: From 1999 to 2020, a total of 121,694 deaths occurred due to MS. The AAMR rose from 23.6 in 1999 to 29.7 in 2020 (APC 0.65), with a stable trend till 2018 (APC -0.22) followed by an abrupt increase towards 2020 (APC 9.27). Women had higher AAMR than men. Non-Hispanic (NH) Whites exhibited the highest AAMR (28.5), followed by NH Blacks (25.9), NH American Indians/Alaska Natives (9.6), Hispanics or Latino (6.8), and NH Asian or Pacific Islanders (1.9). AAMRs also varied substantially by region (Midwest: 32.4; Northeast: 26.9; West: 26.2; South: 19.4). States with the highest AAMRs were Montana, Wyoming, Colorado, and Oregon. The states with lower daily sunlight had higher AAMRs (r = -0.559, p = 0.000). AAMRs were comparable in urban (25) and rural (26.3) areas. Most deaths occurred in medical facilities (33.92 %) and nursing homes / long-term care (30.80 %), followed by home (27.79 %), and hospice (4.06 %). Adults ≥ 65 years depicted the highest mortality rates (CR 64.4) while adults aged 25 to 44 years showed the lowest rates (CR 4.6)., Conclusion: We found an overall stable trend in MS-related mortality rates in the US till 2018 with a sharp increase thereafter. We observed highest mortality among women and NH White adults, among residents of Midwest and Northeast regions, and among adults ≥ 65 years. Higher disease burden in recent years calls for devising timely policies focused on these high-risk populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Biomarkers predictive of disability outcomes in individual multiple sclerosis (MS) patients undergoing autologous haematopoietic stem cell transplantation (AHSCT) are currently lacking. As correlations between spinal cord atrophy and clinical disability in MS were previously described, in this study spinal cord size was investigated in MS patients treated with AHSCT, exploring whether baseline spinal cord volume may predict disability progression after AHSCT., Methods: relapsing-remitting (RR-) and secondary-progressive (SP-) MS patients treated with AHSCT (BEAM/ATG regimen) at a single academic centre in Florence, who performed at least two standardized brain magnetic resonance imaging (MRIs) scans (acquired between one-year pre-AHSCT to 5 years after AHSCT) were included. Cervical spinal cord atrophy was estimated as upper cervical spinal cord cross-sectional area (SCCSA). Brain volume loss (BVL) was analysed at the same timepoints., Results: Eleven (8 RR-; 3 SP-) MS patients were included. Over a median follow-up of 66 (range 37 - 100) months, no relapses nor brain MRI activity were observed; disability progressed in 2 cases (both SP-MS). Baseline SCCSA was associated with EDSS change between pre- and one-year post-AHSCT. Compared to patients who stabilized, patients who progressed after AHSCT tended to have lower SCCSA at C4 level at baseline and year 1 after AHSCT. Longitudinal changes in SCCSA or BVL did not correlate with EDSS change., Conclusions: Baseline pre-AHSCT SCCSA, but not its longitudinal changes nor BVL, predicted EDSS change within the two years following AHSCT. SCCSA may represent a biomarker of treatment response and a promising screening tool for assessing patient eligibility for high-impact treatments such as AHSCT., Competing Interests: Declaration of competing interest Dr. Mariottini reports no conflicts of interest relevant to this paper; she discloses speaker's honoraria and non-financial support from Sanofi, Viatris, Genzyme, Biogen, Novartis, and Janssen, outside the submitted work. Ms. Stack, Dr. Nair, Dr. Nozzoli, Dr. Wu, Dr. Marchi, Dr. Boncompagni, Dr. Repice, Prof. Fainardi, Dr. Di Pasquale, and Dr. Carlesi have no conflicts to disclose relevant to the paper. Dr. Saccardi discloses personal fee from Sanofi. Dr. Jacobson has no conflicts to disclose relevant to the paper. Prof. Massacesi has no conflicts to disclose relevant to the paper; he reports personal fees and non-financial support from Biogen, Novartis, Merck Serono, Teva, Sanofi, and Janssen, outside the submitted work., (Copyright © 2024. Published by Elsevier B.V.)

Background: Extensive research has explored the role of gut microbiota in multiple sclerosis (MS). However, the impact of microbial communities in the oral cavity and respiratory tract on MS is an emerging area of investigation., Purpose: We aimed to review the current literature related to the nasal, oral, and lung microbiota in people with MS (PwMS)., Methods: We conducted a narrative review of clinical and preclinical original studies on PubMed that explored the relationship between the bacterial or viral composition of the nasal, lung, and oral microbiota and MS. Additionally, to find relevant studies not retrieved initially, we also searched for references in related review papers, as well as the references cited within the included studies., Results and Conclusions: Thirteen studies were meticulously reviewed in three sections; oral microbiota (n = 8), nasal microbiota (n = 3), and lung microbiota (n = 2), highlighting considerable alterations in the oral and respiratory microbiome of PwMS compared to healthy controls (HCs). Genera like Aggregatibacter and Streptococcus were less abundant in the oral microbiota of PwMS compared to HCs, while Staphylococcus, Leptotrichia, Fusobacterium, and Bacteroides showed increased abundance in PwMS. Additionally, the presence of specific bacteria, including Streptococcus sanguinis, within the oral microbiota was suggested to influence Epstein-Barr virus reactivation, a well-established risk factor for MS. Studies related to the nasal microbiome indicated elevated levels of specific Staphylococcus aureus toxins, as well as nasal glial cell infection with human herpes virus (HHV)-6 in PwMS. Emerging research on lung microbiome in animal models demonstrated that manipulating the lung microbiome towards lipopolysaccharide-producing bacteria might suppress MS symptoms. These findings open avenues for potential therapeutic strategies. However, further research is crucial to fully understand the complex interactions between the microbiome and MS. This will help identify the most effective timing, bacterial strains, and modulation techniques., Competing Interests: Declaration of competing interest There are no financial/ personal relationships with any people or organizations that could inappropriately influence this study. There are no potential competing interests including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Multiple Sclerosis (MS) is a common autoimmune inflammatory disease of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) allows a sensitive assessment of the CNS and is established for diagnostic, prognostic and (therapy-) monitoring purposes. Especially lesion counting in T2- or Fluid Attenuated Inversion Recovery (FLAIR)-weighted images plays a decisive role in clinical routine. Software-packages allowing an automatic evaluation of image data are increasingly established aiming a faster and improved workflow. These programs allow e.g. the counting, spatial attribution and volumetry of MS-lesions in FLAIR-weighted images. Research has shown that 3D-FLAIR-sequences are superior to 2D-FLAIR-sequences in visual evaluation of lesion burden in MS. An influence on the automatic analysis is expectable but not yet systematically studied. This work will therefore investigate the influence of 2D- and 3D datasets on the results of an automatic assessment., Material and Methods: In this prospective study, 80 Multiple Sclerosis patients underwent a clinically indicated routine MRI examination. The clinical routine protocol already including a 3D-FLAIR sequence was adapted by an additional 2D-FLAIR sequence also conform to the 2021 MAGNIMS-CMSCNAIMS consensus recommendations. To obtain a quantitative analysis for assessment of amount, dissemination and volume of the lesions, the acquired MR images were post-processed using the CE-certified Software mdbrain (mediaire, Berlin, Germany). The resulting data were statistically analysed using the paired t-test for normally distributed data and the Wilcoxon-signed-rank-test for not normally distributed data respectively. Demographic data and data such as the subtype, duration, severity and therapy of the disease were collected, pseudonymized and evaluated., Results: There is a significant difference concerning the total number and lesion volume with more lesions being detected (2D: 29.7, +/- 20.22 sd; 3D: 40.1 +/- 31.67 sd; p < 0.0001) but lower total volume (2D: 6.24 +/- 6.11 sd; 3D: 5.39 +/- 6.37 sd; p < 0.0001) when using the 3D- sequence. Especially significantly more small lesions in the unspecific white matter and infratentorial region were detected by using the 3D-FLAIR sequence (p < 0.0001) compared to the 2D-FLAIR image. Main reason for the lower total volume in the 3D-FLAIR sequence was the calculated volume for periventricular lesions which was significantly beneath the calculated volume from the 2D-FLAIR sequence (p < 0.0001)., Conclusion: Automatic lesion counting and volumetry is feasible with both 2D- and 3D-weightend FLAIR images. Still, it leads to partly significant differences even between two sequences that both are conform to the 2021 MAGNIMS-CMSCNAIMS consensus recommendations. This study contributes valuable insights into the impact of using different input data from the same patient for automated MS lesion evaluation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The Multiple Sclerosis Walking Scale-12 (MSWS-12) has typically been delivered through paper-and-pencil or computer-based