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Julia Sabin,1 Elisa Salas,2 Jesús Martín-Martínez,3 Antonio Candeliere-Merlicco,4 Francisco Javier Barrero Hernández,5 Ana María Alonso Torres,6 José Luis Sánchez-Menoyo,7 Laura Borrega,8 María Rodríguez-Rodríguez,9 Montserrat Gómez-Gutiérrez,10 Sara Eichau,11 Miguel Ángel Hernández-Pérez,12 Carmen Calles,13 Eva Fernandez-Diaz,14 Olga Carmona,15 Aida Orviz,16 Ana López-Real,17 Pablo López-Muñoz,18 Amelia Mendoza Rodríguez,19 Eduardo Aguera-Morales,20 Jorge Maurino2 1Department of Neurology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 2Medical Department, Roche Farma, Madrid, Spain; 3Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 4Department of Neurology, Hospital Rafael Méndez, Lorca, Spain; 5Department of Neurology, Hospital Clínico Universitario San Cecilio, Granada, Spain; 6Department of Neurology, Hospital Regional Universitario de Málaga, Málaga, Spain; 7Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao, Spain; 8Department of Neurology, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain; 9Department of Neurology, Hospital Universitario Lucus Augusti, Lugo, Spain; 10Department of Neurology, Hospital San Pedro de Alcántara, Cáceres, Spain; 11Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain; 12Department of Neurology, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain; 13Department of Neurology, Hospital Universitario Son Espases, Palma de Mallorca, Spain; 14Department of Neurology, Hospital Universitario de Albacete, Albacete, Spain; 15Department of Neurology, Fundació Salut Empordà, Figueres, Spain; 16Department of Neurology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 17Department of Neurology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; 18Department of Neurology, Hospital Arnau de Vilanova, Llíria, Spain; 19Department of Neurology, Complejo Asistencial de Segovia, Segovia, Spain; 20Department of Neurology, Hospital Universitario Reina Sofía, Córdoba, SpainCorrespondence: Jorge Maurino, Ribera del Loira 50, Madrid, 28042, Spain, Tel + 34 913 24 81 00, Email jorge.maurino@roche.comPurpose: Shared decision-making is critical in multiple sclerosis (MS) due to the uncertainty of the disease trajectory over time and the large number of treatment options with differing efficacy, safety and administration characteristics. The aim of this study was to assess patients’ decisional conflict regarding the choice of a disease-modifying therapy and its associated factors in patients with mid-stage relapsing-remitting multiple sclerosis (RRMS).Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS (2017 revised McDonald criteria) and disease duration of 3 to 8 years were included. The level of uncertainty experienced by a patient when faced with making a treatment choice was assessed using the 4-item Decisional Conflict Scale. A battery of patient-reported and clinician-rated measures was administered to obtain information on symptom severity, illness perception, illness-related uncertainty, regret, MS knowledge, risk taking behavior, preferred role in the decision-making process, cognition, and self-management. Patients were recruited during routine follow-up visits and completed all questionnaires online using electronic tablets at the hospital. A multivariate logistic regression analysis was conducted.Results: A total of 201 patients were studied. Mean age (Standard deviation) was 38.7 (8.4) years and 74.1% were female. Median disease duration (Interquartile range) was 6.0 (4.0– 7.0) years. Median EDSS score was 1.0 (0– 2.0). Sixty-seven (33.3%) patients reported a decisional conflict. These patients had lower MS knowledge and more illness uncertainty, anxiety, depressive symptoms, fatigue, subjective symptom severity, a threatening illness perception, and poorer quality of life than their counterparts. Lack of decisional conflict was associated with MS knowledge (Odds ratio [OR]=1.195, 95% CI 1.045, 1.383, p=0.013), self-management (OR=1.049, 95% CI 1.013, 1.093, p=0.018), and regret after a healthcare decision (OR=0.860, 95% CI 0.756, 0.973, p=0.018) in the multivariate analysis.Conclusion: Decisional conflict regarding the selection of a disease-modifying therapy was a common phenomenon in patients with mid-stage RRMS. Identifying factors associated with decisional conflict may be useful to implement preventive strategies that help patients better understand their condition and strengthen their self-management resources.Keywords: multiple sclerosis, disease-modifying therapies, decision-making, decisional conflict, disease-related knowledge, self-management

