[Core data set for real world data in multiple sclerosis: customization for latin america from a global task force recommendation]. / Core data set para la generación de datos de la vida real en esclerosis múltiple: adaptación de una iniciativa global para América Latina.

INTRODUCTION: The primary objective of the core data set is to reduce heterogeneity and promote harmonization among data sources in EM, thereby reducing the time needed to execute real life data collection efforts. Recently, a group led by the Multiple Sclerosis Data Alliance has developed a core data set for collecting real-world data on multiple sclerosis (MS) globally. Our objective was to adapt this global data set to the needs of Latin America, so that it can be implemented by the registries already developed and in the process of development in the region. MATERIAL AND METHODS: A working group was formed regionally, the core data set created globally was adapted (translation process into Spanish, incorporation of regional variables and consensus on variables to be used). Consensus was obtained through the remote Delphi methodology of a round of questionnaires and remote discussion of the core data set variables. RESULTS: A total of 25 professionals from Latin America carried out the adaptation process between November 2022 and July 2023. Agreement was established on a core data set of nine categories and 45 variables, version 2023 to suggest its implementation in developed or developing registries, and MS cohorts in the region. CONCLUSION: The core data set seeks to harmonize the variables collected by registries and cohorts in MS in Latin America in order to facilitate said collection and allow collaboration between sources. Its implementation will facilitate real life data collection and collaboration in the region.

TITLE: Core data set para la generación de datos de la vida real en esclerosis múltiple: adaptación de una iniciativa global para América Latina.Introducción. Los objetivos primarios del core data set son reducir la heterogeneidad y promover la armonización entre las fuentes de datos en la esclerosis múltiple (EM), reduciendo así el tiempo necesario para ejecutar esfuerzos en la recolección de datos de vida real. Recientemente, un grupo liderado por la Multiple Sclerosis Data Alliance ha desarrollado un core data set para la recolección de datos del mundo real en EM a nivel global. Nuestro objetivo ha sido adaptar y consensuar este conjunto de datos globales a las necesidades de América Latina para que pueda ser implementado por los registros ya desarrollados y en proceso de desarrollo en la región. Material y métodos. Se conformó un grupo de trabajo regionalmente y se adaptó el core data set creado globalmente (proceso de traducción al español, incorporación de variables regionales y consenso sobre variables que se iban a utilizar). El consenso se obtuvo a través de la metodología Delphi remoto de ronda de cuestionarios y discusión a distancia de las variables del core data set. Resultados. Veinticinco profesionales de América Latina llevaron adelante el proceso de adaptación entre noviembre de 2022 y julio de 2023. Se estableció un acuerdo sobre un core data set de nueve categorías y 45 variables, versión 2023, con la sugerencia de implementarlo en registros desarrollados o en vías de desarrollo y cohortes de EM en la región. Conclusión. El core data set busca armonizar las variables recolectadas por los registros y las cohortes de EM en América Latina con el fin de facilitar dicha recolección y permitir una colaboración entre fuentes. Su implementación facilitará la recolección de datos de vida real y la colaboración en la región.

Lignocellulosic biomass-based glycoconjugates for diverse biotechnological applications.

Glycoconjugates are the ubiquitous components of mammalian cells, mainly synthesized by covalent bonds of carbohydrates to other biomolecules such as proteins and lipids, with a wide range of potential applications in novel vaccines, therapeutic peptides and antibodies (Ab). Considering the emerging developments in glycoscience, renewable production of glycoconjugates is of importance and lignocellulosic biomass (LCB) is a potential source of carbohydrates to produce synthetic glycoconjugates in a sustainable pathway. In this review, recent advances in glycobiology aiming on glycoconjugates production is presented together with the recent and cutting-edge advances in the therapeutic properties and application of glycoconjugates, including therapeutic glycoproteins, glycosaminoglycans (GAGs), and nutraceuticals, emphasizing the integral role of glycosylation in their function and efficacy. Special emphasis is given towards the potential exploration of carbon neutral feedstocks, in which LCB has an emerging role. Techniques for extraction and recovery of mono- and oligosaccharides from LCB are critically discussed and influence of the heterogeneous nature of the feedstocks and different methods for recovery of these sugars in the development of the customized glycoconjugates is explored. Although reports on the use of LCB for the production of glycoconjugates are scarce, this review sets clear that the potential of LCB as a source for the production of valuable glycoconjugates cannot be underestimated and encourages that future research should focus on refining the existing methodologies and exploring new approaches to fully realize the potential of LCB in glycoconjugate production.

