Utilidad de las medidas de atrofia cerebral en el diagnóstico y seguimiento de la esclerosis múltiple

La esclerosis múltiple (EM) es una enfermedad inflamatoria desmielinizante del sistema nervioso central. Su evolución es muy variable entre individuos, como también lo es la respuesta de éstos al tratamiento. Las medidas clínicas de actividad son solo parcialmente útiles para predecir los cambios en la evolución de la enfermedad. Además, la resonancia magnética (RM), aunque altamente sensible para detectar lesiones, presenta solo una moderada correlación con la evolución de la discapacidad. El daño neuroaxonal sobre las lesiones como en el tejido cerebral aparentemente normal es probablemente la causa subyacente de discapacidad permanente. Las medidas de atrofia cerebral mediante RM reflejan la pérdida tisular y es posible obtenerlas actualmente mediante programas informáticos de procesamiento de imagen. No obstante, el papel de la atrofia como biomarcador pronóstico en EM es poco conocido, por lo que se planteó investigar su valor en situaciones de práctica clínica habitual, como son la predicción del riesgo de conversión a EM clínicamente definida (EMCD) tras un síndrome clínico aislado (SCA) y la predicción de progresión de la discapacidad a pesar de iniciar terapia modificadora de la evolución de la enfermedad (TME). Para ello, se analizaron los exámenes de RM de dos cohortes prospectivas: 1)cohorte SCA, compuesta de 176 pacientes con un SCA, en los que se realizó un examen de RM convencional a los 3 meses del inicio de los síntomas y al año y que fueron seguidos un mínimo de 2 años; 2)cohorte TME, compuesta de 105 pacientes con EMCD que iniciaron TME con interferón β (IFNβ), en los que se realizó un examen de RM convencional previamente al inicio de IFNβ y al año, y que fueron seguidos ≥2 años y hasta completar 4 años. Los análisis volumétricos se realizaron mediante los programas SIENA (Structural Imaging Evaluation, using Normalization, of Atrophy) para el cálculo del porcentaje de cambio del volumen cerebral (PCVC) y SPM (Statistical Parametric Mapping) para el cálculo de los porcentajes de cambio del volumen de sustancia gris (%cVSG) y blanca (%cVSB). Se investigó la relación entre las variables de volumetría cerebral y el curso clínico, y se encontraron valores de corte en los cambios de volumen cerebral de predicción de un peor pronóstico clínico. En la cohorte SCA se determinó la relación con la conversión a EMCD, y en la cohorte TME la relación con la progresión de la discapacidad, mediante análisis de supervivencia de Kaplan-Meier, y mediante análisis multivariante de regresión de Cox, ajustando por variables demográficas, clínicas y de RM. En términos generales, en ambas cohortes, un mayor grado de atrofia cerebral global medida con PCVC se relacionó con un peor pronóstico clínico. Los pacientes con SCA que desarrollaron EMCD tuvieron mayores descensos del PCVC (-0,65% frente a +0,059%; p 0.001). Además, los descensos del PCVC mayores a -0,817% predijeron de forma independiente una conversión a EMCD más precoz. Los cambios observados en los pacientes con SCA que desarrollaron EMCD se debieron a cambios en la sustancia gris, pero no en la sustancia blanca. Los pacientes con EM tratados con IFNβ que desarrollaron progresión clínica tras 4 años de seguimiento tuvieron mayores descensos en PCVC y en el %cVSB. Los descensos superiores a -0,86% de PCVC o descensos superiores a -2,49% de %cVSB se relacionaron con una probabilidad de ≃4 veces más de desarrollar progresión clínica tras el inicio de IFNβ. En resumen, los resultados indican que los cambios del volumen cerebral a tan corto plazo como un año son predictores de la evolución clínica posterior, tanto en pacientes al inicio de la enfermedad como en aquellos que acaban de iniciar terapia con IFNβ.Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Its evolution varies widely among individuals, and so is their response to treatment. Measures of MS clinical activity are only partially useful to predict changes in the evolution of the disease. On the other hand, magnetic resonance imaging (MRI), although highly sensitive to detect lesions, only has a moderate correlation with the evolution of disability. The axonal damage in both lesions and normal-appearing white matter is probably the underlying cause of permanent disability. The measures of brain atrophy by MRI reflect tissue loss and it is possible to obtain them nowadays, using softwares for image processing. However, there is little information on the clinical relevance of atrophy as a prognostic biomarker in MS, so we set out to investigate whether the measurement of brain atrophy can be useful in routine clinical practice situations, such as predicting the risk of conversion to clinically definite MS (CDMS) after a clinically isolated syndrome (CIS) and the prediction of disability progression after starting disease-modifying drugs (DMD). For this purpose, the images from the MRI scans of two prospectively followed cohorts of patients were analyzed: 1) CIS cohort, composed of 176 patients with CIS, in which conventional MRI scans were performed at 3 months of the onset of symptoms and one year after, and that were followed up at least 2 years; 2) DMD cohort, composed of 105 CDMS patients who started their first immunomodulatory therapy with interferon β (IFNβ), in which conventional MRI scans were performed prior to starting IFNβ therapy and one year after, and that were followed up a minimum of 2 years and up to 4 years. Volumetric analyses were performed using SIENA (Structural Imaging Evaluation, using Normalization, of Atrophy) software for determining the percentage brain volume change (PBVC), and SPM (Statistical Parametric Mapping) software for calculating the percentages of grey and white matter volume changes. The relationship between brain volume variables and the disease clinical course was investigated and appropriate methodologies were used to find cutoff values in brain volume changes for the identification of patients at higher or lower risks of worse clinical outcomes. In particular, in the CIS cohort the relation of brain volume change with the development of CDMS, and in the DMD cohort the relation with the progression of disability were determined by Kaplan-Meier survival curves analyses, and by Cox proportional hazards multivariate regression analyses, adjusting for demographic, clinical and MRI parameters. Overall, in both cohorts a greater degree of cerebral atrophy as measured with PBVC was associated to a worse prognosis. CIS patients who developed a second relapse had greater declines in PBVC (-0.65% vs. +0.059%; p 0.001). Moreover, declines of PBVC greater than -0.817% were independent predictors of an earlier conversion to CDMS. The volume decreases observed in CIS patients who developed MS were due to changes in the grey matter, whereas no significant changes were detected in the white matter. MS patients treated with IFNβ who developed clinical progression after 4 years of follow-up had greater decreases in PBVC and in the percentage of white matter change (PWMC). Declines beyond -0.86% in PBVC or beyond -2.49% in PWMC increased up to 4 times the risk of developing clinical progression after the beginning of IFNβ therapy. In summary, these results indicate that changes in brain volume in such a short period as one year are predictive of the posterior clinical course, not only at disease onset, but also in patients starting treatment with IFNβ