Susana Sainz de la Maza,1 Jorge Maurino,2 Tamara Castillo-Triviño,3 Mónica Borges,4 Berta Sebastián Torres,5 Javier Sotoca,6 Ana María Alonso Torres,7 Ana B Caminero,8 Laura Borrega,9 José L Sánchez-Menoyo,10 Francisco J Barrero-Hernández,11 Carmen Calles,12 Luis Brieva,13 María Rosario Blasco,14 Julio Dotor García-Soto,4 Ana Rodríguez-Regal,15 Laura Navarro-Cantó,16 Eduardo Agüera-Morales,17 Moisés Garcés,18 Olga Carmona,19 Laura Gabaldón-Torres,20 Lucía Forero,21 Mariona Hervás,22 Rocío Gómez-Ballesteros2 1Department of Neurology, Hospital Universitario Ramón y Cajal, Madrid, Spain; 2Medical Department, Roche Farma, Madrid, Spain; 3Department of Neurology, Hospital Universitario Donostia, San Sebastián, Spain; 4Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain; 5Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 6Department of Neurology, Hospital Universitari Vall d´Hebrón, Barcelona, Spain; 7Department of Neurology, Hospital Regional Universitario de Málaga, Málaga, Spain; 8Department of Neurology, Complejo Asistencial de Ávila, Ávila, Spain; 9Department of Neurology, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain; 10Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao, Spain; 11Department of Neurology, Hospital Universitario Clínico San Cecilio, Granada, Spain; 12Department of Neurology, Hospital Universitari Son Espases, Palma de Mallorca, Spain; 13Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain; 14Department of Neurology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 15Department of Neurology, Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; 16Department of Neurology, Hospital General Universitario de Elche, Elche, Spain; 17Department of Neurology, Hospital Universitario Reina Sofía, Córdoba, Spain; 18Department of Neurology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; 19Department of Neurology, Fundació Salut Empordà, Figueres, Spain; 20Department of Neurology, Hospital Francesc de Borja, Gandía, Spain; 21Department of Neurology, Hospital Universitario Puerta del Mar, Cádiz, Spain; 22Department of Neurology, Consorci Corporació Sanitària Parc Taulí, Sabadell, SpainCorrespondence: Jorge Maurino, Medical Department, Roche Farma, Ribera del Loira, 50, Madrid, 28042, Spain, Tel +34 913 24 81 00, Email jorge.maurino@roche.comBackground: Hopelessness is a risk factor for depression and suicide. There is little information on this phenomenon among patients with relapsing-remitting multiple sclerosis (RRMS), one of the most common causes of disability and loss of autonomy in young adults. The aim of this study was to assess state hopelessness and its associated factors in early-stage RRMS.Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0– 5.5 were included. The State-Trait Hopelessness Scale (STHS) was used to measure patients´ hopelessness. A battery of patient-reported and clinician-rated measurements was used to assess clinical status. A multivariate logistic regression analysis was conducted to determine the association between patients’ characteristics and state hopelessness.Results: A total of 189 patients were included. Mean age (standard deviation-SD) was 36.1 (9.4) years and 71.4% were female. Median disease duration (interquartile range-IQR) was 1.4 (0.7, 2.1) years. Symptom severity and disability were low with a median EDSS (IQR) score of 1.0 (0, 2.0). A proportion of 65.6% (n=124) of patients reported moderate-to-severe hopelessness. Hopelessness was associated with older age (p=0.035), depressive symptoms (p=< 0.001), a threatening illness perception (p=0.001), and psychological and cognitive barriers to workplace performance (p=0.029) in the multivariate analysis after adjustment for confounders.Conclusion: Hopelessness was a common phenomenon in early-stage RRMS, even in a population with low physical disability. Identifying factors associated with hopelessness may be critical for implementing preventive strategies helping patients to adapt to the new situation and cope with the disease in the long term.Keywords: relapsing-remitting multiple sclerosis, hopelessness, depressive symptoms, workplace difficulties, suicide

This work addresses the task allocation problem in spatial crowdsensing with altruistic participation, tackling challenges like declining engagement and user fatigue from task overload. Unlike typical models relying on financial incentives, this context requires alternative strategies to sustain participation. This paper presents a new solution, the Volunteer Task Allocation Engine (VTAE), to address these challenges. This solution is not based on economic incentives, and it has two primary goals. The first one is to improve user experience by limiting the workload and creating a user-centric task allocation solution. The second goal is to create an equal distribution of tasks over the spatial locations to make the solution robust against the possible decrease in participation. Two approaches are used to test the performance of this solution against different conditions: computer simulations and a real-world experiment with real users, which include a qualitative evaluation. The simulations tested system performance in controlled environments, while the real-world experiment assessed the effectiveness and usability of the VTAE with real users. This research highlights the importance of user-centered design in citizen science applications with altruistic participation. The findings demonstrate that the VTAE algorithm ensures equitable task distribution across geographical areas while actively involving users in the decision-making process.

Background: Patients with multiple sclerosis (MS) have to deal with a variable disease trajectory often associated with disability and productivity loss., Objective: This study aimed to assess illness-related uncertainty and associated correlates in patients with relapsing-remitting multiple sclerosis (RRMS) beyond the near diagnosis phase., Methods: We conducted a multicenter, non-interventional study including patients diagnosed with RRMS (2017 revised McDonald criteria) and a disease duration of 3 to 8 years. Perceived uncertainty was measured using the Mishel Uncertainty of Illness Scale (MUIS). Associations between the MUIS and different patient-based outcome measures were analyzed using Spearman's rank correlation., Results: A total of 201 patients were studied (mean age (standard deviation): 38.7 (8.4) years, 71.4 % female). The median disease duration (interquartile range) was 6.0 (4.0-7.0) years and the median EDSS score was 1.0 (0.0-2.0). The mean MUIS score was 38.2 (10.8). Perceived uncertainty was positively correlated with fatigue (p < 0.001), symptom severity (p < 0.001), anxiety (p < 0.001), depressive symptoms (p < 0.001), and a threatening illness perception (p < 0.001), and negatively correlated with self-management (p < 0.001), self-efficacy (p < 0.001), processing speed (p < 0.001), knowledge of MS (p = 0.006), and quality of life (p < 0.001)., Conclusion: Illness-related uncertainty was common in a population of mid-stage RRMS. Identifying uncertainty and its associated factors may be useful for implementing preventive strategies to help patients cope with the disease throughout life., Competing Interests: Declaration of competing interest J.S. received honoraria for lecturing, consulting or travel expenses from Biogen, Merck, Teva, Novartis, BMS, Janssen, Almirall, Roche and Sanofi. J.M-M. served on scientific advisory boards and/or received speaking honoraria, research funding and support to attend scientific meetings from Biogen, Merck, Novartis, Roche and Teva. F.B. received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi and Teva. A.A. received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall and Novartis. J.S-M. received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and participated in clinical trials of Biogen, Merck and Roche. L.B. received compensation for consulting services, speaking honoraria and support to attend scientific meetings from Bayer, Celgene, Biogen, Sanofi, Merck, Novartis, Roche, Almirall and Teva. M. G-G. received honoraria as speaker from Biogen, BMS, Janssen, Merck, Mylan, Novartis, Roche, Sanofi and Bial. S.E. received consulting fees and lecture honoraria from Biogen, Novartis, Sanofi, Merck, Roche and Almirall. C.C. received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi, Novartis, Biogen, Roche, and BMS. E.F-D. received honoraria and travel expenses for participation in scientific meetings and advisory boards from Almirall, Biogen, Merck, Roche and Sanofi. O.C. received honoraria for speaker services and advisory boards from Sanofi, Roche, Janssen and Merck. A.O. received research grants, travel support, advisory activities or honoraria for speaking engagements from Almirall, Biogen, BMS, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. A.L-R. received speaker and consultation fees, and congress travel support from Biogen, Janssen, Merck, Novartis, Roche and Sanofi. A. M. received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. E.A. received speaking honoraria from Roche, Novartis, Merck, Sanofi and Biogen. E.S. and J.M. are employees of Roche Farma Spain. The rest of the authors declared no potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.