administration., Purpose: This study examined the validity of inferences from scores derived via a telephone administration of the MSWS-12 applied as part of screening of participants with walking dysfunction into a clinical trial of exercise training in MS., Method: The MSWS-12 was administered on two occasions separated by approximately 2 weeks through the telephone and then in-person (i.e., computer-based administration). Participants further completed the Patient Determined Disease Steps (PDDS) scale, timed 25-foot walk (T25FW), six-minute walk (6MW), Modified Fatigue Impact Scale (MFIS), and Multiple Sclerosis Impact Scale-29 (MSIS-29), and underwent a neurological exam for generating an expanded disability status scale (EDSS) score. The primary set of data (Full Sample) for analyses included all persons who passed the telephone screening for inclusion with MSWS-12 scores between 25 and 75 (N = 374). The secondary set of data (Truncated Sample) included only persons with MSWS-12 scores between 25 and 75 for both the telephone and computer administrations of the MSWS-12 (N = 248)., Results: The results in the Full Sample indicated a difference in overall and item levels scores between the telephone and computer data collections, and the computer version had higher internal consistency and stronger unidimensionality. Nevertheless, MSWS-12 scores from both modes of administration had comparable correlations with the T25FW, 6MW, EDSS, PDDS, MFIS, and MSIS-29, but the correlation between the two MSWS-12 administrations did not approach unity. There was a systematic difference in scores between telephone and computer administrations across levels of walking dysfunction based on a Bland-Altman plot, and the difference was predicted by MFIS physical, 6MW, and EDSS scores. The comparison of results between the Full and Truncated Samples suggested that the primary analysis might have been influenced by the larger range of scores on the computer than telephone administrations of the MSWS-12., Conclusion: The telephone administration of the MSWS-12 provides an efficient and cost-effective measure of walking dysfunction in persons with MS., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in the publication of this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In the field of research for new validated surrogate biomarkers of treatment efficacy, disease activity and progression in Multiple Sclerosis (MS), serum neurofilament light-chain (sNFL) are actually the best candidate for MS patient monitoring. However, before they can be implemented in clinical practice, their usefulness as additional red flag routine measure must be demonstrated. To tackle the problem, this real-life cross-sectional study at the Regional Referring Center for Multiple Sclerosis (CRESM) aims to characterize sNFL levels and prevalence of elevated sNFL, according to our age-dependent cut-off values, in a large group of patients with different types of MS and treatment conditions., Methods: 908 serum samples from as many MS patients being admitted at CRESM for diagnostic definition and/or during routinary treatment monitoring were consecutively collected between January 2019 and January 2020. sNFL levels were measured by single molecule array (Simoa™) technology on SR-X instrument using NF-light assays (Quanterix); results were interpreted using previously published cut-off values., Results: Primary and Secondary Progressive MS (PPMS, SPMS) forms demonstrate higher levels and prevalence of elevated sNFL (PPMS= 32 %, SPMS= 21 %) compared to the Relapse and Remitting one (RRMS = 12 %). Besides, naïve samples of RRMS and PPMS subtypes showed higher prevalence of elevated sNFL (RRMS naïve= 31 %, PPMS naïve=67 %) compared to samples from patients treated for more than 12 months (RRMS treat>12m= 9 %, PPMS treat>12m= 19 %); treated SPMS patients demonstrated higher sNFL levels and a prevalence (22 %) of elevated sNFL compared to RRMS treated patients. Focusing on RRMS, no statistical difference was found between groups of patients treated for whatever time (up to or more than 60 months) and with either DMT type (high or low-efficacy DMT). Finally, RRMS patients treated with all DMTs for more than 12 months, with the exception of teriflunomide and alemtuzumab showed a prevalence of elevated sNFL in the range of 5-10 %., Conclusion: in a real-world setting comprising about 1000 MS patients, sNFL quantification was elevated in 5-to-67 % of patients, in different MS forms and treatment conditions. Elevated levels of sNFL must be considered a red-flag suggesting the need of a further clinical monitoring in any circumstance, as it can be indicative of new inflammation, ongoing degeneration or co-morbidities. This study supports the introduction of sNFL quantification in everyday patient management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Bertolotto reports financial support was provided by Roche SpA. Antonio Bertolotto reports financial support was provided by Italian Multiple Sclerosis Association. Paola Valentino reports a relationship with Biogen that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Roche SpA that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Merck & Co Inc that includes: funding grants. Paola Valentino reports a relationship with Quanterix Corp that includes: funding grants. Simona Malucchi reports a relationship with Biogen that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Merck & Co Inc that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Roche SpA that includes: speaking and lecture fees and travel reimbursement. Serena Martire reports a relationship with Biogen that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Serena Martire reports a relationship with Novartis that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Almirall that includes: board membership, consulting or advisory, and funding grants. Antonio Bertolotto reports a relationship with Bayer that includes: board membership and consulting or advisory. Antonio Bertolotto reports a relationship with Biogen that includes: board membership, consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Genzyme Corporation that includes: board membership and consulting or advisory. Antonio Bertolotto reports a relationship with Novartis that includes: funding grants, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Sanofi that includes: speaking and lecture fees and travel reimbursement. Antonio Bertolotto reports a relationship with Associazione San Luigi Gonzaga ONLUS that includes: funding grants. Antonio Bertolotto reports a relationship with Fondazione per la Ricerca Biomedica ONLUS that includes: funding grants. Antonio Bertolotto reports a relationship with Mylan Pharmaceuticals Inc that includes: funding grants. Antonio Bertolotto reports a relationship with Italian Multiple Sclerosis Association that includes: funding grants. Rugiada Bottero reports a relationship with Novartis that includes: consulting or advisory. Rugiada Bottero reports a relationship with Sanofi that includes: consulting or advisory. Rugiada Bottero reports a relationship with Merck that includes: consulting or advisory. Alessia Di Sapio reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Sanofi that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Alexion that includes: speaking and lecture fees and travel reimbursement. Alessia Di Sapio reports a relationship with Merck that includes: travel reimbursement. Alessia Di Sapio reports a relationship with Genzyme Corporation that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Autologous haematopoietic stem cell transplant (HSCT) is considered an effective treatment for highly active multiple sclerosis (MS). To date, most research has focused primarily on disease outcome measures, despite the significant impact of neuropsychological symptoms on MS patients' quality of life. The current systematic review aimed to examine whether HSCT for MS impacts neuropsychological outcome measures such as cognition, fatigue, mood, and quality of life., Methods: The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42023474214). Systematic searches were carried out in six databases (PsycINFO, PubMed, Embase, Scopus, CINAHL and Web of Science) based on the following inclusion criteria: (i) published in peer-reviewed journals in English; (ii) longitudinal studies of adults with MS (iii) at least one neuropsychological outcome was assessed pre- and post-HSCT using standardised measures. Risk of bias was assessed using the National Heart, Lung and Blood Institute (NHLBI) quality assessment tools. A narrative synthesis was used to present results., Results: Eleven studies were included in the review. Long-term improvements in quality of life post-HSCT were identified. In terms of cognition and fatigue, the evidence was mixed, with some post-HSCT improvements identified. Decline in cognitive performance in the short-term post-HSCT was observed. No changes in mood were identified post-HSCT. Arguments for interpreting these results with caution are presented based on risk of bias. Arguments for interpreting these results with caution are presented based on risk of bias. Limitations of the evidence are discussed, such confounding variables and lack of statistical power., Conclusion: The evidence base for the impact of HSCT for MS on neuropsychological outcomes is limited. Further research is required to progress understanding to facilitate clinician and patient understanding of HSCT treatment for MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No known declarations of interest to state., (Copyright © 2024. Published by Elsevier B.V.)

