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Background Immunocompromised patients are at high risk of developing persisting/prolonged COVID-19. Data on the early combined use of antivirals and monoclonal antibodies in this population are scarce.Research design and methods We performed an observational, prospective study, enrolling immunocompromised outpatients with mild-to-moderate COVID-19, treated with a combination of sotrovimab plus one antiviral (remdesivir or nirmatrelvir/ritonavir) within 7 days from symptom onset. Primary outcome was hospitalization within 30 days. Secondary outcomes were: needing for oxygen therapy; development of persistent infection; death within 60 days and reinfection or relapse within 90 days.Results We enrolled 52 patients. No patient was hospitalized within 30 days of disease onset, required oxygen administration, died within 60 days, or experienced a reinfection or clinical relapse within 90 days.The clearance rates were 67% and 97% on the 14th day after the end of therapy and at the end of the follow-up period, respectively.Factors associated with longer infection were initiation of therapy 3 days after symptom onset and enrollment for more than 180 days from the beginning of the study. However, only the latter factor was independently associated with a longer SARS-CoV-2 infection, suggesting a loss of efficacy of this strategy with the evolution of SARS-CoV-2 variants.Conclusions Early administration of combination therapy with a direct antiviral and sotrovimab seems to be effective in preventing hospitalization, progression to severe COVID-19, and development of prolonged/persisting SARS-CoV-2 infection in immunocompromised patients.

Disruptions to brain networks, measured using structural (sMRI), diffusion (dMRI), or functional (fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the relevance of regions in the core of the connectome but yielding mixed results depending on the studied connectivity domain. Using a multilayer network approach, we integrated these three modalities to portray an enriched representation of the brain's core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, we selected PwMS and healthy controls with complete multimodal brain MRI acquisitions from 13 European centers within the MAGNIMS network. Physical disability and cognition were assessed with the Expanded Disability Status Scale (EDSS) and the symbol digit modalities test (SDMT), respectively. SMRI, dMRI, and resting-state fMRI data were parcellated into 100 cortical and 14 subcortical regions to obtain networks of morphological covariance, structural connectivity, and functional connectivity. Connectivity matrices were merged in a multiplex, from which regional coreness-the probability of a node being part of the multiplex core-and coreness disruption index (κ)-the global weakening of the core-periphery structure-were computed. The associations of κ with disease status (PwMS vs. healthy controls), clinical phenotype, level of physical disability (EDSS ≥ 4 vs. EDSS < 4), and cognitive impairment (SDMT z-score < -1.5) were tested within a linear model framework. Using random forest permutation feature importance, we assessed the relative contribution of κ in the multiplex and single-layer domains, in addition to conventional MRI measures (brain and lesion volumes), in predicting disease status, physical disability, and cognitive impairment. We studied 1048 PwMS (695F, mean ± SD age: 43.3 ± 11.4 years) and 436 healthy controls (250F, mean ± SD age: 38.3 ± 11.8 years). PwMS showed significant disruption of the multiplex core-periphery organization (κ = -0.14, Hedges' g = 0.49, p < 0.001), correlating with clinical phenotype (F = 3.90, p = 0.009), EDSS (Hedges' g = 0.18, p = 0.01), and SDMT (Hedges' g = 0.30, p < 0.001). Multiplex κ was the only connectomic measure adding to conventional MRI in predicting disease status and cognitive impairment, while physical disability also depended on single-layer contributions. In conclusion, we show that multilayer networks represent a biologically and clinically meaningful framework to model multimodal MRI data, with disruption of the core-periphery structure emerging as a potential connectomic biomarker for disease severity and cognitive impairment in PwMS., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: CD20 + T lymphocytes are a subset of circulating T cells presenting the CD20 + receptor, a molecular marker of B lineage. CD20 + T lymphocytes are thought to play a pivotal role in multiple sclerosis (MS) pathology, especially at progressive stages. We aimed to investigate the correlation between CD20 + T lymphocytes and neuropsychological features (i.e., cognition, depression, anxiety, fatigue, and sleep quality) in MS patients., Methods: We enrolled 90 MS patients. Each patient underwent cognitive assessment (Brief International Cognitive Assessment for Multiple Sclerosis) and psychometric assessment (modified Fatigue Impact Scale, Beck Anxiety Inventory, Beck Depression Inventory, Pittsburgh Sleep Quality Index). Cognitive status was defined through the cerebral functional score., Results: Forty-four of 90 patients were relapsing-remitting (49%) and 46 were progressive patients (51%). Seventy patients (18.9%) showed CD20 + T lymphocytes in peripheral blood with a mean level of 0.38 ± 1.2%. Patients with CD20 + T lymphocytes were more likely to be at progressive phases (76.5% vs. 23.5%, p = 0.02) and showed a higher Expanded Disability Status Scale score (median [range] = 6.0 [1.5-7.5] vs. 3.5 [1-7.5], p = 0.001). Moreover, patients with CD20 + T lymphocytes showed worse cognitive functioning (p = 0.004), higher global fatigue symptoms (p = 0.02), higher cognitive fatigue (p = 0.01), higher psychosocial fatigue (p = 0.005), and a trend toward worse sleep quality (p = 0.06)., Conclusions: The presence of CD20 + T lymphocytes in the peripheral blood of MS patients was associated with worse neuropsychological functioning and progressive disease stages. Peripheral CD20 + T lymphocytes could potentially serve as markers for both disease progression and development of fatigue in MS patients., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The rearranged during transfection (RET) receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor family and by the growth differentiation factor-15 cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

Background and Objectives: Editors of scientific journals play a key role in the health-related research process. Our study aims to characterize the demographics, work habits, decision-making processes, and ethical challenges faced by editors of neurological journals and to evaluate associations between editor or journal characteristics and editorial decisions, as well as sources of conflict of interest., Methods: Cross-sectional study involving editors from neurological journals that fell above the 50th percentile in the Scimago rankings. Editors were invited to complete a 16-item anonymous online survey. Data on demographics, editorial processes, decision-making, and ethical issues were collected and analysed., Results: 64 editors completed the survey (35.94% were aged 55-65 years, 68.75% had over 7 years of experience); journals' impact factors(IF) ranged from 1 to 10 (mean 3.412 ± 0.260). When reviewers were blinded to authors, editors relied more on reviewers' decisions (p = < 0.007). Editors with more years of experience relied less on reviewers' decisions (p = 0.009). Higher IF journals were associated with more frequent conflicts of interest between authors (p = 0.019) and reviewers (p = 0.033). Younger editors faced more ethical dilemmas related to scientific conduct and plagiarism (p = 0.008 and p = 0.016). Younger editors and those working for journals with higher IF were more likely to face ethical dilemmas related to editorial decisions (p = 0.016 and p = 0.042)., Discussion: The study highlights relevant aspects of the editorial process in neurological journals, emphasizing the influence of blinding procedures and the inconsistent handling of decision-making and ethical challenges. Addressing these issues through collaboration and standardized guidelines can promote the integrity of the process, ensuring high-quality and trustworthy scientific research., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflict of interest. Ethical approval: The Ethical Committee of the University of Campania "Luigi Vanvitelli" approved the study (protocol number 0014460/i)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used in clinical practice and the least time-consuming battery to estimate cognitive function in adults with Multiple Sclerosis (MS), while it has been included in few studies on young MS, also because of the absence of normative values., Objective: The aim of this study is to evaluate the impact of age, sex and education on BICAMS scores in a young adolescent population., Methods: We administered the BICAMS to 169, 11-to-18-year-old, healthy subjects. Linear regression models were used to assess the impact of age, sex, and education on sub-test scores. When statistically significant (p < 0.05), we used the regression coefficient to correct the raw scores., Results: younger age was associated with worse performance on SDMT (β = 1.76; p < 0.05), CVLT-II (β = 3.33; p < 0.05) and BVMT-R (β = 0.62; p < 0.05). Female sex was associated SDMT (β = 2.75 (p < 0.05) and CVLT-II (β = 2.51 (p < 0.05). Educational attainment was associated with better performance on SDMT (β = 1.79 (p = < 0.05) and BVMT-R (β = 0.61; p < 0.05). Cut-off points were suggested at the 5th lowest percentile., Conclusion: Age, sex, and education must be accounted for when applying the BICAMS to young population. Its use in everyday assessment of patients with Pediatric Onset Multiple Sclerosis (POMS) could help to compare and combine data across centers, identifying patients requiring a comprehensive evaluation and ad hoc cognitive stimulation programs., Competing Interests: Declarations. Competing interests: The authors declare that they have no conflict of interest., (© 2024. Fondazione Società Italiana di Neurologia.)