Agricultural Residues as Raw Materials for Pulp and Paper Production: Overview and Applications on Membrane Fabrication.

The need for pulp and paper has risen significantly due to exponential population growth, industrialization, and urbanization. Most paper manufacturing industries use wood fibers to meet pulp and paper requirements. The shortage of fibrous wood resources and increased deforestation are linked to the excessive dependence on wood for pulp and paper production. Therefore, non-wood substitutes, including corn stalks, sugarcane bagasse, wheat, and rice straw, cotton stalks, and others, may greatly alleviate the shortage of raw materials used to make pulp and paper. Non-woody raw materials can be pulped easily using soda/soda-AQ (anthraquinone), organosolv, and bio-pulping. The use of agricultural residues can also play a pivotal role in the development of polymeric membranes separating different molecular weight cut-off molecules from a variety of feedstocks in industries. These membranes range in applications from water purification to medicinal uses. Considering that some farmers still burn agricultural residues on the fields, resulting in significant air pollution and health issues, the use of agricultural residues in paper manufacturing can eventually help these producers to get better financial outcomes from the grown crop. This paper reviews the current trends in the technological pitch of pulp and paper production from agricultural residues using different pulping methods, with an insight into the application of membranes developed from lignocellulosic materials.

Volumetric Scale-Up of a Packed-Bed Ion-Exchange System to Extract Phytate from Thin Stillage.

Phytate is the main form of phosphorus in corn ethanol coproducts and poses digestion issues in monogastric-animal feed. Extracting phytate as a commodity chemical will bring extra revenue to the corn ethanol industry and reduces potential phosphorus pollution from livestock waste management. We assessed a simplified scale-up approach of an ion-exchange separation system applied to extract phytate from thin stillage using volumetric parameters and simplifications of the van Deemter model. Thin stillage is one of the main byproducts generated on dry-grind corn-to-ethanol plants and accounts for the liquid portion of the bottom product generated in the ethanol distillation process. Thin stillage is rich in dissolved phytate, which served as the basis for an ion-exchange extraction system developed with a scalability factor of 50. Under the evaluated conditions, similar breakthrough profiles were obtained when similar Péclet and Stanton numbers were maintained for the scales studied, demonstrating that a simple and straightforward scale-up can be attained if special attention is given to maintaining both parameters as the basis of calculations of the plate numbers of ion-exchange columns.

Trabecular bone score in people with cystic fibrosis.

People with cystic fibrosis (CF) are at increased risk of fractures. Our study found that low trabecular bone score (TBS) (a measure of bone strength) may help identify people with CF at risk of fractures especially when combined with bone density measured by DXA, age, hemoglobin A1c, and transplant status. INTRODUCTION: People with cystic fibrosis (CF) are at increased risk of fractures. This study aims to evaluate the association of trabecular bone score (TBS) with fractures in CF. METHODS: A cross-sectional study of adults with CF who completed bone density between 2009 and 2019. TBS was applied to lumbar spine studies. RESULTS: A total of 202 people with CF were included. A history of fracture was present in 36 (17.8%) subjects. Patients with history of fractures had higher hemoglobin A1c (A1C) (7.8 ± 2.7% vs. 6.7 ± 1.7%, p = 0.024), lower femoral neck (FN) Z/T-score (- 1.05 ± 1.08 vs. - 0.44 ± 1.08, p = 0.012), and lower TBS (1.36 ± 0.13 vs. 1.40 ± 0.11, p = 0.05) compared to those without. Lung transplant recipients had a higher prevalence of fractures (50% vs. 14.1%, p < 0.001). The odds ratio (95%CI) of having a fracture for subjects with TBS (≤ 1.2 vs. > 1.2) stratified by FN Z/T-score (≤ - 2.0 or > - 2.0) was 3.88 (0.92, 16.35), p = 0.07. ROC analysis showed TBS was significantly associated with fractures (p < 0.05); however, FN BMD was superior. A model combining FN BMD, age, A1c, transplant, and TBS improved ROC compared to FN BMD + age (0.837 vs. 0.779, p = 0.031). CONCLUSIONS: TBS ≤ 1.2 may identify people with CF at high risk of fractures. A model combining FN BMD, age, A1c, transplant, and TBS was significantly associated with fractures compared to FN BMD + age. Future studies are needed to evaluate the prediction of fractures in people with CF using clinical and bone parameters.

