Disability Progression Research Articles

Comorbid onset of cardiovascular diagnosis and long-term confirmed disability progression in multiple sclerosis: A 15-year follow-up study

BackgroundPeople with multiple sclerosis (pwMS) have greater prevalence of comorbid cardiovascular diseases (CVD) when compared to the general population despite similar frequency of CV risk factors. ObjectiveDetermine the impact of comorbid-onset of CVD diagnosis on long-term confirmed disability progression (CDP). Methods276 pwMS (29 clinically isolated syndrome, 130 relapsing-remitting and 117 progressive) were clinically followed an average of 14.9 years, with a mean of 14.4 clinical visits. Retrospective electronic medical records (EMR) review determined CVD diagnoses (hypertension, hyperlipidemia, diabetes, and heart disease) at baseline and over the follow-up. CDP was determined with ≥1.0 point Expanded Disability Status Scale (EDSS) increase from EDSS <5.5, or ≥ 0.5-point increase from ≥5.5, and was sustained on next clinical visit. ResultsA significantly shorter time to overall CDP was detected in 213 pwMS who had an existing (28 pwMS) or developed new onset (185 pwMS) of CVD, compared to 63 CVD-healthy pwMS over the follow-up (13.4 vs 15.9 years, Mantel-Cox p < 0.001), independent of baseline age and EDSS score. The CVD diagnosis preceded the CDP in 103 pwMS (55.7%), occurred after CDP in 71 pwMS (38.4%) and was concurrent in 11 pwMS (5.9%). Using mixed-effect models adjusted for significant age (F = 56.5, p < 0.001) and time effects (F = 67.8, p < 0.001), the CVD-onset diagnosis was associated with greater accrual of disability, as measured by longitudinal increase in EDSS score (F = 4.207, p = 0.04). Sex was not significant predictor of future disability in our cohort. ConclusionPwMS with an existing or new onset of comorbid CVD diagnosis showed accelerated disability worsening over long-term. There was no temporal relationship between the onset of CVD and CDP within the group that had CVD-onset diagnosis.

Safety and effectiveness of disease-modifying therapies after switching from natalizumab

Introduction: One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined. Objective: The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity. Methods: This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity. Results: Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001). Conclusion: Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.

Biologics or Janus Kinase Inhibitors in Rheumatoid Arthritis Patients Who are Insufficient Responders to Conventional Anti-Rheumatic Drugs.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis.

Impact of sex on clinical outcome in early Multiple Sclerosis

BackgroundPrevious evidence suggests sex differences in the clinical course of relapsing remitting multiple sclerosis (RRMS), but comprehensive early-stage prospective studies are lacking. We aim to quantify the impact of sex on clinical outcomes in early-stage RRMS. MethodsUtilizing prospective cohort data, we assessed the impact of biological sex on time-to-relapse, disability progression (Expanded Disability Status Scale [EDSS]), extremity function (Nine-Hole Peg Test, Timed-25-food walk test), cognition (Paced Auditory Serial Addition Test, Symbol Digit Modalities Test), quality-of-life (Hamburg Quality of Life Questionnaire in Multiple Sclerosis, Short-Form-36), fatigue (Fatigue Severity Scale, Fatigue Scale for Motor and Cognitive functions), and depression (Beck Depression Inventory-II) in clinically isolated syndrome (CIS) or RRMS patients. Inclusion was within 12 months of symptom onset. Linear, negative binomial, mixed, and Cox models estimated male vs. female effects at the four-year follow-up including baseline-to-follow-up course. ResultsWe included 149 patients (65.1 % female). Eighty-five completed four-year follow-up. No sex differences in time-to-relapse emerged (HR = 0.91;95 %CI = 0.53–1.58). Males had no increased risk of EDSS worsening (OR = 0.75;95 %CI = 0.21–2.35) compared to females. Similarly, minor/no sex differences emerged in other outcomes. ConclusionsFour years after first manifestation, neither disease activity (disability progression and relapse rate) nor patient-reported outcomes showed sex-related disparities in this early-MS-cohort. ClinicalTrials.gov Identifier: NCT01371071

Real-World Study of Serum Neurofilament Light Chain Levels in Ocrelizumab-Treated People with Relapsing Multiple Sclerosis.