Energy-related occupant behaviour in the built environment is considered crucial when aiming towards Energy Efficiency (EE), especially given the notion that people are most often unaware and disengaged regarding the impacts of energy-consuming habits. In order to affect such energy-related behaviour, various approaches have been employed, being the most common the provision of recommendations towards more energy-efficient actions. In this work, the authors extend prior research findings in an effort to automatically identify the optimal Persuasion Strategy (PS), out of ten pre-selected by experts, tailored to a user (i.e., the context to trigger a message, allocate a task or providing cues to enact an action). This process aims to successfully influence the employees' decisions about EE in tertiary buildings. The framework presented in this study utilizes cultural traits and socio-economic information. It is based on one of the largest survey datasets on this subject, comprising responses from 743 users collected through an online survey in four countries across Europe (Spain, Greece, Austria and the UK). The resulting framework was designed as a cascade of sequential data-driven prediction models. The first step employs a particular case of matrix factorisation to rank the ten PP in terms of preference for each user, followed by a random forest regression model that uses these rankings as a filtering step to compute scores for each PP and conclude with the best selection for each user. An ex-post assessment of the individual steps and the combined ensemble revealed increased accuracy over baseline non-personalised methods. Furthermore, the analysis also sheds light on important user characteristics to take into account for future interventions related to EE and the most effective persuasion strategies to adopt based on user data. Discussion and implications of the reported results are provided in the text regarding the flourishing field of personalisation to motivate pro-environmental behaviour change in tertiary buildings., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Kalamaras et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p -value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ES and JM are employees of Roche Farma Spain. JS received honoraria for lecturing, consulting, or travel expenses from Biogen, Merck, Teva, Novartis, BMS, Janssen, Almirall, Roche, and Sanofi. JMM served on scientific advisory boards and/or received speaking honoraria, research funding and support to attend scientific meetings from Biogen, Merck, Novartis, Roche, and Teva. FJB received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. AA received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen, and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall, and Novartis. JLSM received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in clinical trials from Biogen, Merck, and Roche. LB received compensation for consulting services, speaking honoraria, and support to attend scientific meetings from Bayer, Celgene, Biogen, Sanofi, Merck, Novartis, Roche, Almirall, and Teva. MGG received speaking honoraria from Biogen, BMS, Janssen, Merck, Mylan, Novartis, Roche, Sanofi, and Bial. SE received consulting fees and lecture honoraria from Biogen, Novartis, Sanofi, Merck, Roche, and Almirall. CC received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi, Novartis, Biogen, Roche, and BMS. EFD received honoraria and travel expenses for participation in scientific meetings and advisory boards from Almirall, Biogen, Merck, Roche, and Sanofi. OC received honoraria for speaker services and advisory boards from Sanofi, Roche, Janssen, and Merck. AO received research grants, travel support, advisory activities, and honoraria for speaking from Almirall, Biogen, BMS, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. ALR received speaker and consultation fees, and congress travel support from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi. AM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. EA received speaking honoraria from Roche, Novartis, Merck, Sanofi, and Biogen. The rest of the authors declared no potential conflicts of interest. The abstract of this article was presented at the European Congress of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) as a poster presentation with interim findings (PCR178; Copenhagen, Denmark; November 14, 2023)., (© The Author(s), 2024.)

Enzymes are usually stereospecific against chiral substrates, which is commonly accepted for the amine oxidase family of enzymes as well. However, the FsqB (fumisoquin biosynthesis gene B) enzyme that belongs to the family of sarcosine oxidase and oxidizes L-N-methyl-amino acids, shows surprising activity for both enantiomers of N-methyl-dopa. The aim of this study is to understand the mechanism behind this behavior. Primary docking experiments showed that tyrosine and aspartate residues (121 and 315 respectively) are located on the ceiling of the active site of FsqB and may play a role in fixing the N-methyl-dopa via its catechol moiety and allowing both stereoisomers of this substrate to be in close proximity of the N5 atom of the isoalloxazine ring of the cofactor. Three experimental approaches were used to prove this hypothesis which are: (1) studying the oxidative ability of the variants Y121F and D315A on N-methyl-dopa substrates in comparison with N-methyl-tyrosine substrates; (2) studying the FsqB WT and variants catalyzed biotransformation via high-performance liquid chromatography (HPLC); (3) molecular dynamics simulations to characterize the underlying mechanisms of the molecular recognition. First, we found that the chemical characteristics of the catechol moiety of N-methyl-dopa are important to explain the differences between N-methyl-dopa and N-methyl-tyrosine. Furthermore, we found that Y121 and D315 are specific in FsqB and not found in the model enzyme sarcosine oxidase. The on-bench and theoretical mutagenesis studies show that Y121 residue has a major role in fixing the N-methyl-dopa substrates close to the N5 atom of the isoalloxazine ring of the cofactor. Simultaneously, D315 has a supportive role in this mechanism. Jointly, the experimental and theoretical approaches help to solve the riddle of FsqB amine oxidase substrate specificity., (© 2023 The Authors. Journal of Molecular Recognition published by John Wiley & Sons Ltd.)