Associations of serum phthalate metabolites with thyroid hormones in GraMo cohort, Southern Spain

These results would not have been achieved without the selfless collaboration of the staff from Santa Ana and San Cecilio Hospitals and the participants who took part in the study. Dr. JP Arrebola is under contract within the Ramon y Cajal Program (RYC-2016-20155, Ministerio de Economia, Industria y Competitividad, Spain) and Dr. C Donat-Vargas is under contract within the Atraccion de Talento (from the community of Madrid, Spain) . This study was supported by research grants from Instituto de Salud Carlos III (PI20/01568, PI16/01858) .The general population is continuously exposed to phthalates via various consumer products. Epidemiological research relating phthalate exposure to thyroid function during non-developmental periods is limited. This study aimed to investigate the associations between specific serum phthalate metabolites and indicators of thyroid function in adults. We measured 10 serum phthalate metabolites and thyroid hormones - total triiodothymnine (TT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) - in a subsample of 207 adults from the GraMo cohort. This subsample was made up of men and women (in equal proportions) of middle age (49 +/- 17 years) and from Southern Spain (province of Granada). Data on age, sex, body mass index, residence area, tobacco use, alcohol consumption and attained education were obtained from a questionnaire. Phthalate metabolites were log-transformed and categorized into tertiles. Cross-sectional associations of each metabolite with thyroid hormones were analyzed using multivariable-adjusted linear regression models. The mixture effect of metabolite phthalates was assessed using weighted quantile sum regression. After multivariable-adjustment, the following phthalate metabolites were significantly associated with TT3 in a dose-response manner: MMP (beta = 0.90: 95% confidence interval 0.68,1.12), MEP (beta = 0.67: 0.44, 0.90), MiBP (beta = 0.49: 0.21, 0.77), MiDP (beta = 0.27: 0.03, 0.52), MBzP (beta = 0.51: 0.28, 0.73), MEHP (beta = -0.59: -0.82, -0.35) and MiNP (beta = -0.43: -0.71, -0.14), when comparing highest vs. lowest exposed. The sum of all metabolites was also linked to FT4 levels. No significant associations were observed for TSH except for MiNP. Although phthalate metabolites with different molecular weight showed opposite associations, overall metabolite concentrations seem to associate with increased TT3 and FT4 serum levels. The cross-sectional nature of this analysis limits causal inference.Ramon y Cajal Program (Ministerio de Economia, Industria y Competitividad, Spain) RYC-2016-20155Instituto de Salud Carlos III European Commission PI20/01568 PI16/0185

Dense strontium hexaferrite-based permanent magnet composites assisted by cold sintering process

[EN] The use of rare-earth-based permanent magnets is one of the critical points for the development of the current technology. On the one hand, industry of the rare-earths is highly polluting due to the negative environmental impact of their extraction and, on the other hand, the sector is potentially dependent on China. Therefore, investigation is required both in the development of rare-earth-free permanent magnets and in sintering processes that enable their greener fabrication with attractive magnetic properties at a more competitive price. This work presents the use of a cold sintering process (CSP) followed by a post-annealing at 1100 °C as a new way to sinter composite permanent magnets based on strontium ferrite (SFO). Composites that incorporate a percentage ≤ 10% of an additional magnetic phase have been prepared and the morphological, structural and magnetic properties have been evaluated after each stage of the process. CSP induces a phase transformation of SFO in the composites, which is partially recovered by the post-thermal treatment improving the relative density to 92% and the magnetic response of the final magnets with a coercivity of up to 3.0 kOe. Control of the magnetic properties is possible through the composition and the grain size in the sintered magnets. These attractive results show the potential of the sintering approach as an alternative to develop modern rare-earth-free composite permanent magnets.This work has been supported by the Ministerio Español de Ciencia e Innovación (MICINN), Spain, through the projects MAT2017-86540-C4-1-R and RTI2018-095303-A-C52, and by the European Commission through Project H2020 No. 720853 (Amphibian). C.G.-M. and A.Q. acknowledge financial support from MICINN through the “Juan de la Cierva” program (FJC2018-035532-I) and the “Ramón y Cajal” contract (RYC-2017-23320). S. R.-G. gratefully acknowledges the financial support of the Alexander von Humboldt foundation, Germany. A.S. acknowledges the financialsupport from the Comunidad de Madrid, Spain, for an “Atracción de Talento Investigador” contract (No. 2017-t2/IND5395)

Phylogeny and phylogeography of a recent HIV-1 subtype F outbreak among men who have sex with men in Spain deriving from a cluster with a wide geographic circulation in Western Europe