Serum neurofilament light chain (sNfL) levels have been proposed as a biomarker of the clinical activity, disability progression, and response to treatment of people with multiple sclerosis (PwMS); however, questions remain about its implementation in clinical practice. Ocrelizumab (OCR) has proven effective in improving clinical and radiological outcomes and reducing sNfL levels. This real-life study followed the sNfL levels of 30 PwMS treated for 12 months with OCR and evaluated the usefulness of this biomarker for their short-term prognosis, considering expanded disability status scale (EDSS), annualized relapse rate (ARR), radiological activity, and NEDA-3 values. OCR reduced ARR in 83% of PwMS and radiological activity in 80%. EDSS was maintained, while NEDA-3 was achieved in 70% at 12 months. OCR produced an early reduction in sNfL levels (at 3 months). At baseline, greater MRI-evaluated radiological activity was associated with higher sNfL levels. sNfL levels over the first 12 months of treatment did not predict a suboptimal response or sustained control of the disease. Longer-term studies are needed to explore the predictive usefulness of sNfL levels in PwMS treated with high-efficacy drugs.

Autologous hematopoietic stem cell transplantation as a method of immune prevention of type 1 diabetes mellitus: possibilities and prospects

Type 1 diabetes mellitus (DM) is one of the most common autoimmune disease that is treated with lifelong insulin therapy. Non-target indicators of glycemic control, which are observed in 71% of patients, lead to the formation and progression of diabetes complications, early disability and mortality. In this regard, the search for new approaches to the treatment and prevention of type 1 DM seems to be relevant. Various methods of immunological prophylaxis for the development of type 1 DM have been studied, in particular, the use of monoclonal antibodies. Thus, in November 2022, teplizumab was approved to slow down the clinical progression of the stage of type 1 DM. The prospects for the use of new options for islet cell transplantation are being studied — in June 2023, an allogeneic donor β-cell transplant obtained from the pancreas of donors after death was approved. Another pathogenetically substantiated method for the prevention and treatment of autoimmune diseases is high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-HSCT). HDIT-HSCT demonstrated its effectiveness and cost-effectiveness in various clinical trials. This review provides up-to-date information on modern methods of immunological prophylaxis of type 1 DM.

Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.

In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. EVOLVE-MS-1-an open-label, 96-week, phase3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. ClinicalTrials.gov identifier NCT02634307.

Walking recovery after tethered cord release

After myelomeningocele (MMC) repair, a secondary tethered spinal cord occurs in almost all patients. The tethered spinal cord may result in progressive neurological deterioration and walking disability. This retrospective cohort study aimed to highlight the walking recovery one year after tethered cord release and its relation to the preoperative conus level. We reviewed the medical records at our university hospital from January 2014 to December 2022. The patients who underwent spinal cord untethering following lumbosacral MMC repair were included. We assessed the walking recovery one year after cord release using the modified Benzel scale. Thirty-seven patients met our selection criteria. There were 19 girls (51.4%) and 18 boys (48.6%). Their mean age at presentation was 8.6 years. The preoperative conus vertebral levels ranged between L4 and S3. One year after spinal cord release, 37.8% of the patients regained their walking ability. All the patients whose preoperative conus level was at S2 or S3 regained their walking ability. In contrast, all the patients with preoperative conus levels at L4 or L5 didn’t regain their ability to walk. One-third (33.3%) of patients whose conus was at the S1 level regained their walking ability one year after cord release. One year after tethered cord release, 37.8% of the patients regained their walking ability. We found that the walking recovery was statistically associated with the preoperative conus level. A multicenter prospective study is required to support the results of this study.

COMBAT-MS: A Population-Based Observational Cohort Study Addressing the Benefit-Risk Balance of Multiple Sclerosis Therapies Compared with Rituximab.