Background and Objectives: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS., Methods: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS)., Results: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R 2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes ( B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (Δ R 2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change ( r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (Δ R 2 = 0.064, p < 0.001)., Discussion: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

Competing Interests: Conflicts of interest Drs Skelsey, Loftis, Kaufmann, Siegel, Bhatia, Wangia, and Walker are investigators and/or consultants of DermTech; Drs Rigby, Whitaker, Stone, Moccia, O'Brien, Jansen, and Clarke are employees of DermTech.

Objective: People with multiple sclerosis (MS) might experience symptoms that are usually underestimated. Dysphagia should be evaluated within the Expanded Disability Status Scale (EDSS), but clinicians often do not assess it properly. The objectives of this study are as follows: To assess the prevalence of dysphagia in patients with MS utilizing the Swallowing Disturbance Questionnaire (SDQ); to examine the correlation with the EDSS; to investigate the relationship between dysphagia and clinico-demographic characteristics of MS., Methods: In total, 177 MS patients underwent evaluations with EDSS, SDQ, cognitive functions, anxiety, depression, fatigue, and sleep quality tests. We compared clinico-demographic data of patients with and without dysphagia and native-EDSS to SDQ-EDSS., Results: Out of the 177 MS patients, 56% of individuals were identified having dysphagia according to the SDQ with 41 patients exhibiting mild dysphagia, 31 showing moderate dysphagia and 27 patients having severe dysphagia. Only 6 patients had dysphagia recorded in the EDSS. SDQ-EDSS scores were significantly higher than native scores. Dysphagia was associated with depressive symptoms and sleep quality., Interpretation: Dysphagia affects up to 56% of MS patients. The SDQ questionnaire is useful for identifying dysphagia, which can help in capturing disease progression and preventing complications like aspiration pneumonia. The SDQ-EDSS was higher than the native-EDSS, reflecting the poor ability of the native-EDSS to evaluate certain symptoms such as dysphagia. The SDQ correlated with depressive symptoms, which are associated with a greater perception of MS symptoms, and poor sleep quality, which could be associated with the triggering of pathogenic mechanisms responsible for disease progression., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Plants are continuously exposed to environmental challenges, including pollutants, pesticides, and heavy metals, collectively termed xenobiotics. These substances induce oxidative stress by generating reactive oxygen species (ROS), which can damage cellular components such as lipids, proteins, and nucleic acids. To counteract this, plants have evolved complex metabolic pathways to detoxify and process these harmful compounds. Oxidative stress in plants primarily arises from the overproduction of hydrogen peroxide (H 2 O 2 ), superoxide anions (O 2 •- ), singlet oxygen ( 1 O 2 ), and hydroxyl radicals ( • OH), by-products of metabolic activities such as photosynthesis and respiration. The presence of xenobiotics leads to a notable increase in ROS, which can result in cellular damage and metabolic disruption. To combat this, plants have developed a strong antioxidant defense mechanism that includes enzymatic antioxidants that work together to eliminate ROS, thereby reducing their harmful effects. In addition to enzymatic defenses, plants also synthesize various non-enzymatic antioxidants, including flavonoids, phenolic acids, and vitamins. These compounds effectively neutralize ROS and help regenerate other antioxidants, offering extensive protection against oxidative stress. The metabolism of xenobiotic substances in plants occurs in three stages: the first involves modification, which refers to the chemical alteration of xenobiotics to make them less harmful. The second involves conjugation, where the modified xenobiotics are combined with other substances to increase their solubility, facilitating their elimination from the plant. The third stage involves compartmentalization, which is the storage or isolation of conjugated xenobiotics in specific parts of the plant, helping to prevent damage to vital cellular functions. Secondary metabolites found in plants, such as alkaloids, terpenoids, and flavonoids, play a vital role in detoxification and the defense against oxidative stress. Gaining a deeper understanding of the oxidative mechanisms and the pathways of xenobiotic metabolism in plants is essential, as this knowledge can lead to the formulation of plant-derived strategies aimed at alleviating the effects of environmental pollution and enhancing human health by improving detoxification and antioxidant capabilities, as discussed in this review.

Background: Alzheimer's and other neurodegenerative forms of dementia affect 8 million Europeans. Assistive technologies are suggested to reduce the burden of care and improve the quality of life of person living with dementia. Nonetheless, the acceptance and attitudes toward technological interventions pose challenges not only for people living with dementia and caregivers but also for healthcare workers. This review specifically aims to investigate how these key groups perceive and accept technology in European dementia care settings., Methods: This systematic review was conducted to identify studies, published between 2013 and 2023, that examined the acceptance and attitude of assistive technologies in Alzheimer's and other dementia European settings, following the PRISMA guidelines. Rayyan AI was used for data extraction, and bias was assessed using the Mixed Methods Appraisal Tool., Results: Among the 1,202 identified articles, 13 met the inclusion criteria, revealing a prevailing positivity toward technological interventions in dementia care. Nonetheless, several barriers to adoption, including technological unfamiliarity, and specific dementia-related symptoms that complicate usage were identified. They also unveiled varying attitudes, influenced by factors such as familiarity with technologies, perceived usefulness, and the broader context of the COVID-19 pandemic which accelerated telemedicine and digital solution acceptance during restricted mobility and social distancing., Conclusion: Understanding attitudes toward technology in dementia care is crucial as it influences the adoption and utilization of tech-based interventions, impacting symptom management and quality of life. Addressing these attitudes through tailored interventions and education can enhance well-being and quality of life for people living with dementia, caregivers, and healthcare professionals., Competing Interests: MMo has received financial support by the MUR PNRR Extended Partnership (MNESYS no. PE00000006, and DHEAL-COM no. PNC-E3-2022-23683267); research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck; and honoraria from Biogen, BMS Celgene, Ipsen, Jansenn, Merck, Novartis, Roche, and Sanofi-Genzyme; and serves as editorial board member in Neurology and Multiple Sclerosis Journal. RP has received support from the UK MS Society (Award 146) and has taken part in advisory boards/consultancy for MSD, Sanofi, and BMS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sorrentino, Fiorilla, Mercogliano, Esposito, Stilo, Affinito, Moccia, Lavorgna, Salvatore, Maida, Barbi, Triassi and Palladino.)

Introduction: The Expanded Disability Status Scale (EDSS) is usually calculated through a neurological examination with self-reported performance. This may lead to incorrect assessment of Functional System scores (FSs). Aim of our study was to estimate the difference between EDSS obtained during routine visits, or after specific tests., Methods: We enrolled 670 MS patients that underwent a regular neurology consultation, and visual evaluation using optotype tables, ambulation evaluation with a rodometer, and cognitive assessment with the Brief International Cognitive assessment for MS (BICAMS). We calculated a new integrated EDSS (iEDSS) using the refined values of the FS and compared it to the standard EDSS., Results: Visual, cerebral and ambulation FSs were significantly higher compared with the self-reported counterpart [+ 1.169 (95%CI 1.077, 1.262; p < 0.001), + 0.727 (95%CI 0.653, 0.801; p < 0.001) and + 0.822 (95%CI 0.705, 0.939; p < 0.001), respectively]. Mean iEDSS was higher than EDSS (+ 0.642; p < 0.001). Visual acuity tests worsened the EDSS in 31% of cases, cognitive tests in 10%, ambulation measurement in 35%, all three measurements in 59% of cases., Conclusions: Objective measurement of FSs results in a more accurate EDSS score in almost two-thirds of cases. This could lead to a more thorough evaluation of patients in the transition or progressive phase., (© 2024. The Author(s).)