Background: Fatigue is a common symptom in patients with multiple sclerosis and it can lead to activity limitations. Thus, it is important to analyze the relationship between fatigue and activity outcomes, such as walking speed and mobility., Objectives: To investigate the relationship between fatigue and walking speed and mobility in individuals with multiple sclerosis., Methods: A cross-sectional study was performed. Adults with multiple sclerosis, without cognitive impairments and who were able to walk were recruited. Fatigue was assessed with the Modified Fatigue Impact Scale (MFIS). Walking speed, usual and fast, was assessed with the 10-meter Walk Test (10MWT), and mobility with the Timed Up and Go Test (TUG). Pearson correlation analysis was performed. A significance level of 5 % was used., Results: Thirty participants were included, most of the relapsing-remitting multiple sclerosis (n = 24, 80 %). A mean age of 41 (11) years and the median Expanded Disability Status Scale (EDSS) score was 2.65 (2.18) points. Mean MFIS score was 41.87 ± 19.42 points, mean usual walking speed was 1.02 ± 0.28 m/s, mean fast walking speed was 1.55 ± 0.48 m/s, and the mean total time in the TUG was 10.07 ± 3.05 s. A significant negative correlation of moderate magnitude was found between fatigue and usual walking speed (r=₋0.51, p < 0.05). A significant negative correlation of moderate magnitude was found between fatigue and fast walking speed (r=₋0.54, p < 0.05). A significant, positive correlation of moderate magnitude was found between fatigue and mobility (r = 0.54, p < 0.05)., Conclusion: There was a correlation between fatigue and walking speed and mobility in individuals with multiple sclerosis. These results highlight the need to assess fatigue in individuals with multiple sclerosis, since the presence of fatigue is associated with reduced walking speed and mobility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Optical coherence tomography (OCT) investigations have revealed that the thickness of inner retinal layers becomes decreased in multiple sclerosis (MS) patients, compared to healthy control (HC) individuals. To date, a number of studies have applied machine learning to OCT thickness measurements, aiming to enable accurate and automated diagnosis of the disease. However, there have much less emphasis on other less common retinal imaging modalities, like infrared scanning laser ophthalmoscopy (IR-SLO), for classifying MS. IR-SLO uses laser light to capture high-resolution fundus images, often performed in conjunction with OCT to lock B-scans at a fixed position., Methods: We incorporated two independent datasets of IR-SLO images from the Isfahan and Johns Hopkins centers, consisting of 164 MS and 150 HC images. A subject-wise data splitting approach was employed to ensure that there was no leakage between training and test datasets. Several state-of-the-art convolutional neural networks (CNNs), including VGG-16, VGG-19, ResNet-50, and InceptionV3, and a CNN with a custom architecture were employed. In the next step, we designed a convolutional autoencoder (CAE) to extract semantic features subsequently given as inputs to four conventional ML classifiers, including support vector machine (SVM), k-nearest neighbor (K-NN), random forest (RF), and multi-layer perceptron (MLP)., Results: The custom CNN (85 % accuracy, 85 % sensitivity, 87 % specificity, 93 % area under the receiver operating characteristics [AUROC], and 94 % area under the precision-recall curve [AUPRC]) outperformed state-of-the-art models (84 % accuracy, 83 % sensitivity, 87 % specificity, 92 % AUROC, and 94 % AUPRC); however, utilizing a combination of the CAE and MLP yields even superior results (88 % accuracy, 86 % sensitivity, 91 % specificity, 94 % AUROC, and 95 % AUPRC)., Conclusions: We utilized IR-SLO images to differentiate between MS and HC eyes, with promising results achieved using a combination of CAE and MLP. Future multi-center studies involving more heterogenous data are necessary to assess the feasibility of integrating IR-SLO images into routine clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Radiologically isolated syndrome (RIS) is a condition characterized by asymptomatic, incidentally detected demyelinating plaques in the CNS in a patient without typical clinical findings of multiple sclerosis (MS). This study aimed to compare the mental status and cognitive functions of child and adolescent RIS cases with healthy controls and to investigate the relationship between psychometric test results and the demyelinating lesion characteristics., Methods: The mental status and cognitive functions of 12 RIS cases and 12 healthy controls were compared. Semi-structured interviews, behavioral evaluations, depression and anxiety scales, neuropsychological test battery, and an intelligence test were applied for the evaluation of mental state and cognitive functions. These results were compared with the number and localization of demyelinating lesions., Results: Sustained attention, visual-motor coordination, short-term memory skills, and ability to use visual-spatial information were found worse in the RIS group. There was no correlation between mental state and cognitive functions, and the number and localization of demyelinating lesions., Conclusion: Our study showed that pediatric RIS cases may have worse cognitive performance than healthy controls, but no correlation was found between the number and location of demyelinating lesions and psychiatric findings. Although it is controversial whether psychiatric disorders and cognitive disabilities have predictive value in terms of MS conversion in pediatric RIS cases, these subjects were not included in the scope of this study., Competing Interests: Declaration of competing interest All authors have read the manuscript, agreed with its content, and stated that there is no conflict of interest as competing financial interests or personal relationships that could influence the study reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The primary objective of this clinical trial was to assess whether administrating oral calcifediol (25(OH)D 3 ) could enhance the clinical outcomes of patients diagnosed with multiple sclerosis., Methods: This clinical trial was designed as a randomized, double-blind, two-arm study, with 25 participants receiving daily 50 μg of calcifediol and 25 people receiving daily 50 μg of cholecalciferol. The primary outcomes were serum levels of 25(OH)D 3 , number of relapses, changes in Kurtzke Expanded Disability Status Scale (EDSS), the 25-foot walk, and cognitive function., Results: At the end of the trial, delta serum concentrations of 25(OH)D 3 were 85.32±40.94 ng/ml in the calcifediol group compared to 13.72±11.56 ng/ml in the cholecalciferol group; 84 % of the calcifediol group and none of the cholecalciferol group had circulating 25(OH)D 3 concentrations exceeding 70 ng/ml. While both groups showed an overall trend towards improved cognitive function at the end of the study, the calcifediol group exhibited greater improvements in most cognitive tests. However, the trial had no significant beneficial effects on MS relapse, EDSS score, quality of life, or fatigue in either group, the calcifediol or cholecalciferol., Conclusions: The trial shows that calcifediol is more effective in rapidly increasing 25(OH)D 3 levels in MS patients compared to cholecalciferol when administrated at a similar dosage., Competing Interests: Declaration of competing interest The author A.S. declares that he has been involved in a clinical trial study sponsored by the Solius Company. Furthermore, he received a fee for statistical analysis in relation to the aforementioned study. This disclosure is made to ensure transparency and maintain the integrity of the research. The remaing authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cognitive impairment can considerably impact the work life of people who have multiple sclerosis (MS). Cognitive symptoms are associated with an increased likelihood of unemployment, changes in employment and decreased working hours. This qualitative interview-based study aims to gather real-word experiences and perspectives from both people living with MS and healthcare professionals, to explore how cognitive symptoms are experienced in the workplace, how their impact is addressed, and what can be done to support people in managing and minimizing this impact on employment., Methods: Semi-structured, one-to-one interviews were conducted with people living with MS who experience cognitive symptoms, and with healthcare professionals working in MS care. Participants were recruited from a healthcare market research agency based in the United States. The data obtained from the interviews were subsequently analysed using a Grounded Theory method, in order to identify the core themes that form the basis of this paper., Results: A total of 20 participants (n = 10 people living with MS; n = 10 healthcare professionals) from the United States were interviewed. Overall, 9 themes were identified from the raw data, which were grouped into three core themes describing the perspectives and experiences reported by both people living with MS and healthcare professionals: (1) The implications of cognitive symptoms on work; (2) Challenges in addressing cognitive impairment and its impact on work in MS care; (3) Strategies and support for managing the impact of cognitive