To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS). A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics. We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy. This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024.

Serum NfL and GFAP are weak predictors of long-term multiple sclerosis prognosis: A 6-year follow-up

BackgroundSerum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising biomarkers that might be associated with clinical and radiological markers of multiple sclerosis (MS) severity. However, it is not known whether they can accurately identify patients at risk of disability progression in the medium and long term. ObjectivesWe wanted to determine the association between sNfL and sGFAP, Expanded Disability Status Scale score changes, and conversion to secondary progressive MS (SPMS) in a cohort of 133 patients with relapsing remitting MS. MethodsBlood samples were collected at inclusion to measure SNfL and sGFAP by single molecule array and their prognostic value was assessed using a linear mixed model. ResultsIn this cohort, 37 patients (27.8 % of 133) experienced disability progression and 12 patients (9.0 %) converted to SPMS during the follow-up (mean follow-up duration: 6.4 years). Only sNfL (p = 0.03) was associated with conversion to SPMS, and neither SNfL nor sGFAP was associated with disability progression. ConclusionSerum NfL and GFAP do not seem to accurately predict MS outcome in the long term. More studies are needed to determine how serum biomarkers, associated with other clinical and MRI biomarkers, might be used to improve MS prognostication.

Healthcare resource use associated with tumor-induced osteomalacia: a literature review.

Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be non-specific and unrecognized, leading to long delays in diagnosis and treatment, which results in severe and progressive disability in patients with TIO. This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease. A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO. In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (standard deviation) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery. TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.

Framework for personalized prediction of treatment response in relapsing-remitting multiple sclerosis: a replication study in independent data

BackgroundIndividualizing and optimizing treatment of relapsing-remitting multiple sclerosis patients is a challenging problem, which would benefit from a clinically valid decision support. Stühler et al. presented black box models for this aim which were developed and internally evaluated in a German registry but lacked external validation.MethodsIn patients from the French OFSEP registry, we independently built and validated models predicting being free of relapse and free of confirmed disability progression (CDP), following the methodological roadmap and predictors reported by Stühler. Hierarchical Bayesian models were fit to predict the outcomes under 6 disease-modifying treatments given the individual disease course up to the moment of treatment change. Data was temporally split on 2017, and models were developed in patients treated earlier (n = 5517). Calibration curves, discrimination, mean squared error (MSE) and relative percentage of root MSE (RMSE%) were assessed by external validation of models in more-recent patients (n = 3768). Non-Bayesian fixed-effects GLMs were also applied and their outcomes were compared to these of the Bayesian ones. For both, we modelled the number of on-therapy relapses with a negative binomial distribution, and CDP occurrence with a binomial distribution.ResultsThe performance of our temporally-validated relapse model (MSE: 0.326, C-Index: 0.639) is potentially superior to that of Stühler’s (MSE: 0.784, C-index: 0.608). Calibration plots revealed miscalibration. Our CDP model (MSE: 0.072, C-Index: 0.777) was also better than its counterpart (MSE: 0.131, C-index: 0.554). Results from non-Bayesian fixed-effects GLM models were similar to the Bayesian ones.ConclusionsThe relapse and CDP models rebuilt and externally validated in independent data could compare and strengthen the credibility of the Stühler models. Their model-building strategy was replicable.

Altered Cerebrospinal Fluid Neurofilament Light Chain but Not Neurogranin Levels Are Associated with Response to Ocrelizumab Treatment in Relapsing-Remitting Multiple Sclerosis: A Preliminary Study