Background: Current guidelines recommend a stringent follow-up regimen that includes interval cystoureteronephscopy, CT urography, and selective urine cytology sampling for upper tract urothelial carcinoma (UTUC) patients undergoing endoscopic treatment and management. There are no recommendations regarding FISH analysis. Our purpose was to assess the efficacy of cytology and FISH as part of the follow-up protocol and its significance to clinical decision-making in this scenario., Methods: The medical records of all patients who managed endoscopically for UTUC at our institute between 2014 and 2022 were retrospectively analyzed. Demographic and clinical data, histology, cytology, and FISH results were collected. FISH analysis was considered malignant according to Paris criteria., Results: During the study period, 62 patients underwent 561 ureteroscopies as part of the treatment and follow-up regimen of low-grade UTUC. Urine from the affected upper tract was sampled for cytology in 377 procedures, and FISH analyses were performed in 273. In 75.4% of FISH analyses, the result was different from the cytology results: FISH found malignant aberrations in 15.5% of cases where cytology was benign. Furthermore, FISH classified all the cells defined as atypical via cytology as either benign or malignant. In only one case (0.17%), the urinary cytology report changed the follow-up regimen., Conclusion: Cytology may be omitted from the follow-up protocol of low-grade UTUC. In the handful of cases cytology does assist the diagnosis of UTUC, there is an additional benefit to performing FISH analysis, particularly when cellular atypia is reported in the cytology results., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in-silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. Moreover, the therapeutic potential of neoantigen-based vaccines may be enhanced using an optimal delivery platform that elicits robust de novo immune responses., Methods: We developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction, as well as the interaction between the peptide/MHC-I complex and the TCR, in its prediction strategy. Moreover, to maximize neoantigens' therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance., Results: We generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments., Conclusions: Our results indicate the relevance of incorporating other immunogenic determinants beyond the binding of neoantigens to MHC-I. Thus, neoVLPs loaded with neoantigens enhancing the interaction with the TCR can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy., (© 2024. The Author(s).)

Background: The EMCOVID project conducted a multi-centre cohort study to investigate the impact of COVID-19 on patients with Multiple Sclerosis (pwMS) receiving disease-modifying therapies (DMTs). The study aimed to evaluate the seroprevalence and persistence of SARS-CoV-2 antibodies in MS patients enrolled in the EMCOVID database. The DMTs were used to manage MS by reducing relapses, lesion accumulation, and disability progression. However, concerns arose regarding the susceptibility of pwMS to COVID-19 due to potential interactions between SARS-CoV-2 and the immune system, as well as the immunomodulatory effects of DMTs., Methods: This prospective observational study utilized data from a Multiple Sclerosis and COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data, SARS-CoV-2 serology, and symptoms of COVID-19 were extracted for pwMS receiving any type of DMT. The relationship between demographics, MS phenotype, DMTs, and COVID-19 was evaluated. The evolution of SARS-CoV-2 antibodies over a 6-month period was also assessed., Results: The study included 709 pwMS, with 376 patients providing samples at the 6-month follow-up visit. The seroprevalence of SARS-CoV-2 antibodies was higher among pwMS than the general population, with Interferon treatment being significantly associated with greater seroprevalence (16.9% vs. 8.4%; p 0.003). However, no other specific DMT showed a significant association with antibody presence. A total of 32 patients (8.5%) tested positive for IgG, IgM, or IgA antibodies against SARS-CoV-2 at baseline, but then tested negative at 6 months. Most of the pwMS in the cohort were asymptomatic for COVID-19 and, even among symptomatic cases, the prognosis was generally favourable., Conclusion: pwMS undergoing DMTs exhibited a higher seroprevalence of COVID-19 than the general population. Interferon treatment was associated with a higher seroprevalence, suggesting a more robust humoral response. This study provides valuable insights into the seroprevalence and persistence of SARS-CoV-2 antibodies in pwMS and contributes to our understanding of the impact of COVID-19 amongst this population.

Molecular dynamics simulations often struggle to obtain sufficient sampling to study complex molecular events due to high energy barriers separating the minima of interest. Multiple enhanced sampling techniques have been developed and improved over the years to tackle this issue. Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that works by adding a biasing potential, lifting the energy landscape up, and decreasing the height of its barriers. GaMD allows one to increase the sampling of events of interest without the need of a priori knowledge of the system or the relevant coordinates. All required acceleration parameters can be obtained from a previous search run. Upon its development, several improvements for the methodology have been proposed, among them selective GaMD in which the boosting potential is selectively applied to the region of interest. There are currently four selective GaMD methods that have shown promising results. However, all of these methods are constrained on the number, location, and scenarios in which this selective boosting potential can be applied to ligands, peptides, or protein-protein interactions. In this work, we showcase a GROMOS implementation of the GaMD methodology with a fully flexible selective GaMD approach that allows the user to define, in a straightforward way, multiple boosting potentials for as many regions as desired. We show and analyze the advantages of this flexible selective approach on two previously used test systems, the alanine dipeptide and the chignolin peptide, and extend these examples to study its applicability and potential to study conformational changes of glycans and glycosylated proteins.