Background: Fatigue is a common symptom in Multiple Sclerosis (MS), but its determinants are not clarified yet. Sensory processing sensitivity (SPS) is a personality trait characterized by enhanced sensitivity towards endogenous and exogenous stimuli, and higher attention toward minimal stimuli, resulting in overarousal and fatigue., Objective: to evaluate the association between SPS and fatigue in MS patients., Methods: 192 consecutive MS patients (age of 43.3 ± 12.1 years; females 67.2 %; median EDSS of 2.5 (0 - 7)) underwent clinical (EDSS, age, gender), cognitive (BICAMS, Trial Making Test [TMT]), psychosocial (Beck Anxiety Inventory [BAI], Beck Depression Inventory [BDI], Modified Fatigue Impact Scale [MFIS]) and sensitivity evaluation (Highly Sensitive Person [HSP]Scale). Patients were classified as HSP if the score was greater than 14. A stepwise regression model was applied to explore association between SPS and MFIS total scores and sub-scores, by accounting for age, gender, education, EDSS, Cerebral FS scores, TMT-Part A and part B scores, BAI, BDI, and Pittsburgh Sleep Quality Index (PSQI)., Results: Total HSP was 17.2 ± 6.8 and 129 patients (67 %) were classified as highly sensitive persons (HSP). HSP patients were more female patients (p = 0.02) with a longer disease duration (p = 0.03). HSP people showed higher total MFIS score (27.6 ± 20.6 vs 13.2 ± 14.1, p < 0.001), higher physical MFIS score (p < 0.001), higher cognitive MFIS score (p < 0.001), higher psychosocial MFIS score (p < 0.001) vs non-HSP patients. Higher total MFIS was associated with SPS trait (coeff. 6.9, p = 0.006). Specifically, SPS trait was associated with higher cognitive MFIS (coeff. 5.3, p < 0.001) and higher psychosocial MFIS (coeff. 0.7, p = 0.02)., Conclusion: SPS was associated with fatigue. Since SPS could be easily and quickly assessed in clinical settings, SPS could unveil a higher propensity of a patient toward fatigue occurrence over the disease course and could provide hints for possible preventive cognitive behavior therapy., Competing Interests: Declaration of competing interest MM has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck; honoraria from Biogen, BMS Celgene, Ipsen, Janssen, Merck, Novartis, Roche, and Sanofi-Genzyme. AC has received research grants from Almirall, research grants from ECTRIMS-MAGNIMS and honoraria from Almirall, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen and Novartis. MP has received research grants from Italian MS Foundation and Baroni Foundation, honoraria from HEALTH&LIFE S.r.l. and Biogen and sponsorship for travel/meeting expenses from Novartis, Roche and Merck. DC has received research grant from Merck. RL has received honoraria from Biogen, Merck, Novartis, Roche, and Teva. VBM has received research grants from the Italian MS Society, and Roche, and honoraria from Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. AE, ME, FL, ALS, FF have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028., Methods: A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020-2022) were collected from IQVIA ® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers., Results: The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices., Conclusion: Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service., (© 2024. The Author(s).)

Background: Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment., Objectives: to compare the efficacy of natalizumab versus fingolimod in POMS., Methods: This is an observational longitudinal multicentre study including natalizumab- and fingolimod-treated POMS patients (N-POMS and F-POMS, respectively). We collected Annual Relapse Rate (ARR), Expanded Disability Status Scale (EDSS), Symbol Digit Modality Test (SDMT), and MRI activity at baseline (T0), 12-18 months (T1), and last available observation (T2)., Results: We enrolled 57 N-POMS and 27 F-POMS patients from six Italian MS Centres. At T0, N-POMS patients showed higher ARR (p = 0.03), higher EDSS (p = 0.003) and lower SDMT (p = 0.04) at baseline compared with F-POMS. Between T 0 and T 1 ARR improved for both N-POMS and F-POMS (p < 0.001), while EDSS (p < 0.001) and SDMT (p = 0.03) improved only for N-POMS. At T 2 (66.1 ± 55.4 months) we collected data from 42 out of 57 N-POMS patients showing no further ARR decrease., Conclusion: Both natalizumab and fingolimod showed high and sustained efficacy in controlling relapses and natalizumab also associated to a disability decrease in POMS. This latter effect might be partly mediated by the high inflammatory activity at baseline in N-POMS., (© 2024. The Author(s).)

Objective: Blood neurofilament light chain (NfL) is robustly associated with disease worsening in multiple sclerosis (MS), though potentially affected by concomitant factors also determining neuro-axonal loss. We investigated the association between plasma NfL (pNfL) measured with Lumipulse™ immunoassay and demographic and clinical variables in MS., Methods: This cross-sectional study included 685 people with MS (age 49.7 ± 12.4 years; sex 65.55% females). On the same day, we collected plasma samples, along with demographics, comorbidities, and clinical variables (MS disease duration, expanded disability status scale (EDSS), Symbol Digit Modalities Test (SDMT), descriptor of disease progression, current disease modifying treatment (DMT), number of previous DMTs, evidence of disease activity in the past year (i.e. relapse or MRI new lesions), EDSS progression). pNfL was evaluated using Lumipulse™ fully automated chemiluminescent enzyme immunoassay., Results: On multivariable linear regression model, higher pNfL was associated with higher EDSS (Coeff = 1.73; 95%CI 0.78, 2.68; p < 0.01), recent disease activity (Coeff = 15.70; 95%CI = 5.35, 26.06; p < 0.01), and presence of cardiovascular comorbidity (Coeff = 3.84; 95%CI 0.48, 7.20; p = 0.025). Lower pNfL was found in patients on DMT treatment (Coeff = -10.23; 95%CI -18.42, -2.04; p = 0.015), when compared with no DMT (reference). For 77.81% of our population there was correspondence between pNfL levels and two previously-validated cutoffs., Conclusions: pNfL measured using Lumipulse™ confirms known associations with MS activity, disability and treatments, and related confounding (e.g., cardiovascular comorbidity), thus granting further utilization in research and clinical practice., Competing Interests: Declaration of competing interest Marcello Moccia has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck; honoraria from Biogen, BMS Celgene, Ipsen, Merck, Novartis, Roche, and Sanofi-Genzyme. Vincenzo Brescia Morra and Roberta Lanzillo received research grants from the Italian MS Society, and Roche, and honoraria from Bayer, Biogen, BMS Celgene, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. Antonio Carotenuto has received research grants from Almirall and ECTRIMS- MAGNIMS and honoraria from Almirall, BMS Celgene, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen and Novartis., (Copyright © 2023. Published by Elsevier B.V.)

Background: While music-based therapy (MBT) has been shown to improve motor and non-motor features in multiple sclerosis (MS), benefits of tango have never been assessed., Objective: To evaluate the benefits of tango classes on quality of life (QoL), mood, fatigue, gait, balance, perception of cognitive disorder and sexuality in people with MS., Methods: 7 participants (age 41.14 ± 14.27 years, disease duration 14.14 ± 7.6 years) and respective partners undertook one-hour weekly classes for 20 weeks. Participants had early-stage MS (EDSS<3.5). They were assessed for mood (ZUNG rating scale; Beck Depression Inventory -II); balance (Berg Balance Test; Tinetti scale), cognition (MS Neuropsychological Screening Questionnaire), SD (Multiple Sclerosis Intimacy and Sexuality Questionnaire), fatigue (Fatigue Severity Scale) and QoL (36-Item Short Form Survey)., Results: Group comparison of pre-post change scores showed a general improvement in all the outcome measures, which was significant in mood, SD, cognition and QoL., Discussions and Conclusion: Tango classes provides benefits to pwMS, especially on non-motor symptoms. Follow-up assessment is required to confirm the durability of these effects., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The wearing-off phenomenon is common in people with multiple sclerosis (MS) treated with ocrelizumab. We aim to evaluate the presence and severity of wearing-off to ocrelizumab in relation to demographic and MS clinical variables, immune profiling, and a marker of neuroaxonal damage (plasma neurofilament light chain (pNfl))., Methods: This cross-sectional study included MS patients treated with ocrelizumab from at least 1 year. Wearing-off questionnaire and blood samples were collected between 21 and 23 weeks after the previous ocrelizumab infusion. Lymphocyte subpopulations were evaluated on peripheral blood using flow cytometry. PNfl was evaluated using fully automated chemiluminescent enzyme immunoassay., Results: We included 106 people with MS (age 49.5 ± 11.6 years; females 42.3%; wearing-off 57.6%). On regression models, wearing-off was associated with higher pNfl, CD8, CD3, and CD3CD27 lymphocytes. Most frequent wearing-off symptoms were cognitive, sensory, and balance problems; wearing-off started < 1 week (9.4%), 1-4 weeks (10.7%) or > 4 weeks (10.7%) before infusion; 44.8% of the complaints were moderate to severe. Severity of wearing-off was associated with higher pNfl and CD8 lymphocytes., Conclusions: Wearing-off is common in people with MS treated with ocrelizumab, and is associated with reduced immunomodulation (higher T lymphocytes) and increased neuroaxonal damage, suggesting reduced treatment response., (© 2024. The Author(s).)

Background: Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes., Methods: We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs., Results: At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression., Conclusions: Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes., (© 2024. The Author(s).)

Background: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT., Methods: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy., Results: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01)., Conclusions: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative., (© 2024. The Author(s).)

