Impacto sobre el control metabólico y la calidad de vida de la adición de un sistema de monitorización continua de glucosa a tiempo real a pacientes con Diabetes tipo 1 en tratamiento intensivo con infuso continuo de insulina

El término diabetes engloba una serie de síndromes caracterizados por la aparición de hiperglucemia secundaria a un déficit de secreción de insulina, de su acción o bien ambas. La diabetes tipo 1 (DM1) tiene base autoinmune, produciéndose indefectiblemente un estado de insulinopenia que da lugar a hiperglucemia. Desde el DCCT se conoce la necesidad de un adecuado control metabólico en la DM1 por medio de una insulinoterapia intensiva para evitar la aparición de complicaciones crónicas secundarias a la hiperglucemia. Las nuevas tecnologías en DM1 engloban el tratamiento con infusor subcutáneo continuo de insulina(ISCI), los sistemas de monitorización continua de glucosa(SMCG-tr) y el uso de la telemedicina(TM) en el tratamiento/seguimiento de los pacientes diabéticos entre otros. El tratamiento ISCI, se basa en la infusión subcutánea de insulina (generalmente análogos de insulina rápida) de forma continua de forma que se genera un perfil más fisiológico de insulinoterapia con una línea o pauta basal y una administración de insulina en forma de bolos, prandiales (para cubrir la hiperglucemia de la ingesta) o correctores (para manejar picos de hiperglucemia). Los SMCG-tr son sistemas de sensor de glucosa en el espacio intersticial, de forma que el paciente recibe de forma contínua y a tiempo real ( con un cierto decalaje temporal) información glucémica completa, con incluso información de tendencias glucémicas según tasa de cambio o alarmas en determinados niveles de hiper o hipoglucemia. La TM, está en boga en el seguimiento particularmente de pacientes afectos de enfermedades crónicas, engloba diversas formas de contacto a distancia entre pacientes y personal sanitario, ya sea telefónica, via teleconferencia, via página web o por mail, entre otras. El uso de la TM ahorra al paciente desplazamientos al centro sanitario y evita ausencias laborales por este motivo. En esta tesis, se exponen varios estudios realizados en pacientes con DM1 en tratamiento con ISCI. En el estudio principal, se añadió al tratamiento ISCI de los pacientes un SMCG-tr. Se realizó una evaluación tras 3 meses de uso del sistema integrado de ISCI y SMCG-tr (SAP) el 100% del tiempo, y posteriormente una nueva evaluación tras 3 meses de uso del sistema SAP a tiempo parcial (50%).Tras esos dos periodos de uso del SMCG-tr, de 6 meses en total, se retiró el SMCG-tr y se evaluó nuevamente a los pacientes 3 meses más tarde. La evaluación que se realizó abarcaba tanto aspectos endocrino-metabólicos ( antropometría, control glucémico, variabilidad glucémica) como psicológicos y de calidad de vida, realizando asimismo una encuesta de satisfacción de uso del SMCG-tr. Tras 3 meses de uso del SMCG-tr el 100% del tiempo se redujo de forma estadísticamente significativa la HbA1c(-0,57%) y tras 3 meses de uso del SMCG-tr a tiempo parcial se redujo la HbA1c respecto a la basal de forma igualmente significativa (-0,42%). Entre los niveles de HbA1c a los 3 y 6 meses no hubo diferencias estadísticamente significativas. Tras 3 meses sin uso del SMCG-tr,ya con el tratamiento ISCI solamente, la HbA1c se deterioró nuevamente, con vuelta a un nivel semejante al basal (-0,05 sin diferencias significativas). En cuanto a hipoglucemias graves, se objetivó una reducción de HG graves en la evaluación a los 6 meses, así como un descenso de Hyposcore. No se objetivaron reducciones estadísticamente significativas de los parámetros de variabilidad glucémica, ni tampoco en valoración global de calidad de vida, aunque sí hubo reducción de miedo a hipoglucemias con el uso del SMCG-tr. A pesar de que la valoración global del SMCG-tr de los pacientes fue muy buena, con niveles superiores al 70 e incluso 80% de puntuaciones de satisfacción en la encuesta, sólo el 60% de los pacientes tras la finalización del estudio desearon continuar utilizando el sistema. En un segundo estudio, a los pacientes que continuaron utilizando el SMCG-tr, se les realizó seguimiento telemático ( vía email, con envíos mensuales), durante 6 meses, valorando de igual manera parámetros de control metabólico, variabilidad glucémica y calidad de vida. Se realizó una valoración prebasal, con un periodo de 6 meses con visita presencial y adiestramiento de uso del sistema telemático, posteriormente una valoración basal, a partir de la cual el contacto con el equipo sanitario fue mediante TM y una valoración 6 meses tras el inicio del seguimiento por TM. Se produjo una reducción estadísticamente significativa de HbA1c ( -0,27% respecto a basal, -0,53% respecto a prebasal) con el uso de la telemedicina (TM), con reducción asimismo de ciertos marcadores de variabilidad glucémica( MAGE, MODD). Se produjeron cambios en calidad de vida, particularmente en el subgrupo de pacientes sin complicaciones crónicas y en los de peor control metabólico inicial( HbA1c>7%). En un tercer estudio, se evaluó la adherencia al uso del sistema combinado SAP a largo plazo, 7 años después del estudio inicial, comprobando que sólo un 20% de los pacientes continuaban utilizando el sistema; aunque la HbA1c era menor en el grupo de pacientes que aún utilizaban el SMCG-tr frente a los que no lo hacían (6,58 vs. 7,07%)estas diferencias no llegaron a alcanzar significación estadística. Tampoco marcadores de variabilidad glucémica mostraban diferencias significativas. Entre las causas referidas por los pacientes para el abandono del sistema, la más frecuente fue el estrés que les generaba el sistema en su vida diaria, seguida de las molestias de las alarmas y finalmente la discordancia entre los datos del SMCG-tr y la glucemia capilar