Background: Malignant ureteral obstruction (MUO) is a sequela of advanced malignant disease that requires renal drainage, with tandem ureteral stents (TUSs) being a viable option. This study aimed to evaluate the TUS failure rate, associated risk factors, and the feasibility of replacing failed TUSs with a new pair of stents., Methods: A retrospective analysis of MUO patients treated with TUS insertion from 2014 to 2022 was conducted. TUS failure was defined as urosepsis, recurrent urinary tract infections, acute kidney failure, or new hydronephrosis on imaging. Cox proportional hazard regression analysis identified the independent predictors of TUS failure., Results: A total of 240 procedures were performed on 186 patients, with TUS drainage failing in 67 patients (36%). The median time to failure was 7 months. Multivariate analysis revealed female gender (OR = 3.46, p = 0.002), pelvic mass (OR = 1.75, p = 0.001), and distal ureteral obstruction (OR = 2.27, p = 0.04) as significant risk factors for TUS failure. Of the failure group, 42 patients (22.6%) underwent TUS replacement for a new pair. Yet, 24 (57.2%) experienced a second failure, with a median time of 4.5 months. The risk factors for TUS second failure included a stricture longer than 30 mm (OR = 11.8, p = 0.04), replacement with TUSs of the same diameter (OR = 43, p = 0.003), and initial TUS failure within 6 months (OR = 19.2, p = 0.006)., Conclusions: TUS insertion for the treatment of MUO is feasible and has good outcomes with a relatively low failure rate. Primary pelvic mass and distal ureteral obstruction pose higher risks for TUS failure. Replacing failed TUSs with a new pair has a success rate of 42.8%. Consideration should be given to placing larger diameter stents when replacing failed TUS.

Determining the presence of water molecules at protein-ligand interfaces is still a challenging task in free-energy calculations. The inappropriate placement of water molecules results in the stabilization of wrong conformational orientations of the ligand. With classical alchemical perturbation methods, such as thermodynamic integration (TI), it is essential to know the amount of water molecules in the active site of the respective ligands. However, the resolution of the crystal structure and the correct assignment of the electron density do not always lead to a clear placement of water molecules. In this work, we apply the one-step perturbation method named accelerated enveloping distribution sampling (AEDS) to determine the presence of water molecules in the active site by probing them in a fast and straightforward way. Based on these results, we combined the AEDS method with standard TI to calculate accurate binding free energies in the presence of buried water molecules. The main idea is to perturb the water molecules with AEDS such that they are allowed to alternate between regular water molecules and non-interacting dummy particles while treating the ligand with TI over an alchemical pathway. We demonstrate the use of AEDS to probe the presence of water molecules for six different test systems. For one of these, previous calculations showed difficulties to reproduce the experimental binding free energies, and here, we use the combined TI-AEDS approach to tackle these issues.

Disability accrual is mainly driven by progression independent of relapse activity, which is present even in early stages of relapsing-remitting multiple sclerosis (RRMS) and sometimes overlooked. This multicenter, non-interventional study evaluated whether patient-reported outcomes measures (PROMs) could capture disability in 189 early-stage RRMS patients (mean age: 36.1 ± 9.4 years, 71.4% female, mean disease duration: 1.4 ± 0.8 years, median EDSS: 1.0). The 9-Hole Peg Test (9-HPT), NeuroQoL Upper Extremity (NeuroQoL-UE), Timed 25-Foot Walk (T25-FW), Multiple Sclerosis Walking Scale (MSWS-12), Symbol Digit Modalities Test (SDMT), and Perceived Deficits Questionnaire (PDQ-5) were used to assess hand function, gait, and cognition, respectively. These functions were at least mildly affected in this early-stage population, finding significant correlations between PROMs and clinical assessments. PROMs could enable early-stage RRMS patients to communicate their perceived disability in different domains, assisting clinicians in disease monitoring and decision making., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JM, NM, and RGB are employees of Roche Pharma Spain. SSM received payment for lecturing or travel expenses from Merck-Serono, Biogen, Sanofi-Genzyme, Roche, and Novartis. JMM has served on scientific advisory boards and/or has received speaking honoraria, research funding, and support to attend scientific meetings from Biogen, Merck, Novartis, Roche and Teva. JS has received speaking honoraria, compensation for consulting services and support to attend scientific meetings from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi, Roche, and Teva. AA has received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen, and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall, and Novartis. ABC has received courses and honoraria for her participation as speaker/meeting moderator/symposia organizer from Alter, Almirall, Bayer, Bial, Biogen, Bristol-Myers-Squibb, Lilly, Merck-Serono, Mylan, Novartis, Roche, Sanofi-Genzyme, Teva, and UCB; and support to attend scientific meetings from Biogen, Bial, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. JLSM has received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and has participated in clinical trials from Biogen, Merck, and Roche. FJBH has received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, and Teva. CC has received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi-Genzyme, Novartis, Biogen, Roche, and Bristol-Myers-Squibb. LB has received compensation for consulting services, speaking honoraria and support to attend scientific meetings from Bayer, Celgene, Biogen, Genzyme, Merck, Novartis, Roche, Almirall, and Teva. JDGS has received compensation for consulting services and speaking honoraria from Biogen, Novartis, Merck, UCB, Sanofi-Genzyme, Roche, Almirall, and Teva. MCA has received compensation for consulting services from Genzyme, Roche, Novartis, Sanofi, and Biogen. LNC has received compensations from Sanofi-Genzyme, Merk, Biogen, and Roche. EA has received speaking honoraria from Roche, Novartis, Merck, Sanofi, and Biogen. MGR has received speaking honoraria from Biogen, Sanofi, Almirall, and Novartis. OC has participated in studies and has received speaking honoraria from Roche, Merck, Biogen, and Novartis. LGT has received speaking honoraria from Biogen, Novartis, Merck, Bayer, Sanofi-Genzyme, Almirall, Roche, and Teva. MH has participated in observational studies and has received compensation for consulting services and speaking honoraria from Roche, Merck, Sanofi, Biogen, Novartis, and Bayer. The rest of the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Up-to-date guidelines on the management of upper tract urothelial carcinoma (UTUC) are continuously published. We aim to assess the variability of diagnosis and treatment strategies in the endoscopic management of UTUC and adherence to European Association of Urology and National Comprehensive Cancer Network guidelines. A 15-question survey was designed to query practitioners on approaches to clinical practice and knowledge about endoscopic treatment indications and techniques. It was emailed to all members of the Endourologic Society through the society's office, and to all Israeli non-member endourologists. Eighty-eight urologists participated in the survey. Adherence to guidelines on indications for endoscopic management was only 51%. Most of the survey respondents (87.5%) use holmium laser for tumor ablation, and ~50% use forceps for biopsy while the other half use baskets. Only 50% stated that they would use Jelmyto ® for specific indications. Most (80%) indicated that they repeat the ureteroscopy 3 months after the first one, and 52.3% continue with follow-up ureteroscopy every 3 months during the first year after diagnosis. There is vast variability among endourologists in the technical aspects of UTUC, the indications for endoscopic management, and adherence to the available guidelines for managing UTUC.

