Integrated Management of Multiple Sclerosis Spasticity and Associated Symptoms Using the Spasticity-Plus Syndrome Concept: Results of a Structured Specialists’ Discussion Using the Workmat® Methodology

Esclerosi múltiple; Espasticitat; CannabinoidesMúltiple esclerosis; Espasticidad; CannabidiolMultiple sclerosis; Muscle spasticity; CannabidiolBackground: Multiple sclerosis (MS) treatment has radically improved over the last years; however, MS symptom management is still challenging. The novel Spasticity-Plus syndrome was conceptualized to frame several spasticity-related symptoms that can be addressed together with broad-spectrum medication, such as certain cannabinoid-based drugs. The aim of this project was to gain insight into Spanish neurologists' clinical experience on MS spasticity and associated symptoms, and to assess the acknowledgment and applicability of the Spasticity-Plus syndrome concept in patients with MS. Methods: Ten online meetings were conducted using the Workmat® methodology to allow structured discussions. Fifty-five Spanish neurologists, experts in MS management, completed and discussed a set of predefined exercises comprising MS symptom assessment and its management in clinical practice, MS symptoms clustering in clinical practice, and their perception of the Spasticity-Plus syndrome concept. This document presents the quantitative and qualitative results of these discussions. Results: The specialists considered that polytherapy is a common concern in MS and that simplifying the management of MS spasticity and associated manifestations could be useful. They generally agreed that MS spasticity should be diagnosed before moderate or severe forms appear. According to the neurologists' clinical experience, symptoms commonly associated with MS spasticity included spasms/cramps (100% of the specialists), pain (85%), bladder dysfunction (62%), bowel dysfunction (42%), sleep disorders (42%), and sexual dysfunction (40%). The multiple correspondence analysis revealed two main symptom clusters: spasticity-spasms/cramps-pain, and ataxia-instability-vertigo. Twelve out of 16 symptoms (75%) were scored >7 in a 0-10 QoL impact scale by the specialists, representing a moderate-high impact. The MS specialists considered that pain, spasticity, spasms/cramps, bladder dysfunction, and depression should be a treatment priority given their frequency and chance of therapeutic success. The neurologists agreed on the usefulness of the new Spasticity-Plus syndrome concept to manage spasticity and associated symptoms together, and their experience with treatments targeting the cannabinoid system was satisfactory. Conclusions: The applicability of the new concept of Spasticity-Plus in MS clinical practice seems possible and may lead to an integrated management of several MS symptoms, thus reducing the treatment burden of disease symptoms.The study was funded by an investigational grant from Almirall S

Amantadine and/or transcranial magnetic stimulation for fatigue associated with multiple sclerosis (FETEM): study protocol for a phase 3 randomised, double-blind, cross-over, controlled clinical trial

Introduction Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), and effective treatments are lacking. Amantadine is one of the most used treatments, although its efficacy is under debate. Transcranial magnetic stimulation (TMS) is a promising intervention that has shown positive effects in some preliminary investigations. We aim to investigate the effect of 6 weeks of amantadine and/or TMS in fatigue due to MS. Methods and analysis The study is a national, multicentre, phase 3, randomised, double-blind, cross-over, placebo-controlled and sham-controlled clinical trial. Adult patients with relapsing-remitting MS, Expanded Disability Status Scale score of 1.5–4.5 and Fatigue Severity Score>4 are eligible for the trial. Participants will be randomised to one of the sequences of the study. Each sequence consists of four periods of 6 weeks of treatment and three washout periods of 12–18 weeks. All patients will receive all the combinations of therapies. The primary outcome is the Modified Fatigue Impact Scale. The secondary outcomes are the Symbol Digit Modalities Test (cognition), Beck Depression Inventory-II (depressive symptoms) and Short-Survey 12 (quality of life). Safety and cost-effectiveness will also be evaluated. An exploratory substudy including MRI and blood biomarkers will be conducted. Ethics and dissemination The study is approved by the Ethics Committee of the Hospital Clinico San Carlos and the Spanish Agency of Medications and Medical Devices. All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences

Multiple sclerosis and bilingualism: some initial findings

It has been suggested that bilingualism is beneficial for executive control and could have positive long-term effects by delaying the onset of symptoms of degenerative diseases. This research investigates, for the first time, the impact of bilingualism on executive control (monitoring and inhibitory control) in individuals with Multiple Sclerosis (MS), a neurodegenerative disease which commonly causes deficiencies in the cognitive system. Bilingual and monolingual adults, with and without an MS diagnosis, performed a flanker task with two degrees of monitoring demands (high monitoring vs. low monitoring). Results showed that bilingual MS patients had inhibitory control and monitoring abilities that were similar to healthy bilingual controls. In contrast, monolingual MS patients showed similar inhibitory control but significantly worse monitoring abilities compared to monolingual healthy controls. We propose that the similar behaviour between bilingual groups suggests that bilingualism might counteract cognitive deficits related to MS, especially with respect to monitoring. The high monitoring cost observed in monolingual patients seems related to underlying deficits in monitoring and possibly switching, executive control abilities commonly impaired in MS patients from early stages. Our findings provide some preliminary evidence for the cognitive reserve hypothesis in bilingual MS patients

XIII Reunión Post-ECTRIMS : revisión de las novedades presentadas en el Congreso ECTRIMS 2020 (I)

Introducción: Desde hace más de una década, tras el congreso ECTRIMS, se celebra en España la reunión Post-ECTRIMS, donde neurólogos expertos en esclerosis múltiple (EM) de toda España se reúnen para revisar las principales novedades presentadas en el ECTRIMS (en esta ocasión, celebrado junto con el ACTRIMS). Objetivo: En el presente artículo, publicado en dos partes, se resumen las ponencias que tuvieron lugar en la reunión Post-ECTRIMS, celebrada los días 16 y 17 de octubre de 2020 de forma virtual. Desarrollo. En esta primera parte se incluyen los últimos resultados acerca del impacto del ambiente y el estilo de vida sobre el riesgo de EM y su curso clínico, y el papel de la epigenética y los factores genéticos sobre estos procesos. Se discuten los hallazgos en investigación preclínica y clínica sobre los subtipos de linfocitos identificados, y la implicación de los folículos linfoides y la afectación meníngea en la enfermedad. Los cambios en la estructura cerebral se abordan a nivel microscópico y macroscópico, incluyendo resultados de técnicas de imagen de alta resolución. También se presentan los últimos avances sobre biomarcadores para el diagnóstico y el pronóstico de la EM, y sobre la afectación del microbioma en estos pacientes. Por último, se esbozan los resultados de registros de pacientes sobre el impacto de la COVID-19 en los pacientes con EM. Conclusiones: Ha habido nuevos datos sobre factores de riesgo de la EM, impacto de la EM a nivel celular y estructural, papel del microbioma en la enfermedad, biomarcadores y la relación entre COVID-19 y EM.Introduction. For more than a decade, following the ECTRIMS Congress, the Post-ECTRIMS Meeting has been held in Spain, where neurologists with expertise in multiple sclerosis (MS) from all over the country meet to review the most relevant latest developments presented at the ECTRIMS congress (on this occasion held together with ACTRIMS). Aim. This article, published in two parts, summarises the presentations that took place at the Post-ECTRIMS Meeting, held online on 16 and 17 October 2020. Development. This first part includes the latest results regarding the impact of the environment and lifestyle on risk of MS and its clinical course, and the role of epigenetics and genetic factors on these processes. Findings from preclinical and clinical research on the lymphocyte subtypes identified and the involvement of lymphoid follicles and meningeal involvement in the disease are discussed. Changes in brain structure are addressed at the microscopic and macroscopic levels, including results from high-resolution imaging techniques. The latest advances on biomarkers for the diagnosis and prognosis of MS, and on the involvement of the microbiome in these patients are also reported. Finally, results from patient registries on the impact of COVID-19 in MS patients are outlined. Conclusions. There have been new data on MS risk factors, the impact of MS at the cellular and structural level, the role of the microbiome in the disease, biomarkers, and the relationship between COVID-19 and MS

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Carvacrol-loaded chitosan nanoparticles maintain quality of fresh-cut carrots