Lowering the Toxicity of Cd to Theobroma cacao Using Soil Amendments Based on Commercial Charcoal and Lime.

Carbonaceous and calcareous materials are commonly used as amendments to decrease the Cd mobility in contaminated soils. This study evaluated the effect of amendments applied to cocoa seedlings in the greenhouse, considering the mobilization of soil cadmium toward the seedlings as the main response. The experimental conditions considered soil artificially contaminated with Cd at a concentration of 50 mg Cd kg-1 and applications of amendments in different treatments with the presence of charcoal dust and calcium carbonate. The charcoal was characterized by microscopy and by adsorption tests, and it proved to be a material with macropores, with a maximum capacity of 8.06 mg Cd g-1 and favorable kinetic behavior according to the adjustment of the data obtained to the pseudo-second-order model. The results also showed that the application of liming decreased the mobility of Cd toward the seedlings, with the liming combined with charcoal leading to the absence of Cd in the cocoa seedlings, considering a residual concentration of Cd in the soil of 35 mg Cd kg-1. The results, although limited to a small scale, demonstrated the possibility of applying low-cost and easy-to-handle amendments for the control of Cd in cocoa plantations.

Does the controlled ovarian stimulation increase the weight of women undergoing IVF treatment?

OBJECTIVE: Women undergoing assisted reproductive treatment are usually concerned about the side effects caused by high doses of gonadotropin. A common inquiry of patients is concerning the weight gain as a consequence. The aim of this study was to evaluate if controlled ovarian stimulation increase the weight of women undergoing IVF treatment. Study design This retrospective cohort study included 734 women undergoing IVF treatment between January 2017 and May 2018 and had body weight measured on the day of ovarian stimulation starting (basal-weight) and on the hCG trigger day (hCG-weight). The difference of hCG-weight and basal-weight was calculated and correlated to number of oocytes retrieved and ovarian stimulation protocol. For 358 women, two international validated questionnaires to evaluate the anxiety and binge eating were applied at the end of ovarian stimulation and also associated to the body weight gain. RESULTS: The basal-weight and hCG-weight were paired compared and demonstrate a statistically significant weight gain from basal to hCG-weight of a mean of 387.7 ± 720.4 g (p < 0.001). The weight gain had a positive correlation with the number of oocytes retrieved (Pearson correlation, r = 0.181; p < 0.001) but no correlation with the ovarian stimulation protocol. Regarding the questionnaires answered by patients, neither anxiety score (Pearson: r = -0,031; p = 0,561) nor binge eating score (Pearson: r = 0,069; p = 0,199) were correlated with weight gain from basal-weight to hCG- weight. However, patients who felt eating more during the treatment had a higher weight gain (p < 0.001) independently of the number of oocytes retrieved. CONCLUSIONS: The weight gain is possibly a result from edema and is clinically irrelevant despite of the statistical significance and will probably be resolved in some days after oocytes retrieval. A small "weight gain" was observed and associated to the number of oocytes retrieved regardless of protocol and medication used in the ovarian stimulation.

[Argentinean consensus guidelines on the identification and clinical care of secondary progressive multiple sclerosis]. / Consenso sobre la identificación y seguimiento de la esclerosis múltiple secundaria progresiva en Argentina.

INTRODUCTION: The identification, diagnosis, follow-up, and treatment of patients with secondary progressive multiple sclerosis (SPMS) show significant differences between health care professionals in Argentina. AIM: To provide consensus recommendations on the management of patients with SPMS in Argentina to optimize patient care. DEVELOPMENT: A panel of expert neurologists from Argentina dedicated to the diagnosis and care of multiple sclerosis patients gathered during 2019 and 2020 to carry out a consensus recommendation on the diagnosis and treatment of SPMS patients in Argentina. To achieve consensus, the methodology of 'formal consensus-RAND/UCLA method' was used. Recommendations were established based on published evidence and the expert opinion. Recommendations focused on how to define SPMS and how to follow SPMS patients. CONCLUSION: The recommendations of this consensus guidelines attempt to optimize the care of SPMS patients in Argentina.