Introduction: Ocrelizumab is a CD20-targeting monoclonal antibody used for treatment of multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) neurofilament light (NFL) chain levels are reduced in MS patients under ocrelizumab treatment indicating a preventive action against neuro-axonal degeneration. Our aim, in this preliminary study, was to explore the impact of ocrelizumab treatment on synaptic integrity through assessment of neurogranin levels. Methods: Thirteen relapsing-remitting multiple sclerosis (RRMS) patients resistant to first-line immunomodulating agents were enrolled and followed up for 24 months under ocrelizumab treatment. Disease activity was monitored by periodic EDSS, MSSS, and cranial-spinal MRI assessments. No evidence of disease activity (NEDA)-3 was determined, and CSF levels of NFL (marker of neuro-axonal integrity) and neurogranin (marker of synaptic integrity) were measured by ELISA at baseline and 12-month ocrelizumab treatment. Results: Seven RRMS patients, who preserved NEDA-3 status during 24-month follow-up, showed ≥30% NFL level decrease, whereas 6 patients with stable/increased NFL levels displayed relapse, MRI lesion, or disability progression. Although most RRMS patients exhibited increased CSF levels of neurogranin under ocrelizumab treatment, patients with and without neurogranin level increase did not differ in terms of clinical features and NEDA-3 status. Baseline neurogranin levels negatively correlated with baseline EDSS scores. Conclusion: Our results confirm that NFL effectively monitors treatment response of RRMS patients under ocrelizumab treatment. Neurogranin does not appear to exhibit a similar benefit in screening of RRMS disease activity. Nevertheless, lower neurogranin levels are associated with increased disability in RRMS indicating a potential disease activity biomarker function.

Optical Coherence Tomography Advanced Parameters in Patients With Multiple Sclerosis: Ophthalmological and Neurological Assessments

PurposeTo evaluate ophthalmological, neurological, radiological, and laboratory data in patients with multiple sclerosis (MS) and to identify new ophthalmological factors that could be helpful as biomarkers of the disease, potentially leading to an earlier prediction of disease course and disability progression. DesignRetrospective, cross-sectional-study. MethodsBest-corrected visual acuity (BCVA), ophthalmological biomicroscopy of the anterior segment and fundus, structural optical coherence tomography (OCT) with retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), and OCT Angiography (OCTA) with vascular density (VD) were performed. The following clinical and neuro-radiological features were assessed: MS phenotype, disease duration, clinical severity, type of treatment, and T2-weighted lesion load plus T1-weighted Gd+-enhancing lesion number on the last brain and spinal cord MRI. ResultsOne hundred and six patients (212 eyes) were analyzed. Sixty-six of them (62.2 %) had MS and 40 (37.8%) were matched healthy controls (HCs). patients with MS showed lower RNFL, GCC, and VD in the radial peripapillary capillary plexus than controls in both eyes (p<0.05). By Performing a logistic regression with a distinct MS outcome for both eyes, we were able to demonstrate that the value that was most predictive of MS was the average GCC thickness (p=0.009). Regression analysis demonstrated that patients with a higher T2-weighted lesions showed a lower RNFL thickness value and reduced GCC and VD values than those with a low lesion load (p<0.01 and p<0.05, respectively). Similarly, relapsing MS patients showed lower RNFL values (p<0.05). ConclusionsSeveral OCT- and OCTA-optic nerve parameters could be useful prognostic biomarkers for the MS disease course in clinical practice. However, it is necessary to do additional research with larger sample sizes in order to validate these findings.

The efficacy of physeal bar resection with guided growth in the treatment of physeal arrest with angular limb deformity