This work received support from the Dirección General de Farmacia, Ministerio de Sanidad, Servicios Sociales e Igualdad, Government of Spain, grant EC11-272; European Network of Excellence EUROPRISE (Rational Design of HIV Vaccines and Microbicides), grant LSHP-CT-2006-037611; European Research Infrastructures for Poverty Related Diseases (EURIPRED). Seventh Framework Programme: FP7-Capacities-infrastructures-2012-1, grant agreement 312661; Instituto de Salud Carlos III, Subdirección General de Evaluación, and Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I + D + I, through project RD12/0017/0026; Consellería de Sanidade, Government of Galicia, Spain (MVI 1291/08); and the Osakidetza-Servicio Vasco de Salud, Basque Country, Spain (MVI-1255-08). Marcos Pérez-Losada was supported by a DC D-CFAR Research Award from the District of Columbia Developmental Center for AIDS Research (P30AI087714) and by an University Facilitating Fund award from George Washington University. Aurora Fernández-García is supported by CIBER in Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain.We recently reported the rapid expansion of an HIV-1 subtype F cluster among men who have sex with men (MSM) in the region of Galicia, Northwest Spain. Here we update this outbreak, analyze near full-length genomes, determine phylogenetic relationships, and estimate its origin. For this study, we used sequences of HIV-1 protease-reverse transcriptase and env V3 region, and for 17 samples, near full-length genome sequences were obtained. Phylogenetic analyses were performed via maximum likelihood. Locations and times of most recent common ancestors were estimated using Bayesian inference. Among samples analyzed by us, 100 HIV-1 F1 subsubtype infections of monophyletic origin were diagnosed in Spain, including 88 in Galicia and 12 in four other regions. Most viruses (n = 90) grouped in a subcluster (Galician subcluster), while 7 from Valladolid (Central Spain) grouped in another subcluster. At least 94 individuals were sexually-infected males and at least 71 were MSM. Seventeen near full-length genomes were uniformly of F1 subsubtype. Through similarity searches and phylogenetic analyses, we identified 18 viruses from four other Western European countries [Switzerland (n = 8), Belgium (n = 5), France (n = 3), and United Kingdom (n = 2)] and one from Brazil, from samples collected in 2005?2011, which branched within the subtype F cluster, outside of both Spanish subclusters, most of them corresponding to recently infected individuals. The most probable geographic origin and age of the Galician subcluster was Ferrol, Northwest Galicia, around 2007, while the Western European cluster probably emerged in Switzerland around 2002. In conclusion, a recently expanded HIV-1 subtype F cluster, the largest non-subtype B cluster reported in Western Europe, continues to spread among MSM in Spain; this cluster is part of a larger cluster with a wide geographic circulation in diverse Western European countries.Publisher PDFPeer reviewe

Quantifying the patient´s perspective in neuromyelitis optica spectrum disorder: Psychometric properties of the SymptoMScreen questionnaire

Background: The assessment of self-reported outcomes in neuromyelitis optica spectrum disorder (NMOSD) is limited by the lack of validated disease-specific measures. The SymptoMScreen (SyMS) is a patient-reported questionnaire for measuring symptom severity in different domains affected by multiple sclerosis (MS), but has not been thoroughly evaluated in NMOSD. The aim of this study was to assess the psychometric properties of the SyMS in a sample of patients with NMOSD. Methods: A non-interventional, cross-sectional study in adult subjects with NMOSD (Wingerchuk 2015 criteria) was conducted at 13 neuroimmunology clinics applying the SyMS. A non-parametric item response theory procedure, Mokken analysis, was performed to assess the underlying dimensional structure and scalability of items and overall questionnaire. All analyses were performed with R (v4.0.3) using the mokken library. Results: A total of 70 patients were studied (mean age: 47.5 ± 15 years, 80% female, mean Expanded Disability Status Scale score: 3.0 [interquartile range 1.5, 4.5]). Symptom severity was low (median SyMS score: 19.0 [interquartile range 10.0, 32.0]). The SyMS showed a robust internal reliability (Cronbach's alpha: 0.90 [95% confidence interval 0.86, 0.93]) and behaved as a unidimensional scale with all items showing scalability coefficients > 0.30. The overall SyMS scalability was 0.45 conforming to a medium scale according to Mokken's criteria. Fatigue and body pain were the domains with the highest scalability coefficients. The SyMS was associated with disability (rho: 0.586), and physical and psychological quality of life (rho: 0.856 and 0.696, respectively). Conclusions: The SyMS shows appropriate psychometric characteristics and may constitute a valuable and easy-to-implement option to measure symptom severity in patients with NMOSD