symptoms., Conclusion: The real-world insights of PwMS and HCPs gained from this qualitative study show that a multi-faceted approach to addressing cognitive impairment and its impact on the employment of PwMS is required. Workplace adjustments can range from self-implemented changes to changes put in place by employers to accommodate the various ways in which cognitive symptoms may impact a person's work. This study provides valuable information on how people living with MS can be affected by cognitive symptoms in the context of their employment; furthermore, that preparing early when possible and maintaining a proactive approach to managing their impacts on work are important for maintaining a good quality of life., Competing Interests: Declaration of competing interest Sarah A Morrow has served as an advisory board member or received consulting fees from Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche, Sanofi Genzyme and Teva Neurosciences; has participated in a speaker's bureau for Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche and Sanofi Genzyme; has received research support from Biogen Idec, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche and Sanofi Genzyme; and has participated as a site investigator in clinical trials sponsored by Bristol Myers Squibb/Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche and Sanofi Genzyme. Nektaria Alexandri is an employee of Merck Healthcare KGaA, Darmstadt, Germany. David Yeandle is a member of the MS in the 21st Century Steering Group, Southampton, UK. Maija Pontāga has received honoraria or personal fees from Merck KGaA, Darmstadt, Germany. Marja-Liisa Sumelahti has received honoria or personal fees from Merck KGaA, Darmstadt, Germany, Novartis, Pfizer, Teva, Novartis, Lundbeck, Abbvie and Eli Lilly for lecturing or participating in advisory boards. She is also principal investigator for trials sponsored by Roche, Lundbeck, Novartis and Teva., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Magnetic resonance imaging [MRI] findings in Neuromyelitis optica spectrum disorder [NMOSD] and Multiple Sclerosis [MS] patients could lead us to discriminate toward them. For instance, U-fiber and Dawson's finger-type lesions are suggestive of MS, however linear ependymal lesions raise the possibility of NMOSD. Recently, artificial intelligence [AI] models have been used to discriminate between NMOSD and MS based on MRI features. In this study, we aim to systematically review the capability of AI algorithms in NMOSD and MS discrimination based on MRI features., Method: We searched PubMed, Scopus, Web of Sciences, Embase, and IEEE databases up to August 2023. All studies that used AI-based algorithms to discriminate between NMOSD and MS using MRI features were included, without any restriction in time, region, race, and age. Data on NMOSD and MS patients, Aquaporin-4 antibodies [AQP4-Ab] status, diagnosis criteria, performance metrics (accuracy, sensitivity, specificity, and AUC), artificial intelligence paradigm, MR imaging, and used features were extracted. This study is registered with PROSPERO, CRD42023465265., Results: Fifteen studies were included in this systematic review, with sample sizes ranging between 53 and 351. 1,362 MS patients and 1,118 NMOSD patients were included in our systematic review. AQP4-Ab was positive in 94.9% of NMOSD patients in 9 studies. Eight studies used machine learning [ML] as a classifier, while 7 used deep learning [DL]. AI models based on only MRI or MRI and clinical features yielded a pooled accuracy of 82% (95% CI: 78-86%), sensitivity of 83% (95% CI: 79-88%), and specificity of 80% (95% CI: 75-86%). In subgroup analysis, using only MRI features yielded an accuracy, sensitivity, and specificity of 83% (95% CI: 78-88%), 81% (95% CI: 76-87%), and 84% (95% CI: 79-89%), respectively., Conclusion: AI models based on MRI features showed a high potential to discriminate between NMOSD and MS. However, heterogeneity in MR imaging, model evaluation, and reporting performance metrics, among other confounders, affected the reliability of our results. Well-designed studies on multicentric datasets, standardized imaging and evaluation protocols, and detailed transparent reporting of results are needed to reach optimal performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years., Methods: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement., Results: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irene Schiavetti reports a relationship with Roche, Biogen, Horizon, Novartis, Hoya, Hippocrates Research, D.M.G Italia, Eyepharma, DreamsLab that includes: consulting or advisory. Livia Pasquali reports a relationship with Alexion, Biogen, Sanofi, Merck, Novartis, Roche that includes: consulting or advisory and travel reimbursement. Elisabetta Signoriello reports a relationship with Almirall, Biogen, Genzyme, Novartis, Teva that includes: board membership and travel reimbursement. Maria Pia Sormani reports a relationship with Biogen Idec, Merck Serono, Teva, Genzyme, Roche, Novartis, GeNeuro, Medday that includes: consulting or advisory. Jessica Frau reports a relationship with Biogen, Bristol, Novartis, Genzyme, Merck, Teva, Alexion that includes: board membership, consulting or advisory, and speaking and lecture fees. Daniele Caliendo reports a relationship with Merck that includes: funding grants. Alessio Signori reports a relationship with Roche, Horizon, Novartis that includes: speaking and lecture fees. Andrea Surcinelli reports a relationship with Roche, Merck, Biogen, Sanofi, Novartis that includes: travel reimbursement. Simona Bonavita reports a relationship with Novartis, Merck-Serono, Alexion, BMS, Biogen, Roche, Janssen-Cilag, Horizon that includes: speaking and lecture fees and travel reimbursement. Roberta Fantozzi reports a relationship with Novartis, Roche, Merck Serono, Bristol-Myers Squibb that includes: board membership and consulting or advisory. Antonio Carotenuto reports a relationship with Almirall, ECTRIMS- MAGNIMS, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen, Novartis that includes: funding grants. Doriana Landi reports a relationship with Biogen, Merck Serono, Teva, Bristol Myers Squibb, Mylan, Novartis, Roche, Horizon, Alexion, Sanofi-Genzyme, Novartis, Bayer-Schering that includes: speaking and lecture fees and travel reimbursement. Giacomo Lus reports a relationship with Biogen Idec, Merck Serono, Novartis, Sanofi- Aventis Pharmaceuticals, Teva neuroscience that includes: funding grants. Eleonora Cocco reports a relationship with Biogen, Merck, Novartis, Roche, Genzyme that includes: consulting or advisory and funding grants. Matteo Lucchini reports a relationship with Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Almirall, Horizon, Bayer that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Girolama Alessandra Marfia reports a relationship with Almirall, Bayer-Schering, Biogen, Sanofi Genzyme, Merck Serono, Novartis, Teva, Mylan, Bristol Mayers Squibb, Roche, Biogen that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Matteo Foschi reports a relationship with Merck, Biogen, Sanofi, Roche, Novartis that includes: consulting or advisory and travel reimbursement. Massimiliano Mirabella reports a relationship with Bayer Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva, Mylan, Almirall, CSL Behring, Roche, Ultragenix that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Diego Centonze reports a relationship with Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Protagon, Sandoz, Bristol-Myers Squibb, Alexion, Mitsubishi, Teva, Celgene that includes: board membership, funding grants, and non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Demyelinating disorders of the CNS are a set of chronic, inflammatory, autoimmune conditions. To improve understanding of epidemiology, population characteristics and disease behaviour, an Indian, hospital-based registry has been established to serve as a platform for fostering collaborative research. The following article outlines the development, governance and current status of the Indian Multiple Sclerosis and Allied Demyelinating Disorders Registry and Research Network (IMSRN), the country's first scientific database and dedicated expert research network of these disorders., Methods: Multiple reviews and stakeholder meetings were held to set up the registry. The IMSRN was formally initiated in August 2021 across 26 tertiary care centres. The registry is governed by the Indian Council of Medical Research (ICMR), New Delhi and its task force committee. The online secure database captures detailed clinical and imaging patient details at baseline and periodic follow up. Periodic meetings of the task force and collaborators are held to discuss the progress, improvements and research proposals., Results: The IMSRN is currently active and recruiting patients following an informed consent. As of current, more than 3336 patients including RIS (N = 8), CIS (N = 134), MS (N = 1674), NMOSD (N= 561), MOGAD (N = 404), ADEM (N = 46), CRION (N = 21), CLIPPERS (N = 2), and GFAP (N =1) have been enrolled. 