Background: We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences., Methods: We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs., Results: The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; p < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; p < 0.01); adherence was lower for other highly active DMTs (Coeff = -0.07; 95%CI = -0.10, -0.04; p < 0.01) and low-/medium-efficacy DMTs (Coeff = -0.16; 95%CI = -0.19, -0.14; p < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; p < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = -772.31; 95%CI = -816.95, -727.66; p < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations., Conclusions: From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit-risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs.

Correction to: European Review for Medical and Pharmacological Sciences 2024; 28 (1): 411-418. DOI: 10.26355/eurrev&#95;202401&#95;34930-published online on January 16, 2024. After publication, the authors have applied some corrections to the galley proof: • In the Patients and Methods section of the abstract, "National Health System" is corrected to "National Health Service". • In the Conclusions section of the abstract, "SC PEG-IFN-β-1a and IFN- β-1a" is corrected to "PEG-IFN-β-1a and SC IFN-β-1a". • In the Population section, the study period "January 1st 2015 to December 31st 2019" was not reported; therefore, this specification has been added to the text. • The legend of Figure 1 was wrongly reported as the same as Table I. The correct title of Figure 1 is "Study flow diagram". • Under Tables I, II, and III, "interferon beta 1a IFN-β-1a" is corrected to "interferon beta 1a (IFN-β-1a)". • In Table III, "CS Glatiramer acetate" is corrected to "SC Glatiramer acetate". • In the Conclusions section, "SC IFN-β-1a SC" is corrected to "SC IFN-β-1a". • The funding section has been amended as follows: "This study was sponsored by Biogen Italia (Milan, Italy)." There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34930.

Objective: The aims of this study were to provide population-based estimates of prevalence and incidence of any dementia and Alzheimer's dementia (AD) in the Campania region (South Italy) and to validate towards a clinical registry., Methods: This was a population-based study, using routinely collected healthcare data of individuals living in the Campania region (South Italy) from 2015 to 2020. We included individuals aged ≥65 years alive at the prevalence day (January 1, 2021) who had at least one administrative record for dementia and/or AD from 2015 to 2020. Age-and sex-standardised prevalence rates were calculated using direct standardisation method (European population in 2020 as the reference population). To estimate the incidence, we tested three possible algorithms, which differed for the duration of the time interval between study baseline (January 1, 2015) and index date (first record for dementia and/or AD in administrative databases). We employed a clinical database for the validation of our algorithms towards neuropsychological test results., Results: Among individuals aged over 65 years, 80,392 had dementia, of which 35,748 had AD. The age- and sex-standardised prevalence rates per 1,000 individuals for any dementia and AD were 77.64 (95% confidence interval [CI] = 77.57; 77.68) and 34.05 (95% CI = 34.01; 34.09), respectively. There were 82.10 incident cases of any dementia per 100,000 per year (0.79 sensitivity and 0.62 specificity) and 59.89 incident cases of AD per 100,000 per year (0.80 sensitivity and 0.59 specificity). The capture-recapture method showed a very low number of undetected cases (1.7% for any dementia and 3.0% for AD). Our algorithms showed acceptable performance with the area under the curve ranging from 0.59 to 0.72 and a double likelihood ratio of correctly identifying individuals above and below mini-mental status examination (MMSE) standard cut-offs (24 and 26)., Conclusions: Prevalence and incidence of any dementia and AD in the Campania region (South Italy) from 2015 to 2020 are in line with previous estimates from other countries. Our algorithm, integrating administrative and clinical data, holds potential for assessing dementia's epidemiological burden, identifying risk factors, planning healthcare access, and developing prevention strategies., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: Peginterferon β-1a (PEG-IFN-β-1a) is the most recent interferon beta formulation approved for treating relapsing-remitting multiple sclerosis (RRMS). We aim to describe the real-world utilization of PEG-IFN-β-1a in RRMS and compare it with other injectable disease-modifying therapies (DMTs)., Patients and Methods: In this population-based study, we used 2015-2019 routinely collected healthcare data of the Campania region of Italy from National Healthcare System DMT prescriptions, inpatient and outpatient clinical records of hospitals in Campania, and the Federico II University MS clinical registry for a subset of patients. We included individuals with RRMS receiving new prescriptions of PEG-IFN-β-1a [n=281; age = 38.8±12.3 years; females=70.5%; disease duration = 8.4±8.3 years; Expanded Disability Status Scale (EDSS) at baseline=2.0 (1.0-6.5)], glatiramer acetate [n=751; age = 46.0±11.4 years; females=67.1%; disease duration = 9.8±8.2 years; EDSS=4.0 (1.5-8.5)], and subcutaneous (SC) IFN-β-1a [n=1,226; age = 39.7±11.7 years; females=66.5%; disease duration = 8.2±6.5 years; EDSS 2.5 (1.5-6.5)]. Adherence [medication possession ratio (MPR)], escalation to more effective DMTs, hospitalization rates and costs were measured. We used mixed-effect linear regression models (for adherence, hospitalization rates and costs) and Cox regression models (for escalation) to assess differences between PEG-IFN-β-1a (statistical reference), glatiramer acetate, and SC IFN-β-1a. All models included age, sex, previous treatment/untreated, year of treatment initiation, treatment duration, and adherence as covariates., Results: Adherence was lower in glatiramer acetate (MPR = 0.91±0.1; Coeff=-0.11; p<0.01), and IFN-β-1a (MPR = 0.92±0.1; Coeff=-0.08; p<0.01), compared with PEG-IFN-β-1a (MPR = 1.01±0.1). The probability of escalating to more effective DMTs was higher for glatiramer acetate (14.9%; HR=4.09; p<0.01) and IFN-β-1a (9.1%; HR=3.35; p=0.01), compared with PEG-IFN-β-1a (4.9%). No differences in annualized hospitalization rates were identified between glatiramer acetate [annualized hospitalization rates (AHR) = 0.05±0.30; Coeff=0.02; p=0.31), IFN-β-1a (AHR = 0.02±0.21; Coeff=0.01; p=0.97], and PEG-IFN-β-1a (AHR = 0.02±0.24); however, monthly costs for MS admissions were higher for glatiramer acetate (€49.45±€195.27; Coeff=-29.89; p=0.03), compared with IFN-β-1a (€29.42±€47.83; Coeff=6.79; p=0.61), and PEG-IFN-β-1a (€23.91±€43.90)., Conclusions: SC PEG-IFN-β-1a and IFN-β-1a were used in relatively similar populations, while glatiramer acetate was preferred in older and more disabled patients. PEG-IFN-β-1a was associated with higher adherence and lower escalation rates toward more effective (and costly) DMTs.

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce., Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS., Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose., Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%., Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS., (© 2023. The Author(s).)

In recent years, nucleic acids have emerged as powerful biomaterials, revolutionizing the field of biomedicine. This review explores the multifaceted applications of nucleic acids, focusing on their pivotal role in various biomedical applications. Nucleic acids, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), possess unique properties such as molecular recognition ability, programmability, and ease of synthesis, making them versatile tools in biosensing and for gene regulation, drug delivery, and targeted therapy. Their compatibility with chemical modifications enhances their binding affinity and resistance to degradation, elevating their effectiveness in targeted applications. Additionally, nucleic acids have found utility as self-assembling building blocks, leading to the creation of nanostructures whose high order underpins their enhanced biological stability and affects the cellular uptake efficiency. Furthermore, this review delves into the significant role of oligonucleotides (ODNs) as indispensable tools for biological studies and biomarker discovery. ODNs, short sequences of nucleic acids, have been instrumental in unraveling complex biological mechanisms. They serve as probes for studying gene expression, protein interactions, and cellular pathways, providing invaluable insights into fundamental biological processes. By examining the synergistic interplay between nucleic acids as powerful biomaterials and ODNs as indispensable tools for biological studies and biomarkers, this review highlights the transformative impact of these molecules on biomedical research. Their versatile applications not only deepen our understanding of biological systems but also are the driving force for innovation in diagnostics and therapeutics, ultimately advancing the field of biomedicine.