Perception of Stigma in Patients with Neuromyelitis Optica Spectrum Disorder

Background: Perception of stigma was associated with low self-esteem, psychological problems, and decreased health-seeking behavior among patients with different neurological disorders. The purpose of this study was to assess stigmatization and its impact in patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: A non-interventional study was conducted at thirteen neuroimmunology clinics in Spain. Patients with a diagnosis of NMOSD (2015 Wingerchuk criteria) were included. The 8-item Stigma Scale for Chronic Illness (SSCI-8), the Expanded Disability Status Scale (EDSS), the 29-item Multiple Sclerosis Impact Scale (MSIS-29), the Beck Depression Inventory-Fast Screen (BDI-FS), the MOS Pain Effects Scale (MOS-PES) and the Fatigue Impact Scale for Daily Use (D-FIS) were used to assess the perception of stigma, disability, quality of life, mood, pain, and fatigue, respectively. Associations between outcome measures were analyzed using Spearman's rank correlation. Results: Seventy-one patients were studied (mean age: 47.4 years ± 14.9, 81.7% female, mean time since disease onset: 9.9 years ± 8.1). The median EDSS score was 3.0 (interquartile range 1.5, 4.5). Stigma prevalence was 61.4% (n=43). Thirty-one patients (43.6%) had depression. The SSCI-8 score showed a significant correlation with both physical (rho=0.576, p<0.0001) and psychological (rho=0.608, p<0.0001) MSIS-29 scales scores, EDSS score (rho=0.349, p=0.0033), BDI-FS score (rho= 0.613, p<0.0001), MOS-PES score (rho= 0.457, p<0.0001), and D-FIS score (rho=0.556, p<0.0001). Conclusion: Stigma is a common phenomenon affecting over 6 out of 10 patients with NMOSD. Understanding stigma may be useful to develop educational strategies improving NMOSD knowledge

Cognitive Performance and Health-Related Quality of Life in Patients with Neuromyelitis Optica Spectrum Disorder

Background: The frequency of cognitive impairment (CI) reported in neuromyelitis optica spectrum disorder (NMOSD) is highly variable, and its relationship with demographic and clinical characteristics is poorly understood. We aimed to describe the cognitive profile of NMOSD patients, and to analyse the cognitive differences according to their serostatus; furthermore, we aimed to assess the relationship between cognition, demographic and clinical characteristics, and other aspects linked to health-related quality of life (HRQoL). Methods: This cross-sectional study included 41 patients (median age, 44 years; 85% women) from 13 Spanish centres. Demographic and clinical characteristics were collected along with a cognitive z-score (Rao's Battery) and HRQoL patient-centred measures, and their relationship was explored using linear regression. We used the Akaike information criterion to model which characteristics were associated with cognition. Results: Fourteen patients (34%) had CI, and the most affected cognitive domain was visual memory. Cognition was similar in AQP4-IgG-positive and -negative patients. Gender, mood, fatigue, satisfaction with life, and perception of stigma were associated with cognitive performance (adjusted R-2 = 0.396, p < 0.001). Conclusions: The results highlight the presence of CI and its impact on HRQoL in NMOSD patients. Cognitive and psychological assessments may be crucial to achieve a holistic approach in patient care