340 patients, not meeting the diagnostic criteria for any of the aforementioned disease phenotypes are in the others category. Various research proposals are being developed to study different aspects of these disorders., Conclusion: The IMSRN has been established with a vision to strengthen our understanding about MS, NMOSD, MOGAD, and other demyelinating disorders. This would help answer important questions related to disease profiles and long-term outcomes of patients in the Indian setting. From the standpoint of clinical practice, therapeutics, patient management, research, and national policy building, IMSRN shall serve as a synergising platform for bridging the gap in the aforementioned areas and guiding future research through national and international collaboration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Fatigue is one of the most common symptoms reported by individuals with multiple sclerosis and it contributes to the reduction of the functionality. Therefore, it is important to assess the impact of fatigue on daily living of individuals with multiple sclerosis. The Modified Fatigue Impact Scale (MFIS) is an instrument to assess the perception of the impact of fatigue. However, there have been no investigations about the measurement properties of this instrument administered over the telephone for individuals with multiple sclerosis., Objectives: To verify the concurrent validity, the test-retest reliability, the standard error of measurement (SEM) and the minimal detectable change (MDC) of the MFIS applied over the telephone to assess the perception of the impact of fatigue of individuals with multiple sclerosis., Methods: The MFIS, composed of 21 items covering three domains: physical, cognitive and psychosocial, was applied at three different moments with an interval of 5-7 days. To establish the concurrent criterion validity, the face-to-face application and the first evaluation by telephone were used. The two telephone assessments were used to assess the test-retest reliability The intraclass correlation coefficient (ICC) with 95 % confidence interval (CI) and the Bland-Altman method were used. The standard error of measurement (SEM) and the MDC was calculated according to reliability results., Results: Thirty individuals (40.83 ± 10.61, 60 % female) were included. The median score on the Expanded Disability Status Scale was 2.00 (±4.00). The majority of participants experienced fatigue (n = 17; 56.67 %). A significant and high magnitude correlation (0.70 ≤ ICC ≤ 0.87, p < 0.001) was found in the investigation of concurrent criterion validity. The Bland-Altman method showed a mean difference between 0.70 to 2.17 points between face-to-face and telephone-based application of the MFIS. For test-retest reliability, a significant and very high magnitude correlation (0.91 ≤ ICC ≤ 0.97, p < 0.001) was found. The Bland-Altman method showed a mean difference between -0.03 and -0.77 points between two telephone-based applications. The SEM and the MDC were 0.71 and 1.97 points., Conclusion: The telephone-based application of the MFIS to assess the perceived impact of fatigue in individuals with multiple sclerosis demonstrated adequate measurement properties, and may be a valuable tool to assess patients in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patients diagnosed with multiple sclerosis (MS) commonly encounter heightened postural instability and challenges in aligning their eyes, head, and bodily motions while engaging in specific tasks. This study aims to compare the effects of Cawthorne-Cooksey and mechanical hippotherapy exercises on fatigue, balance, gait, dizziness, and life quality in patients with MS., Methods: The MS patients were randomly divided into Cawthorne-Cooksey (n:25) and mechanical hippotherapy exercise (n:25) groups. In addition to the traditional physical therapy program, Cawthorne-Cooksey and hippotherapy exercises were applied to the groups 3 days a week, for 8 weeks. The trial's clinical number is NCT06005909. The Fatigue Severity Scale (FSS), Fatigue Impact Scale (FIS), Dizziness Handicap Inventory, Tinetti Balance and Gait Assessment Scale, and Ferrans&Powers Quality-of-Life Index were used for pre-and post-treatment assessment., Results: Both groups exhibited a significant decrease in FSS, FIS, and Dizziness Handicap Inventory scores, as well as an increase in Tinetti Balance and Gait Assessment Scale and Ferrans&Powers Quality-of-Life Index scores following treatment. In the inter-group comparison, the Tinetti balance and gait assessment and the Ferrans&Powers quality of life index scores were higher in the hippotherapy group compared to the Cooksey group., Conclusions: Although both forms of physical activity have demonstrated effectiveness in reducing fatigue among individuals with MS, hippotherapy shows superior efficacy in enhancing balance, gait, and overall quality of life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Motor preparation and execution can be impaired in patients with multiple sclerosis (pwMS). These neural processes can be assessed using electroencephalography (EEG). During a self-paced movement, EEG signal amplitude decreases before movement (event-related desynchronization, ERD) and increases after movement (event-related synchronization, ERS)., Objective: To reappraise ERD/ERS changes in pwMS compared to healthy controls (HC)., Methods: This single-center study included 13 pwMS and 10 sex/age-matched HC. 60-channel EEG was recorded during two self-paced movements of the right hand: a simple index finger extension task and a more complex finger tapping task. Clinical variables included MS type, sex, age, disease duration, disability, grip strength, fatigue and attentional performance. EEG variables included ERD and ERS onset latency, duration, and amplitude determined using two methods of signal analyses (based on visual or automated determination) in the alpha and beta frequency bands in five cortical regions: right and left frontocentral and centroparietal regions and a midline region. Neuroimaging variables included the volumes of four deep brain structures (thalamus, putamen, pallidum and caudate nucleus) and the relative lesion load., Results: ERD/ERS changes in pwMS compared to HC were observed only in the beta band. In pwMS, beta-ERD had a delayed onset in the midline and right parietocentral regions and a shortened duration or increased amplitude in the parietocentral region; beta-ERS had a shorter duration, delayed onset, or reduced amplitude in the left parieto/frontocentral region. In addition, pwMS with a more delayed beta-ERD in the midline region had less impaired executive functions but increased caudate nuclei volume, while pwMS with a more delayed beta-ERS in the parietocentral region contralateral to the movement had less fatigue but increased thalami volume., Conclusion: This study confirms an alteration of movement preparation and execution in pwMS, mainly characterized by a delayed cortical activation (ERD) and a delayed and reduced post-movement inhibition (ERS) in the beta band. Compensatory mechanisms could be involved in these changes, associating more preserved clinical performance and overactivation of deep brain structures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Use of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established., Methods: In accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included., Results: The overall incidence of clinical relapse during washout periods ranging from 4.4-10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02-0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %., Conclusions: This systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer Massey reports a relationship with Biogen that includes: speaking and lecture fees. Jennifer Massey reports a relationship with Novartis that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Previous studies have shown that thalamic and hippocampal neurodegeneration is associated with clinical decline in Multiple Sclerosis (MS). However, contributions of the specific thalamic nuclei and hippocampal subfields require further examination., Objective: Using 7 Tesla (7T) magnetic resonance imaging (MRI), we investigated the cross-sectional associations between functionally grouped thalamic nuclei and hippocampal subfields volumes and T1 relaxation times (T1-RT) and subsequent clinical outcomes in MS., Methods: High-resolution T1-weighted and T2-weighted images were acquired at 7T (n=31), preprocessed, and segmented using the Thalamus Optimized Multi Atlas Segmentation (THOMAS, for thalamic nuclei) and the Automatic Segmentation of Hippocampal Subfields (ASHS, for hippocampal subfields) packages. We calculated Pearson correlations between hippocampal subfields and thalamic nuclei volumes and T1-RT and subsequent multi-modal rater-determined and patient-reported clinical outcomes (∼2.5 years after imaging acquisition), correcting for confounders and multiple tests., Results: Smaller volume bilaterally in the anterior thalamus region correlated with worse performance in gait function, as measured by the Patient Determined Disease Steps (PDDS). Additionally, larger volume in most functional groups of thalamic nuclei correlated with better visual information processing and cognitive function, as measured by the Symbol Digit Modalities Test (SDMT). In bilateral medial and left posterior thalamic regions, there was an inverse association between volumes and T1-RT, potentially indicating higher tissue degeneration in these regions. We also observed marginal associations between the right hippocampal subfields (both volumes and T1-RT) and subsequent clinical outcomes, though they did not survive correction for multiple testing., Conclusion: Ultrahigh field MRI identified markers of structural damage in the thalamic nuclei associated with subsequently worse clinical outcomes in individuals with MS. Longitudinal studies will enable better understanding of the role of