Scoring personalized molecular portraits identify Systemic Lupus Erythematosus subtypes and predict individualized drug responses, symptomatology and disease progression

Objectives Systemic Lupus Erythematosus is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. Flares appear unpredictably during the disease course and therapies used are often only partially effective. These challenges are mainly due to the molecular heterogeneity of the disease, and in this context, personalized medicine-based approaches offer major promise. With this work we intended to advance in that direction by developing MyPROSLE, an omic-based analytical workflow for measuring the molecular portrait of individual patients to support clinicians in their therapeutic decisions. Methods Immunological gene-modules were used to represent the transcriptome of the patients. A dysregulation score for each gene-module was calculated at the patient level based on averaged z-scores. Almost 6100 Lupus and 750 healthy samples were used to analyze the association among dysregulation scores, clinical manifestations, prognosis, flare and remission events and response to Tabalumab. Machine learning-based classification models were built to predict around 100 different clinical parameters based on personalized dysregulation scores. Results MyPROSLE allows to molecularly summarize patients in 206 gene-modules, clustered into nine main lupus signatures. The combination of these modules revealed highly differentiated pathological mechanisms. We found that the dysregulation of certain gene-modules is strongly associated with specific clinical manifestations, the occurrence of relapses or the presence of long-term remission and drug response. Therefore, MyPROSLE may be used to accurately predict these clinical outcomes. Conclusions MyPROSLE (https://myprosle.genyo.es) allows molecular characterization of individual Lupus patients and it extracts key molecular information to support more precise therapeutic decisions.PID2020-119032RB-I00 supported by MCIN/AEI/10.13039/501100011033FEDER and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR)European Union’s Horizon 2020EFPIAFEDER/Junta de Andalucía-Consejer’a de Transformación Económica, Industria, Conocimiento y Universidades (grants P20_00335 and B-CTS-40-UGR20)‘Consejería de Transformación Económica, Industria, Conocimiento y Universidades’ (CTEICU)European Union through the European Social Fund (ESF) named ‘Andalucía se mueve con Europa”Andalusian ESF Operational Program 2014–2020ISCIII CD18/00149Ministerio de Universidades (Spain’s Government) and the European Union – NextGenerationE

Píldoras Educativas para la Elaboración del Trabajo Final de Grado en Estudios Ingleses (Lengua y Lingüística).