Melanopsin+RGCs Are fully Resistant to NMDA-Induced Excitotoxicity

We studied short- and long-term effects of intravitreal injection of N-methyl-d-aspartate (NMDA) on melanopsin-containing (m+) and non-melanopsin-containing (Brn3a+) retinal ganglion cells (RGCs). In adult SD-rats, the left eye received a single intravitreal injection of 5µL of 100nM NMDA. At 3 and 15 months, retinal thickness was measured in vivo using Spectral Domain-Optical Coherence Tomography (SD-OCT). Ex vivo analyses were done at 3, 7, or 14 days or 15 months after damage. Whole-mounted retinas were immunolabelled for brain-specific homeobox/POU domain protein 3A (Brn3a) and melanopsin (m), the total number of Brn3a+RGCs and m+RGCs were quantified, and their topography represented. In control retinas, the mean total numbers of Brn3a+RGCs and m+RGCs were 78,903 ± 3572 and 2358 ± 144 (mean ± SD; n = 10), respectively. In the NMDA injected retinas, Brn3a+RGCs numbers diminished to 49%, 28%, 24%, and 19%, at 3, 7, 14 days, and 15 months, respectively. There was no further loss between 7 days and 15 months. The number of immunoidentified m+RGCs decreased significantly at 3 days, recovered between 3 and 7 days, and were back to normal thereafter. OCT measurements revealed a significant thinning of the left retinas at 3 and 15 months. Intravitreal injections of NMDA induced within a week a rapid loss of 72% of Brn3a+RGCs, a transient downregulation of melanopsin expression (but not m+RGC death), and a thinning of the inner retinal layers.This study was supported by the Fundación Séneca, Agencia de Ciencia y Tecnología Región de Murcia (19881/GERM/15), and the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional “una manera de hacer Europa” (SAF2015-67643-P, PI16/00380, RD16/0008/0026 and RD16/0008/0016)

Characteristics of patients with type 2 diabetes mellitus newly treated with GLP-1 receptor agonists (CHADIG Study): a cross-sectional multicentre study in Spain

Objective: Several glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1Ra) have been made recently available in Spain for type 2 diabetes mellitus (DM2) treatment. There are no published data on the clinical and sociodemographic profile of patients initiating treatment with GLP-1Ra in Spain. Our objective was to understand these patients' characteristics in a real-world clinical practice setting. Design: Cross-sectional observational study. Setting: Spanish specialist outpatient clinics. Participants: 403 adults with DM2 initiating GLP-1Ra treatment were included. Primary and secondary outcome measures: Sociodemographic and DM2-related clinical data, including treatment at and after GLP-1Ra initiation and comorbidities, were collected. Results: Evaluable patients (n=403; 50.9% female) were included ( July 2013 to March 2014) at 24 centres by 53 specialists (47 endocrinology, 6 internal medicine), with the following profile (value±SD): age (58.3±10.4 years), diabetes duration (9.9±7 years), body mass index (BMI; 36.2±5.5) and glycated haemoglobin (HbA1c; 8.4±1.4%); 14% had HbA1c≤7%. Previous antidiabetic treatment: 53.8% only oral antidiabetic drugs (OADs), 5.2% insulin and 40% insulin and OAD; of those receiving OAD, 35% single drug, 38.2% 2 drugs and 24% 3 drugs. Concomitant to GLP-1Ra, 55.3% were only on OAD, 36.2% on insulin and OAD, and 7.2% only on insulin. Of those receiving OAD, the GLP-1Ra was mainly associated with 1 drug (65%) or 2 drugs (31.8%). GLP-1Ra are frequently added to existing antidiabetic drugs, with dipeptidyl peptidase-4 inhibitors being the OAD most frequently switched (45% receiving 1 before starting GLP-1Ra, only 2.7% receiving it concomitantly). Conclusions: In Spain, GLP-1Ra therapy is usually started in combination with OADs or OADs and insulin. These drugs are used in relatively young patients often not reaching therapeutic goals with other treatment combinations, roughly a decade after diagnosis and with a relatively high BMI. The latter could be explaine