The effects of carvacrol-loaded chitosan-tripolyphosphate nanoparticles (Np-EO) on the physicochemical, sensory and microbial quality of fresh-cut (FC) carrot slices stored up to 13 days at 5 °C were studied. Np-EO was compared to samples treated by NaOCl (100 mg L− 1), Np (chitosan-tripolyphosphate nanoparticles without carvacrol) or individual chitosan (0.5%) and carvacrol (0.5%) solutions. Np-EO achieved the best sensory scores also avoiding carvacrol-related off-flavours found with the carvacrol solution. Furthermore, whitening of FC carrot slices was highly reduced in Np-EO samples. Np-EO reduced microbial levels in FC carrot slices by 0.6–3.0 log units on processing day compared to untreated (control) samples. Np-EO allowed to reduce the microbial growth in FC carrot slices during the first 9 days of storage similarly to carvacrol solution. Furthermore, Np-EO highly controlled microbial loads at the end of storage showing 2.3 (lactic acid bacteria), 6.1 (yeasts and moulds) and 5.1–5.4 (mesophiles, psychrophiles and Enterobacteriaceae) lower log CFU g− 1 units compared to control samples. Conclusively, Np-EO highly maintained microbial (2–6 lower log CFU g− 1 units compared to control), sensory (up to 2.5 better scores than control) and physicochemical quality of FC carrot slices than control for 13 days at 5 °C. Industrial relevance Natural essential oils industrially extracted from plants are potential alternative substances with high antimicrobial properties when tested in vitro. However, their microbicidal efficacy is greatly reduced due to their low solubility in washing solutions of fresh-cut products. Accordingly, chitosan-tripolyphosphate nanoencapsulation of essential oils such as carvacrol is a great opportunity to increase the antimicrobial properties of carvacrol to be used in fresh-cut fruit and vegetables alternatively to conventional NaOCl sanitation

Microbial inactivations with hydrolysed lactoferrin and other natural antimicrobials in fresh-cut fennel

NNatural antimicrobials (nisin, lactoferrin, thymol and citrus extract) were studied as sustainable alternatives to conventionally used NaOCl in fresh-cut (FC) fennel. Enterobacteriaceae was the most sensitive microbial group to studied sanitizers according to δ values, while psychrophiles were the most resistant. Based on inactivation modelling and sensory scores, nisin (N-250; 0.250 g L−1), lactoferrin (L-50; 50 g L−1), together with hydrolysed L-50 (LFH), were selected and studied comparing to water-washed (CTRL) and NaOCl (150 mg NaOCl L−1) on FC fennel. LFH achieved the highest psychrophilic reduction of 2.5 log units. Although NaOCl achieved the highest mesophilic, Enterobacteriaceae, lactobacilli and yeasts and moulds reductions of 1.7, 1.0, <1.7 and 1.6, respectively, N-250 still achieved 0.50–1.0 log unit reductions compared to CTRL. Conclusively, LFH and N-250 are natural antimicrobial treatments with good microbial inactivation rates which may be a good alternative to conventional NaOCl used by the FC industr

Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer.Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin.Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo.Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer

Presentation_1_Practical tool to identify Spasticity-Plus Syndrome amongst patients with multiple sclerosis. Algorithm development based on a conjoint analysis.PDF

IntroductionThe Spasticity-Plus Syndrome (SPS) in multiple sclerosis (MS) refers to a combination of spasticity and other signs/symptoms such as spasms, cramps, bladder dysfunction, tremor, sleep disorder, pain, and fatigue. The main purpose is to develop a user-friendly tool that could help neurologists to detect SPS in MS patients as soon as possible.MethodsA survey research based on a conjoint analysis approach was used. An orthogonal factorial design was employed to form 12 patient profiles combining, at random, the eight principal SPS signs/symptoms. Expert neurologists evaluated in a survey and a logistic regression model determined the weight of each SPS sign/symptom, classifying profiles as SPS or not.Results72 neurologists participated in the survey answering the conjoint exercise. Logistic regression results of the survey showed the relative contribution of each sign/symptom to the classification as SPS. Spasticity was the most influential sign, followed by spasms, tremor, cramps, and bladder dysfunction. The goodness of fit of the model was appropriate (AUC = 0.816). Concordance between the experts’ evaluation vs. model estimation showed strong Pearson’s (r = 0.936) and Spearman’s (r = 0.893) correlation coefficients. The application of the algorithm provides with a probability of showing SPS and the following ranges are proposed to interpret the results: high (> 60%), moderate (30–60%), or low (DiscussionThis study offers an algorithmic tool to help healthcare professionals to identify SPS in MS patients. The use of this tool could simplify the management of SPS, reducing side effects related with polypharmacotherapy.</p