One of the most challenging aspects in the molecular simulation of proteins is the study of slowly relaxing processes, such as loop rearrangements or ligands that adopt different conformations in the binding site. State-of-the-art methods used to calculate binding free energies rely on performing several short simulations (lambda steps), in which the ligand is slowly transformed into the endstates of interest. This makes capturing the slowly relaxing processes even more difficult, as they would need to be observed in all of the lambda steps. One attractive alternative is the use of a reference state capable of sampling all of the endstates of interest in a single simulation. However, the energy barriers between the states can be too high to overcome, thus hindering the sampling of all of the relevant conformations. Accelerated enveloping distribution sampling (AEDS) is a recently developed reference state technique that circumvents the high-energy-barrier challenge by adding a boosting potential that flattens the energy landscape without distorting the energy minima. In the present work, we apply AEDS to the well-studied benchmark system T4 lysozyme L99A. The T4 lysozyme L99A mutant contains a hydrophobic pocket in which there is a valine (valine 111), whose conformation influences the binding efficiencies of the different ligands. Incorrectly sampling the dihedral angle can lead to errors in predicted binding free energies of up to 16 kJ mol -1 . This protein constitutes an ideal scenario to showcase the advantages and challenges when using AEDS in the presence of slow relaxing processes. We show that AEDS is able to successfully sample the relevant degrees of freedom, providing accurate binding free energies, without the need of previous information of the system in the form of collective variables. Additionally, we showcase the capabilities of AEDS to efficiently screen a set of ligands. These results represent a promising first step toward the development of free-energy methods that can respond to more intricate molecular events.