microstructural integrity in these brain regions in influencing MS outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tamer S. Ibrahim reports financial support was provided by National Institutes of Health. Zongqi Xia reports financial support was provided by National Institutes of Health. Tales Santini reports financial support was provided by Coordination of Higher Education Personnel Improvement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sphingolipids are signaling molecules and structural components of the axolemma and myelin sheath. Plasma sphingolipid levels may reflect disease status of neuromyelitis optica spectrum disorder (NMOSD). We aimed to examine plasma sphingolipids as disease severity biomarkers for NMOSD and compare their characteristics with those of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP)., Methods: We measured plasma sphingolipids, sNfL, and sGFAP levels in NMOSD cases with anti-aquaporin-4-antibody. An unbiased approach, partial least square discriminant analysis (PLS-DA), was utilized to determine whether sphingolipid profiles differ according to the disease state of NMOSD (presence, moderate-to-severe disability [Expanded Disease Severity Scale, (EDSS) > 3.0], and relapses)., Results: We investigated 81 patients and 10 controls. PLS-DA models utilizing sphingolipids successfully differentiated patients with EDSS > 3.0, but failed to identify the presence of disease and relapses. Ceramide-C 14 -a significant contributor to differentiating EDSS > 3.0-positively correlated with EDSS, while its levels were independent of age and the presence of relapses. This characteristic was unique from those of sNfL and sGFAP, which were affected by age and relapses as well as EDSS., Conclusion: Plasma sphingolipids may be useful NMOSD biomarkers for disability with distinct characteristics compared to sNfL and sGFAP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Disease modifying treatments (DMTs) for multiple sclerosis (MS) are effective in preventing both relapses and disability progression. Highly effective treatments (HETs) are more effective than platform therapy in preventing confirmed disability progression (CDP), when used early. Infections may complicate HETs administration, and their prevention through vaccination is crucial in order to assure the safety of people with MS (pwMS). The aim of the present study is to describe the effect of MS DMTs on COVID-19 vaccination and the risk of breakthrough infection in a cohort of pwMS., Materials and Methods: This is a monocentric retrospective observational study conducted at the MS center of the Guglielmo da Saliceto Hospital in Piacenza, Italy. One hundred and fifty-seven (157) pwMS who received two doses of the SARS-CoV-2 vaccine (with 80.3 % receiving a booster dose) were included in the study., Results: fifty-six pwMS (35.7 %) were females, the mean age was 48.6 (SD: 12.87) years, and 59 (37.6 %) had at least one comorbidity. Twenty-five (15.9 %) breakthrough infections were observed, with 17 (68.0 %) classified as mild and 8 (32.0 %) as moderate. A multivariable linear regression model confirmed that B-cell suppressor DMTs and EDSS were factors associated with the latest antibody titre. Patients treated with B-cell suppressors exhibited a risk almost four times higher for breakthrough infections compared to other patients, with a hazard ratio (HR) of 3.72 (95 % CI: 1.50 - 9.27) (p = 0.005)., Conclusions: B-cell suppressor DMTs are associated with the risk of breakthrough COVID-19 in our cohort, but vaccination fully protected pwMS against severe breakthrough disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paolo Immovilli reports a relationship with Roche that includes: speaking and lecture fees. Paolo Immovilli reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. Paolo Immovilli reports a relationship with Sanofi that includes: speaking and lecture fees. Paolo Immovilli reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. Paolo Immovilli reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Paolo Immovilli reports a relationship with Novartis that includes: speaking and lecture fees. Paolo Immovilli reports a relationship with Alexion that includes: speaking and lecture fees. Irene Schiavetti reports a relationship with Biogen that includes: consulting or advisory. Irene Schiavetti reports a relationship with Roche that includes: consulting or advisory. Irene Schiavetti reports a relationship with Horizon Therapeutics USA Inc that includes: speaking and lecture fees. Irene Schiavetti reports a relationship with Novartis that includes: consulting or advisory. Irene Schiavetti reports a relationship with Hoya Corporation that includes: consulting or advisory. Irene Schiavetti reports a relationship with Hippocrates Research that includes: consulting or advisory. Irene Schiavetti reports a relationship with DMG Italia SRL that includes: consulting or advisory. Irene Schiavetti reports a relationship with Eyepharma that includes: consulting or advisory. Irene Schiavetti reports a relationship with DreamsLab that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Satralizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has been approved globally for the treatment of neuromyelitis optica spectrum disorder (NMOSD), based on positive results from two randomized, double-blind, phase 3 studies: SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279). There remains an unmet need to understand the real-world management of NMOSD, especially in patients undergoing tapering of concomitant therapy. We examined real-world treatment patterns, including concomitant glucocorticoids and immunosuppressants, and relapse in satralizumab-treated patients with NMOSD, using a Japanese administrative hospital claims database., Methods: We used retrospective data from the Medical Data Vision hospital-based administrative claims database. The index date was the date of first satralizumab prescription and the study period was set between August 2018 and March 2022. Patients were included in the overall population if they had a first prescription for satralizumab between August 2020 and March 2022, an International Classification of Disease, Version10 code of G36.0 prior to March 2022, and were observable for ≥90 days prior to the index date. The primary endpoint was the percentage of patients with relapse-free reduction of oral glucocorticoids to 0 mg/day at 360 days of continued satralizumab treatment. Secondary endpoints included time to relapse, number of relapses after the index date while being on continuous satralizumab treatment, annualized relapse rate before and after the index date, and concomitant medication use. Relapse and dose reduction were identified using definition specifically developed for this study., Results: Of the 131 patients included in the overall population, most were female (90.8 %), aged 18-65 years (75.6 %), and were prescribed oral glucocorticoids (93.1 %). Azathioprine (19.1 %) and tacrolimus, a calcineurin inhibitor (18.3 %), were the most common immunosuppressants at index date. Six (4.6 %) patients had a history of biologic use (tocilizumab, 1 [0.8 %]; eculizumab, 5 [3.8 %]). Among 111 patients observable for 360 days pre-index, there were 0.6 ± 0.8 (mean ± SD) relapses during 360 days before the index date. The median (interquartile range) duration of satralizumab exposure was 197.0 (57.0-351.0) days. Most (125/131; 95.4 %) patients were relapse-free post-index; 6 (4.6 %) patients relapsed within 90 days after the index date, of which 2 had the first relapse within 7 days after the index date. Among 21 patients with 360-day follow-up, 6 (28.6 %) patients were on 0 mg/day dose of glucocorticoid prescription without relapse 360 days post-index. Of these 6 patients, 2 had no prescription of oral glucocorticoids at the index date and remained glucocorticoid- and relapse-free 360 days after the index date., Conclusion: These real-world data support the phase 3 clinical trials. Our results, over a median duration of satralizumab exposure of 197.0 days, showed that a majority (125/131, 95.4 %) of patients were relapse-free after initiating satralizumab treatment. The number of glucocorticoid-free patients without relapse increased over time under continuous satralizumab prescription. Further studies are needed to confirm if satralizumab can be used as a potential immunosuppressant- and glucocorticoid-sparing agent., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ichiro Nakashima reports a relationship with Chugai Pharmaceutical, Alexion, Mitsubishi Tanabe Pharma, Novartis Pharma, Biogen Japan that includes: consulting or advisory. Ichiro Nakashima reports a relationship with LSI Medience Corporation that includes: non-financial support. Jin Nakahara reports a relationship with Alexion, Biogen, Chugai Pharmaceutical, CSL-Behring, Eisai, JB, Mitsubishi Tanabe Pharma, Novartis, Sanofi, and Takeda Pharmaceutical that includes: speaking and lecture fees. Jin Nakahara reports a relationship with Alexion, Biogen, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma, and Novartis that includes: consulting or advisory. Jin Nakahara reports a relationship with Biogen, Chugai Pharmaceutical, Eisai, JB, Mitsubishi Tanabe Pharma, and Takeda Pharmaceutical that includes: funding grants. Hideo Yasunaga reports a relationship with Chugai Pharmaceutical, Tsumura, Kyowa Kirin, AbbVie, Boehringer Ingelheim, and Japan Blood Products Organization that includes: speaking and lecture fees. Hideo Yasunaga reports a relationship with Novartis, Chugai Pharmaceutical, and Eli Lilly Japan that includes: consulting or advisory. Masami Yamashita reports a relationship with Chugai Pharmaceutical that includes: employment. Nobuo Nishijima reports a relationship with Chugai Pharmaceutical that includes: employment. Mariko Nio reports a relationship with Chugai Pharmaceutical that includes: employment. Kazuo Fujihara reports a relationship with Biogen, Mitsubishi Tanabe Pharma, Novartis, Chugai Pharmaceutical, Roche, Alexion, VielaBio/Horizon Therapeutics, UCB, Merck Biopharma, Japan Tobacco and Abbvie that includes: consulting or advisory. Kazuo Fujihara reports a relationship with Biogen, Eisai, Mitsubishi Tanabe Pharma, Novartis, Chugai Pharmaceutical, Roche, Alexion, VielaBio, Teijin, Asahi Kasei Medical, Merck, and Takeda Pharmaceutical that includes: speaking and lecture fees and travel reimbursement. Kazuo Fujihara reports a relationship with The Ministry of Education, Culture, Sports, Science and Technology of Japan and The Ministry of Health, Welfare and Labour of Japan that includes: funding grants. Atsushi Satomura is former employee of Chugai Pharmaceutical. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: EBV is a necessary but not sufficient factor in the pathophysiology of multiple sclerosis (MS). EBV antibodies to the nuclear antigen (EBNA1) and viral capsid antigen (VCA) rise rapidly prior to MS disease manifestations, and their absence has clinical utility with a high negative predictive value. It remains unclear whether EBV levels act as prognostic, monitoring, or pharmacodynamic/response biomarkers. Substantial literature on this topic exists but has not been systematically reviewed. We hypothesized that EBV levels against EBNA1 and VCA are potential prognostic and monitoring biomarkers in MS, and that patient population, MS clinical phenotype, and EBV assay method may play important roles in explaining variation among study outcomes., Methods: We systematically searched PubMed and EMBASE from inception to April 1, 2022. After removal of duplicates, records were screened by abstract. Remaining full-text articles were reviewed. Clinical and MRI data were extracted from full-text articles for comparison and synthesis., Results: Searches yielded 696 unique results; 285 were reviewed in full, and 36 met criteria for data extraction. Heterogeneity in sample population, clinical outcome measures, assay methods and statistical analyses precluded a meta-analysis. EBV levels were not consistently associated with clinical disease markers including conversion from CIS to RRMS, neurological disability, or disease phenotype. Studies using repeated-measures design suggest that EBNA1 levels may temporarily reflect inflammatory disease activity as assessed by gadolinium-enhancing Magnetic Resonance Imaging (MRI) lesions. Limited data also suggest a decrease in EBV levels following initiation of certain disease-modifying therapies., Conclusion: Heterogeneous methodology limited generalization and meta-analysis. EBV antibody levels are unlikely to represent prognostic biomarkers in MS. The areas of highest ongoing promise relate to diagnostic exclusion and pharmacodynamic/disease response. Use of EBV antibodies as biomarkers in clinical practice remains additionally limited by lack of methodological precision, reliability, and validation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is an immune system disorder that affects the central nervous system (CNS) and progressively damages nerve fibers and protective myelin. People with MS often experience a wide range of complications, including lower urinary tract dysfunction, urinary tract infections (UTIs) and sexual dysfunction. MS is common in young people and can lead to sexual dysfunction (SD) and infertility, which becomes more pronounced as the disease progresses., Results: Over the past two decades, significant advances have been made in the management of MS, which may slow the progression of the disease and alter its course. However, UTI and SD remain significant challenges for these patients. Awareness of the underlying complications of MS, such as UTIs and infertility, is crucial for prevention, early detection and appropriate treatment, as there is a causal relationship between UTIs and the use of corticosteroids during an attack., Conclusion: This article provides an overview of potential microbial pathogens that contribute to the development of MS, as well as an assessment of people with MS who report UTIs and infertility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Multiple sclerosis (MS), which is known as a young-adult age disease, is called late-onset MS (LOMS) when it occurs at the age of 50 and older. In our study, we aimed to analyse the clinical and demographic characteristics, comorbidities, diagnostic and treatment challenges and prognosis of LOMS., Methods: In a retrospective analysis of 136 patients diagnosed with multiple sclerosis (MS) after the age of 50, based on the 2017 McDonald criteria, and who were under observation in eight distinct MS centers across Turkey; demographic information, clinical characteristics of the disease, oligoclonal band (OCB) status, initial and current Expanded Disability Status Scale (EDSS) values, administered treatments, and the existence of spinal lesions on magnetic resonance imaging (MRI) were investigated., Results: The mean age of the 136 patients was 60.96±6.42 years (51-79), the mean age at diagnosis was 54.94±4.30 years, and 89 (65.4 %) of the patients were female. Most of the cases, 61.1 % (83) had at least one comorbidity. In 97 patients who underwent lumbar puncture (LP), OCB positivity was observed in 63.6 %. In 114 patients (83.8 %), spinal lesions were detected on MRI. Eighty-seven patients had relapsing-remitting MS (RRMS) (64 %), 27 patients had secondary progressive MS (SPMS) (19.9 %), and 22 patients had primary progressive MS (PPMS) (16.2 %). The mean EDSS at the time of diagnosis was 2.44±1.46, and the mean current EDSS was 3.15±2.14., Conclusions: In LOMS patients, the rates of delay in the diagnostic process, treatment disruption and progressive disease are higher than in the general MS population. The high rates of LP applying and OCB positivity of this study may indicate the habit of looking for clear evidences in advanged age in our country. This situation and comorbidities may cause a delay in diagnosis and eliminates the window of opportunity for early diagnosis. Although the high number of spinal lesions is a known marker for progressive disease, it is an issue that needs to be discussed whether the increased frequency of progressive course at older ages is due to the nature of the disease or immune aging itself., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The aim of the present systematic review was to investigate the effects of voluntary walking interventions in persons with multiple sclerosis (pwMS). For this purpose, we developed a framework to describe the components of walking interventions., Data Sources: Two databases (MEDLINE/PubMed and EMBASE) were searched in January 2023., Study Selection: Included studies enrolled pwMS and evaluated walking interventions with a duration of 2 weeks or longer. Further, they evaluated at least one walking-related outcome. Both RCTs and non-controlled studies were enrolled., Data Extraction: Data were extracted using a customized spreadsheet, which included detailed information on patient characteristics, interventions, outcomes, and results. Based on the extracted results, the effect sizes (ES, Hedge's g) of the walking interventions were calculated if possible. The methodological quality of the included studies and their reporting was determined using the TESTEX evaluation tool., Data Synthesis: Data from a total of n = 200 pwMS was included from N = 7 RCT´s (from 3 we used within-group data) and N = 5 single-group studies. On average 91.7 ± 9.9 % of the planned walking sessions were attended, 8.7 ± 10.5 % of the participants dropped out, and very few adverse events occurred. Walking interventions improved walking performance during short distance walk tests (ES ranging from -0.21 to -0.72, "walking time") and long distance walk tests (ES ranging from 0.27 to 0.72, "walking distance")., Conclusions: Voluntary walking interventions appear to be safe and effective at improving walking performance in pwMS. However, well-powered walking intervention studies are needed to confirm these promising effects. The simplicity of walking interventions makes them highly relevant for ambulatory pwMS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Prognostic markers for relapse and neurological disability following the first clinical event in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remain lacking. We investigated the clinical profiles and early prognostic factors associated with relapsing disease or impaired functional outcome in a large single-center cohort of pediatric MOGAD., Methods: We retrospectively analyzed the clinical and paraclinical data and treatment outcomes of children with MOGAD seen at Children's Health in Dallas, Texas from 2009 to 2022. Univariate analyses were used to evaluate factors from initial event associated with relapsing disease course and impaired functional outcome (modified Rankin scale [mRS] >1) at final follow-up., Results: Our cohort comprised of 87 children of diverse race/ethnicity. Presentation with acute disseminated encephalomyelitis (ADEM) was more frequent in children aged ≤8 years and Caucasian background, whereas presentation with optic neuritis was more common in children aged >8 years and other race/ethnicity. 