Background: COVID-19 pandemic has affected the management of multiple sclerosis (MS)., Objective: To explore the impact of COVID-19 on healthcare delivery to people with MS and the subsequent recovery of the system., Methods: In this population-based study in the Campania Region (Italy), we included people with MS across pre-COVID-19, lockdown, pre-vaccination, and vaccination periods. Differences in continuous outcomes between periods were explored using linear mixed models (annualized hospitalization rate (AHR) and adherence measured as medication possession ratio (MPR)). Differences in disease-modifying treatment (DMT) prescription rates (first DMT prescription, any DMT switch, switch from platform to highly effective DMT, and combination of first DMT prescription and any DMT switch) were assessed using an interrupted time series design., Results: Compared with pre-COVID-19, AHR decreased during the lockdown (Coeff = 0.64;95%CI = -0.69, -0.59; p < 0.01), and remained lower during pre-vaccination and vaccination periods. Adherence decreased during pre-vaccination (Coeff = -0.04;95%CI = -0.05, -0.03; p < 0.01) and vaccination periods (Coeff = -0.07;95%CI = -0.08, -0.07; p < 0.01). After the lockdown, there was an increase in any DMT switch (IRR 2.05 95%CI 1.38,3.05; p < 0.01), in switch from platform to highly effective DMTs (IRR 4.45;95%CI 2.48,8.26; p < 0.01) and in first DMT prescriptions (IRR 2.48;95%CI 1.64,3.74; p < 0.01)., Conclusions: DMT prescriptions quickly returned to pre-pandemic levels, reflecting good health system recovery. However, adherence has remained lower than the past, as from suboptimal care. Assessing long-term COVID-19 impact on MS healthcare is warranted., (© 2023. The Author(s).)

Background: Cognitive impairment frequently affects people with multiple sclerosis (MS). Low vitamin D has been associated with cognitive dysfunction in different neurodegenerative diseases, and, in MS, with motor disability and disease activity. We aim to investigate associations between vitamin D and cognitive status in MS., Methods: In this cross-sectional study, we included 181 MS patients, recruited consecutively at the MS Unit of the Policlinico Federico II University Hospital of Naples, Italy, between January and April 2022, with serum 25‑hydroxy (25-OH) vitamin D measurements using Chemiluminescence-ImmunoAssay, and cognitive assessment using the Brief International Cognitive Assessment for MS (BICAMS), which includes Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II) and Brief Visuospatial Memory Test-Revised (BVMT-R). We collected demographics (age, sex, education), and clinical variables (disease duration, disease subtype, expanded disability status scale (EDSS), disease modifying treatment, relapses in previous 12 months, vitamin D supplementation, comorbidities). For a subset of patients (n = 41, 23.2% of the total sample), we collected Beck Depression Inventory-II, Beck Anxiety Inventory, and Modified Fatigue Impact Scale., Results: At univariable linear regression models, serum 25-OH-vitamin D levels were 0.9 ng/mL higher for each unit increase of SDMT adjusted scores (Coeff=0.93; 95%CI=0.81, 1.04; p<0.01), 0.7 ng/mL higher for each unit increase of CVLT-II adjusted scores (Coeff=0.68; 95%CI=0.53, 0.83; p<0. 01), 0.6 ng/mL higher for each unit increase of BVMT-R adjusted scores (Coeff=0.58; 95%CI=0.43, 0.73; p<0.01), -9.63 ng/mL lower for each impaired BICAMS test (Coeff=-9.63; 95%CI=-11.48, -7.79; p<0.01), and -2.2 ng/mL lower for each unit increase of EDSS (Coeff=-2.16; 95%CI=-3.57, -0.75; p<0.01). At multivariable linear regression models, we confirmed associations between 25-OH-vitamin D and EDSS (Coeff=-2.09; 95%CI=-4.45, -0.43; p<0.01), SDMT (Coeff=0.75; 95%CI=0.60, 0.90; p<0.01), and CVLT-II (Coeff=0.14; 95%CI=0.01, 0.28; p = 0. 04). Results remained unchanged when including depression, anxiety and fatigue scores., Conclusions: Lower serum 25-OH-vitamin D was associated with worse cognitive function in MS. Future studies should consider longitudinal variations in cognitive function in relation to vitamin D supplementation., Competing Interests: Declaration of Competing Interest Marcello Moccia has received research grants from ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from Biogen, BMS Celgene, Janssen, Merck, Roche, and Sanofi-Genzyme.Maria Petracca has received travel/meeting expenses from Novartis, Janssen, Roche and Merck; speaking honoraria from HEALTH&LIFE S.r.l., AIM Education S.r.l. and FARECOMUNICAZIONE E20; honoraria from Biogen; and research grants from Italian MS Foundation and Baroni Foundation. Antonio Carotenuto has received research grants from ECTRIMS-MAGNIMS and Almirall; and has received honoraria from Merk, Novartis, Biogen, Mylan, Roche and Almirall. Vincenzo Brescia Morra has received research grants from Italian MS Federation and Roche; and honoraria from Almirall, Biogen, BMS Celgene, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Viatris., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: The current clinical course descriptors of multiple sclerosis (MS) include a combination of clinical and magnetic resonance imaging (MRI) features. Recently there has been a growing call to base these descriptors more firmly on biological mechanisms. We investigated the implications of proposing a new mechanism-driven framework for describing MS., Methods: In a web-based survey, multiple stakeholders rated the need to change current MS clinical course descriptors, the definitions of disease course and their value in clinical practice and related topics., Results: We received 502 responses across 49 countries. In all, 77% of the survey respondents supported changing the current MS clinical course descriptors. They preferred a framework that informs treatment decisions, aids the design and conduct of clinical trials, allows patients to understand their disease, and links disease mechanisms and clinical expression of disease. Clinical validation before dissemination and ease of communication to patients were rated as the most important aspects to consider when developing any new framework for describing MS., Conclusion: A majority of MS stakeholders agreed that the current MS clinical course descriptors need to change. Any change process will need to engage a wide range of affected stakeholders and be guided by foundational principles., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: Although multiple sclerosis (MS) Intimacy and Sexuality Questionnaire-19 (MSISQ-19) is a widely applied tool, no unique definition of sexual dysfunction (SD) based on its score exists., Objective: To explore the impact of different MSISQ-19 cut-offs on SD prevalence and associated risk factors, providing relevant information for its application in research and clinical settings., Methods: After defining SD according to two different MSISQ-19 cut-offs in 1155 people with MS (pwMS), we evaluated SD prevalence and association with sociodemographic and clinical features, mood status and disability via logistic regression., Results: Depending on the chosen cut-off, 45% to 54% of pwMS reported SD. SD defined as MSISQ-19 score >30 was predicted by age (OR=1.01, p=0.047), cognition (OR=0.96, p=0.004) and anxiety (OR=1.03, p=0.019). SD defined as a score >3 on any MSISQ-19 item was predicted by motor disability (OR=1.12, p=0.003) and cognition (OR= 0.96, p=0.002)., Conclusion: Applying different MSISQ-19 cut-offs influences both the estimated prevalence and the identification of risk factors for SD, a finding that should be considered during study planning and data interpretation. Preserved cognition exerts a protective effect towards SD regardless from the specific study setting, representing a key point for the implementation of preventive and therapeutic strategies., Competing Interests: Declaration of Competing Interest MP discloses travel/meeting expenses from Novartis, Roche and Merck, speaking honoraria from HEALTH&LIFE S.r.l., honoraria for consulting services from Biogen and research grants from Baroni Foundation. A. Carotenuto has received research grants from ALMIRALL, and honoraria from Novartis, Merck and Biogen. M. Moccia has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck, and honoraria from Biogen, Merck, Novartis and Roche. S. Bucello has served on scientific advisory boards for Biogen Idec, Roche, Merck Serono, Novartis, Celgene and Sanofi-Genzyme and has received funding for travel and/or speaker honoraria from Sanofi-Genzyme, Biogen Idec, Teva, Merck Serono and Novartis. MI received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme; received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. M. Clerico received personal compensations for advisory boards, public speaking, editorial commitments or travel grants from Biogen Idec, Merck Serono, Fondazione Serono, Novartis, Roche, Sanofi-Genzyme and Teva. LM received personal compensations for speaking in scientific meeting and for advisory boards and for travel grants from Celgene, Novartis, Biogen, Merck, Roche and Sanofi. LL received speaker honoraria and travel grants from Teva, Merck, Sanofi, Novartis, Biogen, Roche and Bayer. MF is Editor-in-Chief of the Journal of Neurology, has received compensation for consulting services and/ or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA). GB received fees for consultation and Advisory board from Biogen, Almirall, Novartis, Merck, Teva, Roche and Sanofi Genzyme. CP received consulting and lecture fees and research funding and travel grants from Almirall, Bayer, Biogen, Gen- zyme, Merck Serono, Novartis, Roche and Teva. VBM has received research grants from the Italian MS Society, and Roche, and honoraria from Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. RL has received honoraria from Biogen, Merck, Novartis, Roche, and Teva. Other authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Gait impairment is common in multiple sclerosis (MS), but difficult to evaluate in clinical practice. In this proof-of-concept observational study, we compared walking ability recorded by Google Maps Timeline to conventional clinical measures in people with MS., Methods: We used open-access Google Maps Timeline to record the total number of days with walking activity, walking distance, walking time, and walking speed. Each Google Maps Timeline variable was included in a different stepwise linear regression model including all conventional clinical variables., Results: We included nine people with MS (age 43.1 ± 6.6 years; females 55.6%; disease duration 12.7 ± 3.1 years; median Expanded Disability Status Scale 3.0 (range 1.0-5.5)). Higher percentage of days with recorded walking was associated with lower Fatigue Severity Scale ( p  = 0.01), and higher MS Walking Scale ( p  = 0.04). Longer average daily walking distance was associated with shorter Timed-25 Foot Walking Test ( p  = 0.02), lower Expanded Disability Status Scale ( p  = 0.01), and higher Euro-Quality of Life ( p  = 0.04). Longer average daily walking time was associated with shorter Timed-25 Foot Walking Test ( p  = 0.03). Higher walking speed was associated with lower Fatigue Severity Scale ( p  = 0.04)., Conclusion: Google Maps Timeline parameters provide actual estimates of daily walking activities in MS., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DC has received research grants from Merck. LL has received a travel grant and speech fee from Roche, Novartis, Biogen, Mylan, BMS, Almirall, Merck, and Teva. AC has received research grants from Almirall, research grants from ECTRIMS-MAGNIMS, and honoraria from Almirall, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen, and Novartis. MP has received research grants from the Italian MS Foundation and Baroni Foundation, honoraria from HEALTH&LIFE S.r.l. and Biogen, and sponsorship for travel/meeting expenses from Novartis, Roche, and Merck. RL has received honoraria from Biogen, Merck, Novartis, Roche, and Teva. VBM has received research grants from the Italian MS Society, and Roche, and honoraria from Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. MM has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck; honoraria from Biogen, Ipsen, Merck, Roche, and Sanofi-Genzyme., (© The Author(s), 2023.)