Premature physeal arrest can cause progressive deformities and functional disabilities of the lower limbs. This study addressed the outcomes after physeal bar resection with or without guided growth (temporary hemiepiphysiodesis) for the treatment of angular limb deformities. We retrospectively analyzed 27 patients (mean 9 years; range, 3–12 years) who underwent physeal bar resection of the distal femur (15 patients), proximal tibia (3 patients), and distal tibia (9 patients) between 2002 and 2020. Fifteen patients underwent physeal bar resection only (Group A), and the other twelve underwent simultaneous guided growth (Group B). The correction angle (angle change between the preoperative and last follow-up values) was compared and analyzed. The overall mean correction angle was 2.9° (range, − 9 to 18.3°). A total of 12 (45%) patients had a > 5° angular deformity improvement (mean, 9.6°; range, 5–18.3°), 9 (33%) had a < 5° angular change; and 6 (22%) had a > 5° worsening of the angular deformity (mean, 6.7°; range, 5.2–9°). The correction angle in Group B (mean 7.6° ± 6.2) was significantly higher than that in Group A (mean − 0.77° ± 6.3) (P = 0.01). We found six (40%) and zero patients with a > 5° angular deformity increase in Groups A and B, respectively (P < 0.047). The group that underwent physeal bar resection with guided growth showed significantly higher correction angles than the group that underwent physeal bar resection alone. Additionally, none of the patients in the guided growth group experienced an increased angular deformity. Therefore, combining guided growth with physeal bar resection may lead to better outcomes in the treatment of growth arrest with angular deformities.

Listen, talk, understand. Interpersonal communication in a senior project

Studies carried out around the world on the structure of human populations clearly indicate that modern society is “aging”. Demographic indicators show the dynamism of this process, and thus the trend of population ageing will intensify in the coming years. That is why the activation and activity of older people is so important, this is a condition for functioning in society, playing assigned social roles, meeting bio-psychosocial needs and, above all, communicating. Its absence can cause progressive disability, social isolation, loneliness. That is why activating senior projects aimed at increasing independence and counteracting the risk of social marginalization are so important in the lives of seniors. The aim of the research was to establish the factors that determine proper communication with the elderly people. The study involved 86 seniors, participants of the senior project entitled: "Passion - a recipe for eternal youth". A qualitative strategy was used to collect and analyze the data using partially categorized interviews. In order to supplement the information obtained during the interviews, an analysis of the documents held by the senior project organizer was carried out. The presentation of the results of the study was divided into three areas related to communication: listening, talking, understanding. In order to build effective interpersonal communication with seniors, it is important to understand individual experiences, specific needs, expectations and concerns. For seniors in the process of interpersonal communication important elements are: empathy, patience, commitment, as well as understanding their shortcomings related to the aging process. The openness of expressing desires and needs by seniors is fostered by appreciation and listening. In their family environment, they notice a deficit in the area of active listening, as well as the infantilization of the message addressed to them. They emphasize the very important importance of communication in their lives, and identify its lack with loneliness and isolation. They believe that the activity they undertake in the auditory, motor and cognitive spheres affects the slowing down of the aging process, as well as helps in communication. Taking into account the results of the study, it should be proposed to increase the awareness of people working in senior projects on the specifics of interpersonal communication with seniors through the organization of educational trainings in this area, which should be reflected in legal regulations.

Predictive potential of serum and cerebrospinal fluid biomarkers for disease activity in treated multiple sclerosis patients

Background: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS).Methods: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile.Results: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35–5.4) and 2.67 (CI: 1.32–5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5–6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51–6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models.Discussion: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.

Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: NEDA-3 After Re-Baselining in the Phase3 EVOLVE-MS-1 Study.