TITLE: Consenso sobre la identificación y seguimiento de la esclerosis múltiple secundaria progresiva en Argentina.Introducción. Existen diferencias significativas en el diagnóstico, la identificación y el seguimiento de pacientes con esclerosis múltiple secundaria progresiva (EMSP) entre los profesionales de la salud a cargo de su tratamiento. Objetivo. Proveer recomendaciones sobre el tratamiento de los pacientes con EMSP en Argentina con el fin de optimizar su cuidado. Desarrollo. Un grupo de neurólogos expertos en esclerosis múltiple de Argentina elaboró un consenso para el tratamiento de pacientes con EMSP en la región mediante metodología de ronda de encuestas a distancia y reuniones presenciales. Se establecieron 33 recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el diagnóstico y el seguimiento de los pacientes con EMSP. Conclusión. Las recomendaciones establecidas en el presente consenso permitirían optimizar el cuidado y el seguimiento de los pacientes con EMSP en Argentina.

Disease activity impacts disability progression in primary progressive multiple sclerosis.

BACKGROUND: Although solid information on the natural history of primary progressive multiple sclerosis (PPMS) is available, evidence regarding impact of disease activity on PPMS progression remains controversial. OBJECTIVE: To describe the clinical characteristics, presence or absence of MRI activity, and natural history of a PPMS cohort from two referral centers in Argentina and assess whether clinical and/or radiological disease activity correlated with disability worsening. METHODS: Retrospective study conducted at two MS clinics in Buenos Aires, Argentina, through comparative analysis of patients with and without evidence of disease activity. RESULTS: Clinical and/or radiologic activity was presented in 56 (31%) of 178 patients. When stratified by age at onset, we found that for every 10 years of increase in age at onset, risk of reaching EDSS scores of 4 and 6 increased by 26% and 31%, respectively (EDSS 4: HR 1.26, CI 95%: 1.06-1.50; EDSS 6: HR 1.31, CI 95%: 1.06-1.62). Patients who presented clinical exacerbations reached EDSS scores of 6, 7 and 8 faster than those without associated exacerbations (p = 0.009, p = 0.016 and p = 0.001, respectively). Likewise, patients who presented gadolinium-enhancing lesions during the course of disease reached EDSS scores of 7 earlier (p = 0.002). CONCLUSION: Older age at onset and presence of clinical and/or radiological disease activity correlated with accelerated disability progression in this cohort of PPMS patients.

Critical applications of Mucor circinelloides within a biorefinery context.

The establishment of an efficient and feasible biorefinery model depends on, among other factors, particularly the selection of the most appropriate microorganism. Mucor circinelloides is a dimorphic fungus species able to produce a wide variety of hydrolytic enzymes, lipids prone to biodiesel production, carotenoids, ethanol, and biomass with significant nutritional value. M. circinelloides also has been selected as a model species for genetic modification by being the first filamentous oleaginous species to have its genome fully characterized, as well as being a species characterized as a potential bioremediation agent. Considering the potential of replacing several nonrenewable feedstocks is widely dependent on fossil fuels, the exploitation of microbial processes and products is a desirable solution for promoting a green and sustainable future. Here, we introduce and thoroughly describe the recent and critical applications of this remarkable fungus within the context of developing a fungal-based biorefinery.

Sustainable enzymatic approaches in a fungal lipid biorefinery based in sugarcane bagasse hydrolysate as carbon source.

Single cell oil (SCO) was produced from enzymatically hydrolysed sugarcane bagasse by Mucor circinelloides. The fungus was cultured in the hydrolysate medium rich in glucose and xylose being able to assimilate both sugars simultaneously, attaining satisfactory values of lipid accumulation (25 wt%). The main concepts addressed herein were the utilization of these lipids for the production of (i) ethyl esters of fuel grade, and (ii) concentrate of polyunsaturated fatty acids for nutraceutical applications. It was noticed that the fungal lipids also contained carotenoids and that the fungal biomass presented lipolytic activity. The concept of integrating an M. circinelloides-based biorefinery into the sugarcane energy matrix may, thus, present a relevant alternative for the production of high value-added products.

Keggin-structure heteropolyacid supported on alumina to be used in trans/esterification of high-acid feedstocks.