Background: The evolving therapeutic landscape requires more participation of patients with relapsing remitting multiple sclerosis (RRMS) in treatment decisions. The aim of this study was to assess the association between patient's self-perception, cognitive impairment and behavioral factors in treatment choices in a cohort of patients at an early stage of RRMS., Methods: We conducted a multicenter, non-interventional study including adult patients with a diagnosis of RRMS, a disease duration ≤18 months and receiving care at one of the 21 participating MS centers from across Spain. We used patient-reported measures to gather information on fatigue, mood, quality of life, and perception of severity of their MS. Functional metrics (Expanded Disability Status Scale [EDSS], cognitive function by the Symbol Digit Modalities Test [SDMT], 25-foot walk test) and clinical and radiological data were provided by the treating neurologist. The primary outcome of the study was status quo (SQ) bias, defined as participant's tendency to continue taking a previously selected but inferior treatment when intensification was warranted. SQ bias was assessed based on participants treatment preference in six simulated RRMS case scenarios with evidence of clinical relapses and radiological disease progression., Results: Of 189 participants who met the inclusion criteria, 188 (99.5%) fully completed the study. The mean age was 36.6 ± 9.5 years, 70.7% female, mean disease duration: 1.2 ± 0.8 years, median EDSS score: 1.0 [IQR=0.0-2.0]). Overall, 43.1% patients (n = 81/188) had an abnormal SDMT (≤49 correct answers). SQ bias was observed in at least one case scenario in 72.3% (137/188). Participant's perception of their MS severity was associated with higher SQ bias (β coeff 0.042; 95% CI 0.0074-0.076) among those with delayed cognitive processing. Higher baseline EDSS and number of T2 lesions were predictors of delayed processing speed (OR EDSS=1.57, 95% CI: 1.11-2.21, p = 0.011; OR T2 lesions=1.50, 95% CI: 1.11-2.03, p<0.01). Bayesian multilevel model accounting for clustering showed that delayed cognitive processing (exp coeff 1.06; 95% CI 1.04-1.09) and MS symptoms severity (exp coeff 1.28; 95% CI 1.22-1.33) were associated with SQ bias., Conclusion: Over 40% of patients in earlier stages of RRMS experience delays in cognitive processing that might affect their decision-making ability. Our findings suggest that patients' self-perception of disease severity combined with a delay in cognitive processing would affect treatment choices leading to status quo bias early in the course of their disease., Competing Interests: Declaration of Competing Interest G.S was supported by the Heart and Stroke Foundation of Canada Scientist Award following a peer-reviewed competition and reported receiving unrestricted grants and personal fees from Hoffman La Roche (Canada) and Roche Farma (Spain). S.S.M received payment for lecturing or travel expenses from Merck-Serono, Biogen, Sanofi-Genzyme, Roche, and Novartis. B.P.B. has received honoraria as speaker/advisor from Biogen, Sanofi and Bial. J.S. has received speaking honoraria, compensation for consulting services and support to attend scientific meetings from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi, Roche and Teva. A.A. has received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall and Novartis. A.B.C. has received courses and honoraria for her participation as speaker/meeting moderator/symposia organizer from Alter, Almirall, Bayer, Bial, Biogen, Bristol-Myers-Squibb, Lilly, Merck-Serono, Mylan, Novartis, Roche, Sanofi-Genzyme, Teva and UCB; and support to attend scientific meetings from Biogen, Bial, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva. J.L.S-M. has received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and has participated in clinical trials from Biogen, Merck and Roche. F.J.B-H. has received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck-Serono, Novartis, Roche, Sanofi and Teva. C.C. has received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi-Genzyme, Novartis, Biogen, Roche, and Bristol-Myers-Squibb. L.B. has received compensation for consulting services, speaking honoraria and support to attend scientific meetings from Bayer, Celgene, Biogen, Genzyme, Merck, Novartis, Roche, Almirall and Teva. J.D.G-S. has received compensation for consulting services and speaking honoraria from Biogen, Novartis, Merck, UCB, Sanofi-Genzyme, Roche, Almirall and Teva. M.C-A. has received compensation for consulting services from Genzyme, Roche, Novartis, Sanofi and Biogen. L.NC. has received compensations from Sanofi-Genzyme, Merk, Biogen and Roche. E.A. has received speaking honoraria from Roche, Novartis, Merck, Sanofi and Biogen. M.G. has received speaking honoraria from Biogen, Sanofi, Almirall and Novartis. L.G-T. has received speaking honoraria from Biogen, Novartis, Merck, Bayer, Sanofi-Genzyme, Almirall, Roche and Teva. M.H. has participated in observational studies and has received compensation for consulting services and speaking honoraria from Roche, Merck, Sanofi, Biogen, Novartis and Bayer. J.M., R.G-B., and E.G-A. are employees of Roche Farma Spain. The rest of the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022. Published by Elsevier B.V.)

Background: Incidental prostate cancer (IPCa) is encountered in 10% of surgical procedures for benign prostatic obstruction (BPO). Identification of patients with underlying detrimental prostate cancer is paramount for tailored treatment decision-making, but guideline recommendations for this setting are lacking., Objective: To highlight clinical and histological characteristics related to BPO surgery that may predict IPCa with unfavorable pathology., Design, Setting, and Participants: We included men with IPCa who underwent radical prostatectomy (RP) in the short term after IPCa diagnosis. Two cohorts were built according to final pathology for the RP specimen: unfavorable pathology (International Society of Urological Pathology [ISUP] grade group [GG] ≥3 and/or ≥pT3a and/or pN1) versus favorable pathology., Outcome Measurements and Statistical Analysis: We performed multivariate regression analysis for the endpoint, which was unfavorable pathology for the RP specimen. Using the model estimates for prostate-specific antigen (PSA), ISUP GG, age, and prostate volume, we established a model for estimating the risk of unfavorable histopathology., Results and Limitations: Overall, 112 patients were included in the final assessment. On multivariate analysis, PSA (odds ratio [OR] 1.083, 95% confidence interval [CI] 1.003-1.170; p = 0.042), ISUP GG for the specimen from BPO surgery (OR 3.090; 95% CI 1.129-8.457; p = 0.028), and age (OR 1.121, 95% CI 1.026-1.225; p = 0.012) were independent predictors for unfavorable histopathology. On receiver operating characteristic analysis, the area under the curve was 0.751. A novel calculator was developed to predict adverse pathology for men with IPCa. The study is limited by its retrospective design., Conclusions: For men with IPCa, PSA before surgery for BPO, ISUP GG, and age are independent predictors of unfavorable disease. Our results might improve preoperative risk assessment for patient counseling., Patient Summary: We developed a novel calculator to estimate the risk of underlying detrimental disease in men diagnosed with prostate cancer at surgery for benign prostatic obstruction., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The typically low thermodynamic and kinetic stability of enzymes is a bottleneck for their application in industrial synthesis. Baeyer-Villiger monooxygenases, which oxidize ketones to lactones using aerial oxygen, among other activities, suffer particularly from these instabilities. Previous efforts in protein engineering have increased thermodynamic stability but at the price of decreased activity. Here, we solved this trade-off by introducing mutations in a cyclohexanone monooxygenase from Acinetobacter sp., guided by a combination of rational and structure-guided consensus approaches. We developed variants with improved activity (1.5- to 2.5-fold) and increased thermodynamic (+5 °C T m ) and kinetic stability (8-fold). Our analysis revealed a crucial position in the cofactor binding domain, responsible for an 11-fold increase in affinity to the flavin cofactor, and explained using MD simulations. This gain in affinity was compatible with other mutations. While our study focused on a particular model enzyme, previous studies indicate that these findings are plausibly applicable to other BVMOs, and possibly to other flavin-dependent monooxygenases. These new design principles can inform the development of industrially robust, flavin-dependent biocatalysts for various oxidations., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Laparoscopic (LP) and robot-assisted pyeloplasty (RAP) are minimally invasive techniques for correcting uretero-pelvic junction obstruction (UPJO). We retrospectively compared the clinical outcomes of all adults who underwent RAP (n = 41) to those who underwent LP (n = 24) for UPJO at our institution between 2003−2022. Methods: Age, sex, body mass index, surgical side, past abdominal/endoscopic surgeries, pre- and postoperative renal scans, pre- and postoperative serum creatinine levels, operative time (OT), presence of crossing vessels, estimated blood loss, postoperative complications, length of hospital stay, time to JJ stent removal, follow-up length, and postoperative hydronephrosis were analyzed. Results: The groups were demographically comparable. The mean total and skin-to-skin OTs (minutes) were significantly longer in the RAP group than in the LP group (242.4 ± 55 vs. 161.4 ± 40 p < 0.001; 163.7 ± 41.8 vs. 124.3 ± 30.3 p = 0.006, respectively). Hospital stay (days) was shorter in the RAP group (3.3 ± 2.1 vs. 7.3 ± 2.5 p < 0.001). Postoperative complication rates were identical for both groups. The LP group had a significantly longer follow-up period (85.2 ± 73 vs. 19 ± 14 months p < 0.001). The success rates for the LP and RAP groups were 87.5% and 90.6% (p = 0.708). Conclusions: RAP achieves equivalent results to LP, in adult patients. A longer OT may be expected with the robotic system since it can handle more complicated cases., Competing Interests: There is no conflict of interest to disclose.