Diroximel fumarate (DRF) and dimethyl fumarate (DMF) are orally administered fumarate disease-modifying therapies (DMTs) for multiple sclerosis (MS). The safety, tolerability, and exploratory efficacy of DRF were evaluated in the phase3 EVOLVE-MS-1 study. No Evidence of Disease Activity (NEDA-3) is a composite efficacy endpoint used in clinical trials for MS defined as no relapse, no 24-week confirmed disability progression (CDP), no new/newly enlarging T2 lesions, and no new gadolinium-enhancing lesions. As NEDA outcomes in studies may be confounded by initial disease activity, the objective of this analysis was to evaluate NEDA-3 in EVOLVE-MS-1 for newly enrolled patients and patients who were re-baselined after approximately 7weeks. Patients entered EVOLVE-MS-1 as either newly enrolled or having completed the 5-week phase3 EVOLVE-MS-2 study of DRF and DMF. Magnetic Resonance Imaging (MRI) was performed at baseline before each study (approx. 7weeks apart) and at weeks48 and 96 in EVOLVE-MS-1. Therefore, patients entering from EVOLVE-MS-2 were re-baselined after approximately 7weeks. NEDA-3 outcomes on DRF are reported for prior DRF, prior DMF, and de novo patient groups. Of 1057 patients in EVOLVE-MS-1, 239 (22.6%) had rolled over from receiving DRF in EVOLVE-MS-2 ("prior DRF"), 225 (21.3%) had rolled over from receiving DMF in EVOLVE-MS-2 ("prior DMF"), and 593 (56.1%) were newly enrolled ("de novo"). At week48, Kaplan-Meier estimates of NEDA-3 were 72.3% (prior DRF), 72.1% (prior DMF), and 62.1% (de novo); at week96, estimates were 50.2% (prior DRF), 48.2% (prior DMF), and 36.5% (de novo). In EVOLVE-MS-1, after re-baselining at approximately 7weeks, approximately half of DRF-treated patients achieved NEDA-3 at week96, compared with 36.5% of patients who were not re-baselined. Re-baselining may be useful for assessing efficacy of DMTs by mitigating the influence of disease activity prior to the onset of efficacy. NCT03093324 (EVOLVE-MS-2); NCT02634307 (EVOLVE-MS-1).

Treatment Options in Spinal Muscular Atrophy: A Pragmatic Approach for Clinicians.

Spinal muscular atrophy (SMA) is a rare neurodegenerative neuromuscular disorder with a wide phenotypic spectrum of severity. SMA was previously life limiting for patients with the most severe phenotype and resulted in progressive disability for those with less severe phenotypes. This has changed dramatically in the past few years with the approvals of three disease-modifying treatments. We review the evidence supporting the use of currently approved SMA treatments (nusinersen, onasemnogene abeparvovec, and risdiplam), focusing on mechanisms of action, side effect profiles, published clinical trial data, health economics, and pending questions. Whilst there is robust data from clinical trials of efficacy and side effect profile for individual drugs in select SMA populations, there are no comparative head-to-head clinical trials. This presents a challenge for clinicians who need to make recommendations on the best treatment option for an individual patient and we hope to provide a pragmatic approach for clinicians across each SMA profile based on current evidence.

Time-Dependent Deep Learning Prediction of Multiple Sclerosis Disability.

The majority of deep learning models in medical image analysis concentrate on single snapshot timepoint circumstances, such as the identification of current pathology on a given image or volume. This is often in contrast to the diagnostic methodology in radiology where presumed pathologic findings are correlated to prior studies and subsequent changes over time. For multiple sclerosis (MS), the current body of literature describes various forms of lesion segmentation with few studies analyzing disability progression over time. For the purpose of longitudinal time-dependent analysis, we propose a combinatorial analysis of a video vision transformer (ViViT) benchmarked against traditional recurrent neural network of Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM) architectures and a hybrid Vision Transformer-LSTM (ViT-LSTM) to predict long-term disability based upon the Extended Disability Severity Score (EDSS). The patient cohort was procured from a two-site institution with 703 patients' multisequence, contrast-enhanced MRIs of the cervical spine between the years 2002 and 2023. Following a competitive performance analysis, a VGG-16-based CNN-LSTM was compared to ViViT with an ablation analysis to determine time-dependency of the models. The VGG16-LSTM predicted trinary classification of EDSS score in 6years with 0.74 AUC versus the ViViT with 0.84 AUC (p-value < 0.001 per 5 × 2 cross-validation F-test) on an 80:20 hold-out testing split. However, the VGG16-LSTM outperformed ViViT when patients with only 2years of MRIs (n = 94) (0.75 AUC versus 0.72 AUC, respectively). Exact EDSS classification was investigated for both models using both classification and regression strategies but showed collectively worse performance. Our experimental results demonstrate the ability of time-dependent deep learning models to predict disability in MS using trinary stratification of disability, mimicking clinical practice. Further work includes external validation and subsequent observational clinical trials.