Heteropolyacids (HPA) with Keggin structures, such as H3PMo12O40 (H3PMo), have been described as efficient catalysts in trans/esterification reactions due to their tolerance to water and free fatty acids contents, with particularly well-suited characteristics of high proton mobility and stability. The versatile array of HPA is considerably increased when such catalysts are supported onto solid matrices. In this sense, Al2O3 was assessed as support for H3PMo to be used in trans/esterification reactions to produce biodiesel from high-acid feedstocks. The catalyst structure was characterized and applied on trans/esterification reaction of acid oils using ethanol as acyl acceptor. A face centered composite design was employed to conduct the experimental design and results analysis, taking macaw palm oil as study model. The process achieved an optimum level of 99.8% ester content and 4.1 mm2 s-1 viscosity under the following reaction conditions: 190 °C reaction temperature, 50 : 1 ethanol-to-oil molar ratio and 13.0% catalyst concentration. Other tested feedstocks (fungal single cell oil and residual frying oil) were also tested promoting satisfactory results, though the parameters were found to be slightly outside the limits set by the USA (ASTM D6715) standard. The H3PMo/Al2O3 catalyst presented good regeneration and can be reused for up to four reaction cycles and requires lower ethanol-to-oil ratio, temperature, and catalyst concentration in comparison with other data from the literature.

Brain volume loss and no evidence of disease activity over 3 years in multiple sclerosis patients under interferon beta 1a subcutaneous treatment.

The objective of our study was to evaluate the relationship of percentage of annualized brain volume loss (aBVL) and no evidence of disease activity (NEDA) in multiple sclerosis (MS) patients under interferon beta 1-a subcutaneous treatment (IFN-beta) during 3 years of follow up. Relapsing remitting MS (RRMS) patients, with less than three years from disease onset, expanded disability status scale (EDSS) ≤3 and in which IFN beta 1-a 44 mcg was indicated, were included. Demographic, clinical and structural parameters from the magnetic resonance (MR) during the 3 years of follow up were analyzed and compared between patients with and without NEDA (defined as the absence of: (a) three-month confirmed disability progression defined as an increase in EDSS score of 1.0; (b) confirmed relapses; and (c) new or enlarged T2 lesions and/or Gd+ lesions). A total of 87 patients, mean age 33 ±â€¯6 years were included. NEDA was reached by 39 patients at year 3. Percentage of aBVL from baseline to months 24 in NEDA patients was -1.1% vs. -1.54% in patients without NEDA (p < 0.001) and from baseline to month 36 it was -1.43% vs. -2.1% (p < 0.001) in patients with and without NEDA, respectively. At 3 years follow up, patients who received IFN beta 1a and were disease-free had lower percentage of aBVL compared to patients with disease activity.

[Pisa syndrome associated with codeine]. / Sindrome de Pisa asociado a codeina.

TITLE: Sindrome de Pisa asociado a codeina.

Síndrome de Pisa asociado a codeína / Pisa syndrome associated with codeine

No disponible

[Primary lymphoma of the anterior pituitary in an immunocompetent patient]. / Linfoma primario de adenohipofisis en una paciente inmunocompetente.

TITLE: Linfoma primario de adenohipofisis en una paciente inmunocompetente.

[Reversible posterior leukoencephalopathy syndrome with isolated involvement of the brainstem and spinal cord]. / Leucoencefalopatia posterior reversible de afectacion troncoencefalica y medular aislada.

TITLE: Leucoencefalopatia posterior reversible de afectacion troncoencefalica y medular aislada.

[Is endovenous thrombolysis safety and efficacy in ischemic stroke comparable between patients aged over and above 80 years? Experience from an Argentinean cohort]. / Es comparable la seguridad y eficacia del uso de tromboliticos en el ictus isquemico en mayores y menores de 80 años? Experiencia en una cohorte argentina.