Este proyecto plantea elaborar un módulo, estructurado en píldoras educativas (o mini-videos didácticos), para dar una visión general a los estudiantes del último curso de grado de cómo abordar la escritura del TFG

Personal care product use and lifestyle affect phthalate and DINCH metabolite levels in teenagers and young adults

Humans are widely exposed to phthalates and their novel substitutes, and considering the negative health effects associated with some phthalates, it is crucial to understand population levels and exposure determinants. This study is focused on 300 urine samples from teenagers (aged 12-17) and 300 from young adults (aged 18-37) living in Czechia collected in 2019 and 2020 to assess 17 plasticizer metabolites as biomarkers of exposure. We identified widespread phthalate exposure in the study population. The diethyl phthalate metabolite monoethyl phthalate (MEP) and three di (2-ethylhexyl) phthalate metabolites were detected in the urine of >99% of study participants. The highest median concentrations were found for metabolites of low-molecular-weight (LMW) phthalates: mono-n-butyl phthalate (MnBP), monoisobutyl phthalate (MiBP) and MEP (60.7; 52.6 and 17.6 μg/L in young adults). 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) metabolites were present in 68.2% of the samples with a median of 1.24 μg/L for both cohorts. Concentrations of MnBP and MiBP were similar to other European populations, but 5-6 times higher than in populations in North America. We also observed large variability in phthalate exposures within the study population, with 2-3 orders of magnitude differences in urinary metabolites between high and low exposed individuals. The concentrations varied with season, gender, age, and lifestyle factors. A relationship was found between high levels of MEP and high overall use of personal care products (PCPs). Cluster analysis suggested that phthalate exposures depend on season and multiple lifestyle factors, like time spent indoors and use of PCPs, which combine to lead to the observed widespread presence of phthalate metabolites in both study populations. Participants who spent more time indoors, particularly noticeably during colder months, had higher levels of high-molecular weight phthalate metabolites, whereas participants with higher PCP use, particularly women, tended to have higher concentration of LMW phthalate metabolites.Authors thank the Research Infrastructure RECETOX RI (No. LM2018121) and CETOCOEN EXCELLENCE (CZ.02.1.01/0.0/0.0/17_043/0009632) for a supportive background. The work was supported by the Operational Programme Research, Development and Innovation – project Cetocoen Plus (CZ.02.1.01/0.0/0.0/15_003/0000469) and the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 857560. This study has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 733032. We thank all collaborating field workers, laboratory and administrative personnel, and especially the cohort participants who invested their time and provided samples and information for this study. This study reflects only the authors’ view and the European Commission is not responsible for any use that may be made of the information it contains.S

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3′-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence

Association of the PLCB1 gene with drug dependence

Genetic factors involved in the susceptibility to drug addiction still remain largely unknown. MiRNAs seem to play key roles in the drug-induced plasticity of the brain that likely drives the emergence of addiction. In this work we explored the role of miRNAs in drug addiction. With this aim, we selected 62 SNPs located in the 3'UTR of target genes that are predicted to alter the binding of miRNA molecules and performed a case-control association study in a Spanish sample of 735 cases (mainly cocaine-dependent subjects with multiple drug dependencies) and 739 controls. We found an association between rs1047383 in the PLCB1 gene and drug dependence that was replicated in an independent sample (663 cases and 667 controls). Then we selected 9 miRNAs predicted to bind the rs1047383 region, but none of them showed any effect on PLCB1 expression. We also assessed two miRNAs binding a region that contains a SNP in linkage disequilibrium with rs1047383, but although one of them, hsa-miR-582, was found to downregulate PLCB1, no differences were observed between alleles. Finally, we explored the possibility that PLCB1 expression is altered by cocaine and we observed a significant upregulation of the gene in the nucleus accumbens of cocaine abusers and in human dopaminergic-like neurons after cocaine treatment. Our results, together with previous studies, suggest that PLCB1 participates in the susceptibility to drug dependence

Cellular senescence is immunogenic and promotes anti-tumor immunity

Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DCs) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of interferon signaling, enhanced MHC class I machinery, and presentation of senescence-specific self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong anti-tumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.his work was supported by grants from Fondo de Investigación Sanitaria (FIS-PI16/2053) to LA and LG-G. The project has been co-financed with FEDER funds. ML-N was co-financed by Fondo Social Europeo, Programa Operativo de empleo juvenil (YEI)

Desarrollo de estrategias discursivas de posicionamiento en los trabajos científicos universitarios (TFGs, TFMs, TDs, y AC): Análisis de los géneros discursivos, propuestas para la formación y elaboración de píldoras educativas