Background: We aim to evaluate whether fertility, pregnancy, delivery and breastfeeding have been actually improving in women with multiple sclerosis (MS), compared with general population, and in relation to treatment features., Methods: We included 2018-2020 population-level healthcare data on women with MS living in the Campania region (Italy). Fertility, pregnancy and delivery outcomes were obtained from Certificate of Delivery Assistance; breastfeeding was collected up to 6 months after delivery by trained personnel., Results: Out of 2748 women with MS in childbearing age, 151 women delivered 156 babies. Fertility rate was 0.58 live births per woman with MS, compared with 1.29 in Campania region and 1.25 in Italy. Disease-modifying treatment (DMT) continuation during pregnancy was associated with lower birth weight (coeff -107.09; 95% CI -207.91 to -6.26; p=0.03). Exposure to DMTs with unknown/negative effects on pregnancy was associated with birth defects (OR 8.88; 95% CI 1.35 to 58.41; p=0.02). Birth defects occurred in pregnancies exposed to dimethyl fumarate (2/21 exposed pregnancies), fingolimod (1/11 exposed pregnancies) and natalizumab (2/30 exposed pregnancies). After delivery, 18.8% of women with MS were escalated of DMT efficacy, while 50.7% started on same/similar-efficacy DMTs, and 30.5% did not receive DMT. The probability of breastfeeding was higher in women who were treated with breastfeeding-safe DMTs (OR 5.57; 95% CI 1.09 to 28.55; p=0.03)., Conclusions: Fertility rate in women with MS remains below the general population. Family planning and subsequent DMT decisions should aim to achieve successful pregnancy, delivery and breastfeeding outcomes, while controlling disease activity., Competing Interests: Competing interests: MaM has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society and Merck; honoraria from Biogen, Ipsen, Merck, Roche and Sanofi-Genzyme. AC has received research grants from Almirall, research grants from ECTRIMS-MAGNIMS and honoraria from Almirall, Biogen, Roche Sanofi-Genzyme and Novartis. MP has received research grants from Italian MS Foundation and Baroni Foundation, honoraria from HEALTH&LIFE S.r.l. and Biogen and sponsorship for travel/meeting expenses from Novartis, Roche and Merck. RL has received honoraria from Biogen, Merck, Novartis, Roche and Teva. VBM has received research grants from the Italian MS Society, and Roche, and honoraria from Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme and Teva., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Intellectual enrichment and brain reserve modulate the expression of cognitive and motor disability in multiple sclerosis (MS). Their association with fatigue, one of the most debilitating and common symptoms of MS, has never been explored., Materials and Methods: Forty-eight MS patients underwent clinical and MRI examination at baseline and after 1 year. Physical and cognitive MS-related fatigue were evaluated via Modified Fatigue Impact subscales (MFIS-P and MFIS-C). Differences in reserve indexes between fatigued and non-fatigued patients were tested. The relationship between clinico-demographic features, global brain structural damage, indexes of reserve (age-adjusted intracranial volume and cognitive reserve index) and fatigue were tested via correlations and hierarchical linear/binary logistic regression, to predict MFIS-P and MFIS-C (at baseline) or new-onset fatigue and meaningful worsening in MFIS (at follow-up)., Results: At baseline, although a significant difference was identified for cognitive reserve questionnaire between fatigued and non-fatigued patients (18.19 ± 4.76 versus 15.15 ± 3.56, p = 0.015), only depression accounted for significant variance in MFIS-P and MFIS-C (R 2 =0.248, p = 0.002; R 2 =0.252, p<0.001). MFIS-T, MFIS-P and MFIS-C changes over time were associated to depression changes over time (r = 0.56, r = 0.55, and r = 0.57, respectively; all p<0.001). Indexes of reserve did not differ between non-fatigued patients and patients developing new-onset fatigue at follow-up. None of the baseline features was able to predict the new-onset fatigue or meaningful worsening in MFIS at follow-up., Conclusions: Among the explored features, only depression was strongly associated to both physical and cognitive fatigue. Intellectual enrichment and brain reserve did not seem to affect fatigue symptoms in MS patients., Competing Interests: Declaration of Competing Interest Antonio Carotenuto has received research grants from Almirall; honoraria form Novartis, Merck and Biogen; was supported by MAGNIMS/ECTRIMS research fellowship program. Giuseppe Pontillo was supported by MAGNIMS//ECTRIMS research fellowship program (2020) and ESNR research fellowship program (2021). Marcello Moccia has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck, and honoraria from Biogen, BMS Celgene, Ipsen, Merck, Novartis and Roche. Sirio Cocozza discloses Board Membership: Amicus Therapeutics; Payment for Lectures Including Service on Speakers Bureaus: Sanofi; Research Grants: FISM; Telethon. Roberta Lanzillo received personal compensation for speaking or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, and Almirall. Vincenzo Brescia Morra has received honoraria from Almirall, Bayer, Biogen, Merck, Novartis, Roche and Sanofi Genzyme, and research grants from the Italian MS Foundation. Maria Petracca has received travel/meeting expenses from Novartis, Roche and Merck, speaking honoraria from HEALTH&LIFE S.r.l. and honoraria for consulting services from Biogen and research grants from Baroni Foundation. Mario Tranfa, Valentina Iuzzolino, Pierpaolo Perrella, Andrea Elefante and Arturo Brunetti have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case., Materials and Methods: A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898&#95;E901 RET deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells. RET C634R and wild-type cells served as positive and negative controls, respectively., Results: The patient showed primary resistance to vandetanib and secondary resistance to selpercatinib after 12 months. Comprehensive next-generation sequencing of a progressing lesion during selpercatinib showed no additional RET mutation but an acquired complete genetic loss of CDKN2A , CDKN2B, and MTAP genes. Subsequent treatment with cabozantinib and 5-FU-dacarbazine had poor efficacy. In vitro, RET Δ898-901 showed higher ligand-independent RET autophosphorylation compared with RET C634R and similar proliferation rates in cell models. Subcutaneous injection of Δ898-901 NIH 3T3 cells in nude mice produced tumors of around 500 mm 3 in 2 weeks, similarly to RET C634R cells. Selpercatinib inhibited cell growth of Ba/F3 RET Δ898-901 and RET C634R with a similar half maximal inhibitory concentration (IC 50 ) of approximately 3 nM. Vandetanib was five-fold less effective at inhibiting cell growth promoted by RET Δ898-901 mutant (IC 50 , 564 nM) compared with RET C634R one (IC 50 , 91 nM). Cabozantinib efficiently inhibited Ba/F3 RET C634 proliferation (IC 50 , 25.9 nM), but was scarcely active in Ba/F3 RET 898-901 (IC 50 > 1,350 nM)., Conclusion: D898&#95;E901 RET deletion is a gain-of-function mutation and responds to tyrosine kinase inhibitors in MTC. RET Δ898-901 mutant is sensitive to selpercatinib and vandetanib, and acquired resistance to selpercatinib may develop via RET-independent mechanisms.