INTRODUCTION: Enrollment of patients aged above 80 years in trials assessing endovenous thrombolysis (rt-PA) was scarce. The goal of this study is to compare safety and efficacy of endovenous rt-PA between patients aged above 80 and those below 80 years. PATIENTS AND METHODS: A cohort of patients who received rt-PA was prospectively followed. Length of hospital stay, bleeding incidence, in-hospital mortality and 90 days' clinical outcome was compared between patients aged above 80 and those below 80 years. RESULTS: Of 1996 patients admitted at our hospital with ischemic stroke between October 2005 and January 2016, 180 received rt-PA (9%). Mean age was 77 ± 10 years, being 55% of the women. Comparing patients aged above 80 with those below 80 years, in the latter the length of hospital stay was longer with a median length of 15 days (IQR: 6-19) vs 7 days (IQR: 4-12; p = 0.001) and 90 days' clinical outcome was worse (modified Rankin scale 0-1 of 24% vs 41%; p = 0.001). Admission ASPECTS score, bleeding incidence and in-hospital mortality showed no significant differences between both groups. Patients aged over 80 arrived to the hospital earlier (97 ± 34 vs 113 ± 45 min; p = 0.01), however door-to-needle time was longer. CONCLUSIONS: Endovenous thrombolysis in patients aged above 80 years was safe, although its efficacy in assuring a better clinical outcome was not as pronounced as in patients below 80 years.

TITLE: Es comparable la seguridad y eficacia del uso de tromboliticos en el ictus isquemico en mayores y menores de 80 años? Experiencia en una cohorte argentina.Introduccion. La inclusion de mayores de 80 años fue escasa en los estudios que evaluaron la terapia trombolitica. El objetivo de este estudio es comparar la seguridad y eficacia del uso de activador del plasminogeno tisular recombinante en pacientes mayores y menores de 80 años. Pacientes y metodos. Estudio prospectivo de pacientes que recibieron tratamiento trombolitico. Se comparo el tiempo de estancia, la incidencia de sangrado, la mortalidad hospitalaria y la evolucion a 90 dias en pacientes mayores y menores de 80 años. Resultados. De 1.996 pacientes con ictus ingresados entre octubre de 2005 y enero de 2016, 180 recibieron tratamiento trombolitico (9%). La edad media fue de 77 ± 10 años, con un 55% de mujeres. Cuando se compararon los menores y mayores de 80 años, en estos ultimos la estancia hospitalaria fue prolongada, con una mediana de 15 dias (rango intercuartilico: 6-19) frente a siete dias (rango intercuartilico: 4-12; p = 0,001), y la discapacidad a los tres meses fue mayor (escala de Rankin 0-1 del 24% frente al 41%; p = 0,001). La puntuacion ASPECTS de ingreso, la incidencia de sangrado y la mortalidad hospitalaria no mostraron diferencias entre mayores y menores de 80 años. Los pacientes mayores de 80 años tuvieron menor tiempo de demora para llegar al hospital (97 ± 34 frente a 113 ± 45 min; p = 0,01); sin embargo, el tiempo puerta-aguja fue superior en los mayores de 80 años. Conclusion. La terapia trombolitica en los mayores de 80 años fue segura, aunque el grado de beneficio para reducir la discapacidad resulto menor.

Brain structural changes in patients in the early stages of multiple sclerosis with depression.

Some studies suggest an inflammatory mechanism associated with the presence of depression in multiple sclerosis (MS); however, there is little data concerning these findings. The purpose of this study was to investigate the presence of brain structural changes in patients with MS and depression and to compare them with patients suffering from MS without depression and healthy controls. METHODS: A case-control study that included patients with relapsing-remitting MS (RRMS) defined by validated criteria, over 18 years of age, with less than three years from disease onset, EDSS ≤ 3, with no history of previous depression and under immunomodulatory treatment with interferon beta, if any. A control group paired by age and gender was also included. Patients were clinically assessed to determine the presence of depression. Demographic clinical and structural aspects of parameters from the scan, such as lesion volume, total brain volume (TBV), white matter volume (WMV), neocortical gray matter volume (NGMV), and fractional anisotropy (FA) were analyzed. RESULTS: Sixty-five individuals were enrolled: 20 healthy controls, 22 patients with MS without depression, and 23 patients with MS with depression. Patients with MS and depression showed a lower TBV (P = 0.01), NGMV (0.01) together with an increase in lesion burden in T2 (P < 0.01) but not in T1 (P = 0.09) and no differences in global FA among groups (P = 0.23) and in WMV (P = 0.12). CONCLUSION: Patients with RRMS and depression had a reduced total brain volume and a significantly increased lesion burden at T2 MR than patients with RRMS without depression.