El presente proyecto reúne a docentes e investigadoras de dos grupos de investigación UCM consolidados del Departamento de Estudios Ingleses, “Discurso y comunicación en lengua inglesa: estudios de lingüística cognitiva y funcional” (DISCOM-COGFUNC) (930160) y “Lingüística funcional (ingles-español) y sus aplicaciones (FUNCAP)”, que imparten asignaturas afines. Todas las integrantes del equipo han formado parte al menos de uno de los dos proyectos de innovación previos, Innova-2015-188 e Innova-2016-123, sobre Objetos de Aprendizaje Reutilizable (OARs), como son las píldoras educativas, dando así muestra de una continuidad del trabajo en la innovación educativa en el campo de la docencia de lengua y lingüística inglesas. Los objetivos generales propuestos en la solicitud del proyecto han sido la formación de estudiantes y profesores en el uso y desarrollo de estrategias discursivas de posicionamiento en: (a) los trabajos científicos universitarios (TFGs, TFMs, TDs), y (b) los artículos de investigación de los docentes. Se trataba de llevar a cabo el análisis de estos géneros discursivos, realizar propuestas para la formación en el uso de estrategias discursivas, y elaborar materiales y píldoras educativas adecuadas a cada contexto de aprendizaje

HBM4EU-MOM: Prenatal methylmercury-exposure control in five countries through suitable dietary advice for pregnancy – Study design and characteristics of participants

Background: Seafood is a major source of vital nutrients for optimal fetal growth, but at the same time is the main source of exposure to methylmercury (MeHg), an established neurodevelopmental toxicant. Pregnant women must be provided with dietary advice so as to include safely fish in their diet for nutrition and mercury control. The aim of this work is to present the design of a multicentre randomized control trial (RCT), which combines human biomonitoring (HBM) with dietary interventions using seafood consumption advice to pregnant women for MeHg control, and to collect information about other possible sources of exposure to mercury. It also presents the materials developed for the implementation of the study and the characteristics of the study participants, which were self-reported in the first trimester of pregnancy. Methods: The "HBM4EU-MOM" RCT was performed in the frame of the European Human Biomonitoring Initiative (HBM4EU) in five coastal, high fish-consuming European countries (Cyprus, Greece, Spain, Portugal and Iceland). According to the study design, pregnant women (≥120/country, ≤20 weeks gestational age) provided a hair sample for total mercury assessment (THg) and personal information relevant to the study (e.g., lifestyle, pregnancy status, diet before and during the pregnancy, information on seafood and factors related to possible non-dietary exposures to mercury) during the first trimester of pregnancy. After sampling, participants were randomly assigned to "control" (habitual practices) or "intervention" (received the harmonized HBM4EU-MOM dietary advice for fish consumption during the pregnancy and were encouraged to follow it). Around child delivery, participants provided a second hair sample and completed another tailored questionnaire. Results: A total of 654 women aged 18-45 years were recruited in 2021 in the five countries, primarily through their health-care providers. The pre-pregnancy BMI of the participants ranged from underweight to obese, but was on average within the healthy range. For 73% of the women, the pregnancy was planned. 26% of the women were active smokers before the pregnancy and 8% continued to smoke during the pregnancy, while 33% were passive smokers before pregnancy and 23% remained passively exposed during the pregnancy. 53% of the women self-reported making dietary changes for their pregnancy, with 74% of these women reporting making the changes upon learning of their pregnancy. Of the 43% who did not change their diet for the pregnancy, 74% reported that their diet was already balanced, 6% found it difficult to make changes and 2% were unsure of what changes to make. Seafood consumption did not change significantly before and during the first trimester of pregnancy (overall average ∼8 times per month), with the highest frequency reported in Portugal (≥15 times per month), followed by Spain (≥7 times per month). During the first-trimester of pregnancy, 89% of the Portuguese women, 85% of the Spanish women and 90%) were unaware of safe procedures for handling spillage from broken thermometers and energy-saving lamps, though >22% experienced such an incident (>1 year ago). 26% of the women had dental amalgams. ∼1% had amalgams placed and ∼2% had amalgams removed during peri-pregnancy. 28% had their hair dyed in the past 3 months and 40% had body tattoos. 8% engaged with gardening involving fertilizers/pesticides and 19% with hobbies involving paints/pigments/dyes. Conclusions: The study design materials were fit for the purposes of harmonization and quality-assurance. The harmonized information collected from pregnant women suggests that it is important to raise the awareness of women of reproductive age and pregnant women about how to safely include fish in their diet and to empower them to make proper decisions for nutrition and control of MeHg, as well as other chemical exposures.We acknowledge funding for HBM4EU from the European Union’s Horizon 2020 research and innovation program under grant agreement #733032 and the national governments of the participating countries. This publication reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the in formation it contains.info:eu-repo/semantics/publishedVersio