Background and Purpose: The long-term impact of gadolinium retention in the dentate nuclei of patients undergoing administration of seriate gadolinium-based contrast agents is still widely unexplored. The aim of this study was to evaluate the impact of gadolinium retention on motor and cognitive disability in patients with MS during long-term follow-up., Materials and Methods: In this retrospective study, clinical data were obtained from patients with MS followed in a single center from 2013 to 2022 at different time points. These included the Expanded Disability Status Scale score to evaluate motor impairment and the Brief International Cognitive Assessment for MS battery to investigate cognitive performances and their respective changes with time. The association with qualitative and quantitative MR imaging signs of gadolinium retention (namely, the presence of dentate nuclei T1-weighted hyperintensity and changes in longitudinal relaxation R1 maps, respectively) was probed using different General Linear Models and regression analyses., Results: No significant differences in motor or cognitive symptoms emerged between patients showing dentate nuclei hyperintensity and those without visible changes on T1WIs ( P  = .14 and 0.92, respectively). When we tested possible relationships between quantitative dentate nuclei R1 values and both motor and cognitive symptoms, separately, the regression models including demographic, clinical, and MR imaging features explained 40.5% and 16.5% of the variance, respectively, without any significant effect of dentate nuclei R1 values ( P  = .21 and 0.30, respectively)., Conclusions: Our findings suggest that gadolinium retention in the brains of patients with MS is not associated with long-term motor or cognitive outcomes., (© 2023 by American Journal of Neuroradiology.)

Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.

Objective: We aim to validate an algorithm based on routinely-collected healthcare data to detect incidence of multiple sclerosis (MS) in the Campania Region (South Italy) and to explore its spatial and temporal variations., Methods: We included individuals resident in the Campania Region who had at least one MS record in administrative datasets (drug prescriptions, hospital discharge, outpatients), from 2015 to 2020. We merged administrative to the clinical datasets to ascertain the actual date of diagnosis, and validated the minimum interval from our study baseline (Jan 1, 2015) to first MS records in administrative datasets to detect incident cases. We used Bayesian approach to explore geographical distribution, also including deprivation index as a covariate in the estimation model. We used the capture-recapture method to estimate the proportion of undetected cases., Results: The best performance was achieved by the 12-month interval algorithm, detecting 2,150 incident MS cases, with 74.4% sensitivity (95%CI = 64.1%, 85.9%) and 95.3% specificity (95%CI = 90.7%, 99.8%). The cumulative incidence was 36.68 (95%CI = 35.15, 38.26) per 100,000 from 2016 to 2020. The mean annual incidence was 7.34 (95%CI = 7.03, 7.65) per 100,000 people-year. The geographical distribution of MS relative risk shows a decreasing east-west incidence gradient. The number of expected MS cases was 11% higher than the detected cases., Conclusions: We validated a case-finding algorithm based on administrative data to estimate MS incidence, and its spatial/temporal variations. This algorithm provides up-to-date estimates of MS incidence, and will be used in future studies to evaluate changes in MS incidence in relation to different risk factors., Competing Interests: Declaration of Competing Interest Marcello Moccia has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck; honoraria from Biogen, Ipsen, Merck, Roche, and Sanofi-Genzyme. Vincenzo Brescia Morra has received research grants from the Italian MS Society, and Roche, and honoraria from Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. Raffaele Palladino has received research grants from Sanofi-Genzyme. Other authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Spinal cord and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) can provide additional information to brain MRI to determine prognosis of multiple sclerosis (MS). However, the real-world impact of routine use of brain MRI with spinal cord and/or Gd sequences is unknown. Our aim was to evaluate the effect of brain, spinal cord and Gd MRI on treatment decisions in MS., Methods: In this 2015-2020 population-based study, we performed a retrospective analysis on MS patients resident in the Campania Region (South Italy), with disease modifying treatment (DMT) prescription (n = 6,161). DMTs were classified as platform (dimethyl fumarate, glatiramer acetate, interferon-beta, peg-interferon-beta, teriflunomide), or high-efficacy (alemtuzumab, cladribine, fingolimod, natalizumab, ocrelizumab). We evaluated the association between binary MRI variables and switch from platform to high-efficacy DMT using multivariable logistic regression., Results: The likelihood of switch from platform to high-efficacy DMT was 47% higher when including post-Gd acquisitions to brain and/or spinal cord MRI, 59% higher when including spinal cord acquisitions to brain MRI, and 132% higher when including any MRI compared with no MRI (all p < 0.05). The likelihood of switch to high-efficacy DMT decreased over time from treatment start., Conclusion: Our results show that spinal cord and Gd MRI acquisitions can provide relevant information to influence subsequent treatment decisions, especially in early treatment phases, compared with stand-alone brain MRI., Competing Interests: Declaration of Competing Interest Marcello Moccia has received research grants from ECTRIMS-MAGNIMS, UK MS Society, and Merck; and honoraria from Biogen, Merck, Roche, and Sanofi-Genzyme. Raffaele Palladino has received research grants from the UK MS Society, and honoraria from Sanofi. Antonio Carotenuto has received research grants from the ECTRIMS-MAGNIMS and from Almirall, and served on advisory boards for: Merk, Novartis, Roche and Almirall. Maria Petracca discloses travel/meeting expenses from Novartis, Roche and Merck, speaking honoraria from HEALTH&LIFE S.r.l. honoraria for consulting services from Biogen, and research grants from Italian MS Foundation and Baroni Foundation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Traditionally, multiple sclerosis has been categorised by distinct clinical descriptors-relapsing-remitting, secondary progressive, and primary progressive-for patient care, research, and regulatory approval of medications. Accumulating evidence suggests that the clinical course of multiple sclerosis is better considered as a continuum, with contributions from concurrent pathophysiological processes that vary across individuals and over time. The apparent evolution to a progressive course reflects a partial shift from predominantly localised acute injury to widespread inflammation and neurodegeneration, coupled with failure of compensatory mechanisms, such as neuroplasticity and remyelination. Ageing increases neural susceptibility to injury and decreases resilience. These observations encourage a new consideration of the course of multiple sclerosis as a spectrum defined by the relative contributions of overlapping pathological and reparative or compensatory processes. New understanding of key mechanisms underlying progression and measures to quantify progressive pathology will potentially have important and beneficial implications for clinical care, treatment targets, and regulatory decision-making., Competing Interests: Declaration of interests TK received research funding from the German Research Foundation, Interdisciplinary Centre for Clinical Studies (IZKF) Münster, National Multiple Sclerosis Society (USA), European Leukodystrophy Association, Progressive MS Alliance, European Commission (H2020-MSCA-ITN-2018), and Novartis; and received compensation for serving on a scientific advisory board (Novartis) and speaker honoraria from Novartis and Roche. MM has received research grants from MAGNIMS-ECTRIMS, Multiple Sclerosis Society UK, and Merck; consulting fees from Ipsen, BMS Celgene, Biogen, Sanofi-Genzyme, Roche, and Merck; honoraria for lectures from Merck, Roche, and Sanofi-Genzyme; and support for attending meetings from Merck, Biogen, and Sanofi-Genzyme. TC is an employee of the National Multiple Sclerosis Society (USA), which is one of the sponsors of the International Advisory Committee on Clinical Trials in Multiple Sclerosis. JAC has received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; for speaking for H3 Communications; and for serving as an editor of the Multiple Sclerosis Journal. JC has received grants or contracts from Biogen, Merck and UC San Francisco; and has received payments or honoraria for lectures, speaker bureaus, or presentations from Biogen, Merck, Sanofi Genzyme, Novartis, Bristol-Myers, and Roche; participation on Data Safety Monitoring Boards or Advisory Boards from Novartis, Merck, Sanofi Genzyme, and Biogen. JG has received grant and contract research support from the National Multiple Sclerosis Society (USA), Biogen, and Octave Biosciences; serves on a steering committee for a trial supported by Novartis; has received speaker fees from Alexion and BMS; and served on an advisory board for Genentech. XM received speaking honoraria and travel expenses for participation in scientific meetings; has been a steering committee member of clinical trials or participated in advisory boards of clinical trials with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Sandoz, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, Excemed, Multiple Sclerosis International Federation, and National Multiple Sclerosis Society (USA). RAM receives research funding from Biogen Idec and Roche; and is the chair of the Medical Advisory Committee of the Multiple Sclerosis Society of Canada. VWY is funded by research grants from the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, Canadian Cancer Society, and Genentech; has received speaker honoraria from Biogen, EMD Serono, Novartis, Roche, and Sanofi-Genzyme; and is the recipient of unrestricted educational grants from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme, and Teva Canada to support educational activities of the Alberta MS Network, which he directs. AJT reports personal fees as an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for the Multiple Sclerosis Journal receiving an honorarium from SAGE Publications; receives support from the UCLH NIHR Biomedical Research Centre; and receives support for travel as Chair of the Scientific Advisory Committee and International Progressive MS Alliance from the National MS Society (USA) as member, National Multiple Sclerosis Society (USA) Research Programs Advisory Committee, and as a Board member of the European Charcot Foundation; has received payment in the past 36 months (paid to the UCL) from Eisai and from the German Aerospace Centre, Health Research (ERA-NET NEURON); has received fees or support for travel from Hoffman La Roche, Novartis, and CanProCo SAB; had received honoraria or support for travel from EXCEMED and Almirall; has received support for travel to PACTRIMS and has received support for travel to the Multiple Sclerosis Society of Canada; unpaid roles include as a Guarantor of BRAIN, Trustee of the National Brain Appeal (National Hospital for Neurology and Neurosurgery), and as Chair of the Scientific Ambassadors, ‘STOP MS’ Appeal Board (Multiple Sclerosis Society UK). DSR reports personal fees from Bounds Law Group LLC, grants from Vertex, grants from Sanofi-Genzyme, grants from Abata Therapeutics, outside the submitted work; has a patent system and method of automatically detecting tissue abnormalities (US Patent 9,607,392) issued, a patent method of analysing multisequence MRI data for analysing brain abnormalities in a subject (US Patent 9,888,876) issued, a patent Automatic identification of subjects at risk of multiple sclerosis (US Patent application 16/254,710) issued, and a patent high-resolution cerebrospinal fluid-suppressed T2*-weighted magnetic resonance imaging of cortical lesions (US Patent application 62/838,578) pending., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: We aim to evaluate 3-year effects of ocrelizumab (humanized anti-CD20 monoclonal antibody for the treatment of multiple sclerosis (MS)) on lymphocytes, neutrophils and immunoglobulins: (1) when compared with pre-infusion assessment; (2) over the course of treatment; and (3) possible clinical correlates of the observed immunological modifications., Methods: This real-world observational cohort study has been conducted on prospectively collected data from 78 MS patients (mean age 47.8 ± 10.5 years; females 48.7%) commencing on ocrelizumab from 2018, with mean follow-up of 36.5 ± 6.8 months. Clinical data and blood samples were collected every three months. Total lymphocyte count and subpopulations were assessed on peripheral blood using flow cytometry. Serum immunoglobulins were evaluated with nephelometry., Results: When compared with pre-infusion values, we observed reduction of total, CD19 and CD20 lymphocyte counts; however, after the first infusion, their levels remained substantially stable. Over time we observed a progressive reduction of CD8 lymphocytes, while no changes were observed for CD4, CD27, CD3CD27, and CD19CD27. After the first infusion, we observed reduction in IgG, which further decreased during the follow-up. Higher probability of EDSS progression was associated with reduced modulation of CD8 lymphocytes., Interpretation: Ocrelizumab affects both humoral and cellular immune responses. Disability progression over the follow-up was associated with lower CD8 cytotoxic T-lymphocyte reduction. Changes in humoral response are immediate and sustained, while modulation of cellular immunity occurs progressively through regular re-treatment, and is related to clinical stability., (© 2022. The Author(s).)