44.3 % (27/61) had relapsing disease course, of whom 48.0 % had multiple relapses. 30.3 % (23/76) had final mRS >1. Children with abnormal electroencephalogram had reduced relapse risk. Children with ADEM presentation, severe disease, low MOG-IgG titer, and central and systemic inflammation (represented by cerebrospinal fluid pleocytosis and serum leukocytosis, respectively) at onset had higher likelihood of final mRS >1., Conclusion: Abnormal electroencephalogram at the first event was associated with reduced relapse risk while disease severity and peripheral inflammation significantly contributed to final neurological disability. Further studies are needed to validate these findings as early risk factors for disability and relapse and to identify optimal treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Improving aerobic fitness in people with advanced multiple sclerosis (MS) may reduce fatigue, and lower the risk of cardiovascular disease, as has been found for people with mild to moderate MS. Training targeting aerobic fitness can be challenging due to paresis, access to suitable equipment and fatigue. The aim of this study was to investigate whether people with advanced multiple sclerosis could perform functional electrical stimulation (FES) cycling combined with arm crank interval exercise (hybrid FES interval training) training, and its effects on aerobic fitness and fatigue., Methods: Hybrid FES interval training was performed 2 d/wk for 12 weeks. Each session consisted of 40 min of continuous FES cycling with arm crank intervals of 30 s work/30 s rest added concurrently for 20 min. The intensity target was a minimum of 60 % of arm crank power and 'hard' measured by rate of perceived exertion (RPE). Attendance, compliance to intensity and time targets, adverse events, and drop outs were measured. Aerobic fitness was assessed by an arm crank maximal test. Fatigue was measured via the Modified Fatigue Impact Scale (MFIS)., Results: Seven participants (6 female; age 57.1 ± 7.8y; Expanded Disability Status Scale 7.1 ± 0.8) with advanced MS attended 80 ± 10.4 % of the scheduled exercise sessions and there were no adverse events or drop outs. Average RPE at the end of each training session was 15.1 ± 2.1, representing vigorous intensity exercise. Aerobic fitness did not change pre- to post-intervention (14.2 ± 5.7 to 14.8 ± 6.0 mL/kg/min [p = 0.43]), and resulted in a small effect size (ES) (0.30). The reduction in fatigue during the intervention (31.0 ± 10.4 to 21.7 ± 11.4 [p = 0.10]), resulted in a moderate to large ES (-0.77)., Conclusion: Hybrid FES interval training could be performed 2 days per week for 12 weeks and represented vigorous intensity exercise, but there was no change in aerobic fitness. The reduction in participants' perceptions of fatigue represented a moderate to large ES, indicating hybrid FES interval training might be suitable for people with advanced MS who need exercise equipment appropriate for their condition., Clinical Trial Registration: This study was registered with Australian and New Zealand Clinical Trials Register (U1111-1194-2040)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The aim of this study is to evaluate the nutritional status of patients with multiple sclerosis (MS) and to develop suggestions for changing eating habits in a healthy direction., Methods: The study was conducted on 171 participants (80.1 % female; 19.9 % male) diagnosed with MS between the ages of 18-60 who applied to Ankara Hacettepe University Hospital Neurology Outpatient Clinic between June 2021 and March 2023. Body weight, height, body composition, waist circumference, upper mid-arm circumference and hand grip strength were measured in accordance with the technique of anthropometric measurements. A three-day food consumption record was taken to evaluate the energy, macro, and micronutrient content of the diet. Mediterranean Diet Assessment Tool was used to assess adherence to diet., Results: Mean age of the participants was recorded as 35.2 ± 10.81 years. According to the body mass index (BMI) classification, 59.9 % of females were in normal limits, while 61.8 % of males were classified as overweight and obese. However, when evaluated in terms of body composition, body fat percentage was found to be above of normal limits in both genders. Also, 70.8 % of participants were sedentary. The percentage of patients who met their daily energy requirements in women with light and moderate activity was higher than in men, but it was not statistically significant. In participants with high activity level, the percentage of patients meeting energy requirements was below 50 % for both genders. Dietary fat and saturated fat intake were higher than the recommendations, while monounsaturated fatty acids and dietary fiber intake were less. The percentages of patients meeting their calcium requirement was below 50 % in both genders. Mean intake amounts of vegetables, fruits, legumes, nuts, and dairy products were below the Türkiye Nutrition Guideline recommendations., Conclusion: This study shows the nutritional characteristic of patients with MS in detail with different aspects. Although most of the patients were in normal limits in terms of BMI, body fat percentages were found to be above normal limits in both genders. Total fat and saturated fat intakes were found to be high according to scientific recommendations while the intake of food groups required for a fibre-based diet and intake of dairy products were low., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, it was aimed to detect ataxia in patients with Multiple Sclerosis (MS) by utilizing static plantar pressure data and capsule networks (CapsNet), one of the deep learning (DL) architectures. CapsNet is also equipped with a robust dynamic routing mechanism that determines the output of the next capsule. MS is a chronic nervous system disease that shows its effect in the central nervous system and manifests itself with attacks. One of the most common and challenging symptoms of MS is known as ataxia. Ataxia causes loss of control of limb muscle tone or gait disorders, leading to loss of balance and coordination. The diagnosis of ataxia in MS is applied employing the standard Expanded Disability Status Scale (EDSS) score. However, due to reasons such as physician misconception, diagnosis differences among physicians, and incorrect patient information, more unbiased solutions are required for the diagnosis. The results included Sensitivity at 96.34 % ± 1.71, Specificity at 98.11 % ± 2.04, Precision at 98.08 % ± 2.16, and Accuracy at 97.13 % ± 0.33. The main motivation of the study is to show that these deep learning methods can successfully detect ataxia in MS patients using static plantar pressure data. The high-performance measurements of sensitivity, specificity, precision and accuracy emphasize that the proposed system can be an effective tool in clinical practice. In addition, it was concluded that the proposed autonomous system would be a support mechanism to assist the physician in the detection of ataxia in patients with MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk., Methods: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02)., Results: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors., Conclusions: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may., Competing Interests: Declaration of Competing Interest There is no conflict of interest related to this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system with varying progression rates among individuals. The ability to predict disease progression is crucial for treatment decisions with disease-modifying therapies (DMTs). A few cerebrospinal fluid (CSF) biomarkers have been investigated in relation to disease progression, but few have been effectively translated into clinical practice. The aim of this study was to evaluate the diagnostic and prognostic value of known CSF markers, to compare their sensitivity and specificity, and to develop a prognostic model using a combination of markers to predict disease progression., Methods: This retrospective cohort study included 82 patients with a first episode of inflammatory demyelinating symptoms suggestive of MS between January 2018 and January 2021. Patients underwent diagnostic lumbar puncture and other investigations according to the multiple sclerosis (MS) protocol. They were divided into three groups according to MRI findings, relapse rate and EDSS score. CSF marker concentrations were determined by laser nephelometry and electrochemiluminescence immunoassay., Results: The results showed that the number of oligoclonal bands could discriminate the progression-free group from the other groups, but had a lower discriminatory power compared to CSF marker concentrations. Among CSF markers, FLC kappa showed the best discriminatory performance. By combining FLC kappa with gender and lesion localization information, a simple predictor of progression-free group membership was proposed. This predictor showed good sensitivity (91 %) and specificity (65 %)., Conclusion: In conclusion, CSF FLC kappa concentration, together with gender and lesion localization, may be a valuable predictor of disease progression in MS patients. This study highlights the potential of using CSF biomarkers for prognostic purposes and offers a simple approach to predicting disease progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)