Background: Multiple sclerosis is one of the most common causes of neurological disability in young adults with major consequences for their future lives. Improving communication strategies on prognosis may help patients deal with the disease and adjust their long-term life goals. However, there is limited information on patients' preferences of long-term prognosis (LTP) communication and associated factors., Objective: The aim of this study was to describe patients' preferences and assess the factors associated with LTP communication preferences in early-stage relapsing-remitting multiple sclerosis (RRMS) patients., Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration from first attack ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0-5.5 were included. The Prognosis in MS questionnaire was used to assess how much patients want to know about their LTP. Different patient-reported measures were administered to gather information on symptom severity, pain, fatigue, mood/anxiety, quality of life, stigma, illness perception, feeling of hopelessness, self-efficacy, information avoidance and coping strategies. Cognition was assessed using the Symbol Digit Modalities Test (SDMT). A multivariate logistic regression analysis was performed to assess the association between LTP information preference and demographic and clinical characteristics, as well as patients' perspectives., Results: A total of 189 patients were included (mean age: 36.1  ±  9.4 years, 71.4% female, mean disease duration: 1.2  ±  0.8 years). Median EDSS score was 1.0 (IQR = 0.0-2.0). A proportion of 68.5% (n  =  126) of patients had never discussed LTP with their neurologists, whereas 69.2% (n = 126) reported interest in knowing it (73.5% at diagnosis). Bivariate analyses suggested that patients were significantly more likely to have higher LTP information preferences if they were male and had a lower SDMT score. Male gender and a lower SDMT score were predictors of LTP information preferences., Conclusions: Patients with early-stage RRMS want to discuss their LTP shortly after diagnosis. Understanding the factors involved may be useful to design individualized communication strategies., (Copyright © 2022. Published by Elsevier B.V.)

Background: Multiple sclerosis is one of the most common causes of neurological disability in young adults with major consequences for their autonomy and capacity to maintain employment., Objective: The aim of this study was to assess the impact on work productivity in early-stage relapsing-remitting multiple sclerosis (RRMS)., Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0-5.5 were included. Absenteeism, presenteeism, and unpaid work loss due to RRMS were measured using the Valuation of Lost Productivity (VOLP) questionnaire. The EDSS, SymptoMScreen, 5-item Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale, Symbol Digit Modalities Test, and Multiple Sclerosis Work Difficulties Questionnaire were used to gather information on disability, patients' perception of symptom severity, fatigue, mood/anxiety, cognition, and problems in the workplace, respectively. Associations between the VOLP and clinical and work outcomes were analyzed using Spearman's rank correlations., Results: A total of 189 patients were included. Mean age (SD) was 36.1 ± 9.4 years and 71.4% were female. Mean disease duration was 1.2 ± 0.8 years. Median EDSS score was 1.0 (IQR 0, 2.0). One hundred thirty patients (68.8%) were working for pay or self-employed. Fifty-three patients (40.8%) reported absence from work in the past 3 months with an average of 14.3 absent workdays. Their health problems resulted in the loss of 3.4% of their actual work time in the past 7 days. Thirty patients got help (11.8 h) with their unpaid work activities in the past 7 days. Absenteeism was significantly correlated with anxiety and depression (rho=0.298 and 0.291, p<0.001), fatigue (rho=0.214, p = 0.014), and symptom severity (rho=0.213, p = 0.015). Presenteeism was significantly correlated with fatigue (rho=0.375, p<0.001), symptom severity (rho=0.373, p<0.001), depression (rho=0.263, p = 0.008), and disability (rho=0.215, p = 0.031)., Conclusions: Productivity loss even in a RRMS population with short disease duration stresses the need for more efficient treatment control of disease activity from earlier stages., (Copyright © 2021 Elsevier B.V. All rights reserved.)