Introduction: Unemployment can directly affect social status and identity. Assessing and adjusting determinants of early working impairments in a chronic disease can thus reduce its long-term burden. Hereby, we aim to evaluate differences in occupational history and early working impairments between people with multiple sclerosis (MS) and healthy workers., Methods: This is a cross-sectional study comparing 71 workers with MS [age 41.7 ± 9.4 years; females 59.1%; EDSS 2.0 (1.0-6.0)] and 71 controls (age 42.6 ± 11.9 years; females 33.8%). All participants filled in Work Ability Index (WAI), Work Productivity and Activity Impairment (WPAI), European Questionnaire for Quality of Life (EuroQoL), Beck Depression Inventory II (BDI-II), and Pittsburgh Sleep Quality Index (PSQI). In MS, we further collected expanded disability status scale (EDSS), MS Questionnaire for Job difficulties (MSQ-Job), Fatigue severity scale (FSS), and the Brief International Cognitive Assessment for MS (BICAMS)., Results: Workers with MS were more working disabled ( p < 0.01), less exposed to workplace risks ( p < 0.01), and more limited in fitness to work ( p = 0.01), compared with controls. On linear regression models adjusted by age, sex, education, and type of contract, people with MS had worse WAI (Coeff=-5.47; 95% CI = -7.41, -3.53; p < 0.01), EuroQoL (Coeff = -4.24; 95% CI = -17.85, -6.50; p < 0.01), BDI-II (Coeff = 3.99; 95% CI = 2.37, 7.01; p < 0.01), and PSQI (Coeff = 4.74; 95% CI = 3.13, 7.61; p < 0.01), compared with controls, but no differences in WPAI ( p = 0.60). EuroQoL, BDI-II, and PSQI were equally associated with both WAI and WPAI in MS and controls (all p < 0.01). In MS, worse MSQJob was associated with higher EDSS (Coeff = 5.22; 95% CI = 2.24, 7.95; p < 0.01), progressive disease (Coeff = 14.62; 95% CI = 5.56, 23.69; p < 0.01), EuroQoL (Coeff = 4.63; 95% CI = 2.92, 6.35; p < 0.01), FSS (Coeff = 0.55; 95% CI = 0.38, 0.72; p < 0.01), and cognitive impairment (Coeff = 4.42; 95% CI = 0.67, 8.22; p = 0.02)., Discussion: Early factors associated with working difficulties in MS include disability, fatigue, depression, and cognitive dysfunction. Early identification of clinical features potentially causing working difficulties should be considered to enhance job retention, along with targeted prevention and protection measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the authors VB and MM., (Copyright © 2022 Moccia, Fontana, Palladino, Falco, Finiello, Fedele, Lanzillo, Reppuccia, Triassi, Brescia Morra and Iavicoli.)

Aims: We aim to provide real-world evidence on the use of ocrelizumab for treating multiple sclerosis (MS), with specific regard to prescription pattern, adherence, persistence, healthcare resource utilization and related costs, also in relation to other disease-modifying treatments (DMTs)., Methods: We included 2495 people with MS from the Campania Region (South Italy) who received first or switch DMT prescription from Jan 2018 to Dec 2020, and with at least 6-month follow-up. We collected hospital discharge records, drug prescriptions, and related costs, and calculated persistence (time from first prescription to discontinuation or switch to other DMT), adherence (proportion of days covered (PDC)), annualized hospitalization rate (AHR) for MS-related hospital admissions, and DMT costs., Results: Ocrelizumab was the most commonly prescribed DMT (n = 399; age = 45.74 ± 10.98 years; females = 224), after dimethyl fumarate (n = 588) and fingolimod (n = 401); 26% patients treated with ocrelizumab were naïve. When compared with ocrelizumab, the risk of discontinuation was higher for other highly active DMTs (HR = 3.78; p = 0.01), and low/medium efficacy DMTs (HR = 7.59; p < 0.01). When compared with ocrelizumab, PDC was similar to other highly active DMTs (Coeff = 0.01; p = 0.31), but higher for low/medium efficacy DMTs (Coeff = 0.09; p < 0.01). When compared with ocrelizumab, AHR was similar to other highly active DMTs (Coeff = 0.01; p = 0.51), and low/medium efficacy DMTs (Coeff = 0.01; p = 0.55). When compared with ocrelizumab, DMT monthly costs were higher for other highly active DMTs (Coeff = 92.30; p < 0.01), but lower for low/medium efficacy DMTs (Coeff = - 1043.61; p < 0.01)., Discussion: Ocrelizumab was among the most frequently prescribed DMTs, with 26% prescriptions to treatment-naïve patients, suggesting its relevance in addressing unmet clinical needs (e.g., first approved treatment for primary progressive MS). Ocrelizumab was associated with the highest persistence, confirming its favorable benefit-risk profile. Costs for ocrelizumab were lower than those associated to similarly effective DMTs, in absence of changes in healthcare resource utilization., (© 2022. The Author(s).)