Common Variants in 22 Genes Regulate Response to Metformin Intervention in Children with Obesity: A Pharmacogenetic Study of a Randomized Controlled Trial

Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin’s action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES).This research was funded by the Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products (codes and beneficiaries: EC10-243, Ramón Cañete, Reina Sofía Hospital, Córdoba; EC10-056, Ángel Gil, University of Granada and Virgen de las Nieves University Hospital, Granada; EC10-281, Rosaura Leis, Clinic University Hospital of Santiago, Santiago de Compostela; and EC10-227, Gloria Bueno, Lozano Blesa University Clinical Hospital, Zaragoza

Extracellular vesicles from pristane-treated CD38-deficient mice express an antiinflammatory neutrophil protein signature, which reflects the mild lupus severity elicited in these mice

In CD38-deficient (Cd38-/-) mice intraperitoneal injection of pristane induces a lupus-like disease, which is milder than that induced in WT mice, showing significant differences in the inflammatory and autoimmune processes triggered by pristane. Extracellular vesicles (EV) are present in all body fluids. Shed by cells, their molecular make-up reflects that of their cell of origin and/or tissue pathological situation. The aim of this study was to analyze the protein composition, protein abundance, and functional clustering of EV released by peritoneal exudate cells (PECs) in the pristane experimental lupus model, to identify predictive or diagnostic biomarkers that might discriminate the autoimmune process in lupus from inflammatory reactions and/or normal physiological processes. In this study, thanks to an extensive proteomic analysis and powerful bioinformatics software, distinct EV subtypes were identified in the peritoneal exudates of pristane-treated mice: 1) small EV enriched in the tetraspanin CD63 and CD9, which are likely of exosomal origin; 2) small EV enriched in CD47 and CD9, which are also enriched in plasma-membrane, membrane-associated proteins, with an ectosomal origin; 3) small EV enriched in keratins, ECM proteins, complement/coagulation proteins, fibrin clot formation proteins, and endopetidase inhibitor proteins. This enrichment may have an inflammation-mediated mesothelial-tomesenchymal transition origin, representing a protein corona on the surface of peritoneal exudate EV; 4) HDL-enriched lipoprotein particles. Quantitative proteomic analysis allowed us to identify an anti-inflammatory, Annexin A1- enriched pro-resolving, neutrophil protein signature, which was more prominent in EV from pristane-treated Cd38-/- mice, and quantitative differences in the protein cargo of the ECM-enriched EV from Cd38-/- vs WT mice. These differences are likely to be related with the distinct inflammatory outcome shown by Cd38-/- vs WT mice in response to pristane treatment. Our results demonstrate the power of a hypothesis-free and data-driven approach to transform the heterogeneity of the peritoneal exudate EV from pristanetreated mice in valuable information about the relative proportion of different EV in a given sample and to identify potential protein markers specific for the different small EV subtypes, in particular those proteins defining EV involved in the resolution phase of chronic inflammation.Proyecto del plan estatal, Ministerio de Ciencia e Innovacion PT13/0001/011CSIC PT17/0019/0010 PID2020-119567RB-I0

Older Adult Patients in the Emergency Department: Which Patients should be Selected for a Different Approach?

Background: While multidimensional and interdisciplinary assessment of older adult patients improves their short-term outcomes after evaluation in the emergency department (ED), this assessment is time-consuming and ill-suited for the busy environment. Thus, identifying patients who will benefit from this strategy is challenging. Therefore, this study aimed to identify older adult patients suitable for a different ED approach as well as independent variables associated with poor short-term clinical outcomes. Methods: We included all patients >= 65 years attending 52 EDs in Spain over 7 days. Sociodemographic, comorbidity, and baseline functional status data were collected. The outcomes were 30 -day mortality, re -presentation, hospital readmission, and the composite of all outcomes. Results: During the study among 96,014 patients evaluated in the ED, we included 23,338 patients >= 65 years-mean age, 78.4 +/- 8.1 years; 12,626 (54.1%) women. During follow-up, 5,776 patients (24.75%) had poor outcomes after evaluation in the ED: 1,140 (4.88%) died, 4,640 (20.51) returned to the ED, and 1,739 (7.69%) were readmitted 30 days after discharge following the index visit. A model including male sex, age >= 75 years, arrival by ambulance, Charlson Comorbidity Index >= 3, and functional impairment had a C -index of 0.81 (95% confidence interval, 0.80-0.82) for 30 -day mortality. Conclusion: Male sex, age >= 75 years, arrival by ambulance, functional impairment, or severe comorbidity are features of patients who could benefit from approaches in the ED different from the common triage to improve the poor short-term outcomes of this population

Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies

Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.This work was supported by Novartis Pharmaceuticals Spain

Innovación en las enseñanzas universitarias: experiencias presentadas en las III Jornadas de Innovación Educativa de la ULL

En este libro se recoge un conjunto de experiencias de innovación educativa desarrolladas en la ULL en el curso 2011-12. Se abordan distintos ámbitos y ramas del conocimiento, y ocupan temáticas variadas que han sido desarrolladas con rigor, y con un claro potencial para su extrapolación a efectos de la mejora educativa en el ámbito universitario. Esta publicación constituye una primera edición de una serie que irá recogiendo las experiencias de innovación educativa de la ULL. Este es un paso relevante para su impulso en nuestra institución, como lo es el de su vinculación con la investigación educativa, para potenciar su publicación en las revistas científicas en este ámbito cada vez más pujante y relevante para las universidades. Sobre todo representan el deseo y el compromiso del profesorado de la ULL para la mejora del proceso educativo mediante la investigación, la evaluación y la reflexión compartida de nuestras prácticas y planteamientos docentes

Evaluation of the inter and intraobserver reproducibility of the “defect coverage index method”, a new computed tomography assessment method of sagittal graft positioning in arthroscopic bone block procedures

Abstract Purpose To assess the reproducibility of a new 2-dimensional computed tomography (CT) method of assessing graft positioning in arthroscopic bone block procedure. Methods This is a prospective observational study. Twenty-seven patients, (all men, mean [Standard deviation] age at surgery 30.9 [8.49] years) were included. Vertical graft position was assessed on the sagittal view by measuring the amount of glenoid bone defect covered by the graft. The length of the bone defect and the amount of graft covering the defect were measured. Positioning of the graft on the sagittal plane was classified as accurate if the graft covered at least 90% of the defect. Intraobserver and interobserver reproducibility was analyzed using intraclass correlation coefficients (ICC) and Kappa coefficient with 95% confidence. Results Excellent intraobserver reproducibility was found, with an ICC of 0.94 (CI 95%, 0.86-0.97). Interobserver reproducibility was good, with the ICC value of 0.71, ranging from 0.45 to 0.86 (CI 95%). Conclusion This new method of assessing graft positioning in arthroscopic bone block procedures on 2-dimensional computed tomography scans is reliable, with an excellent intraobserver and good interobserver reproducibility. Level of evidence II

Daño autoinducido e ideación suicida en adolescentes: perfil de los pacientes y factores de riesgo

La ideación suicida, el suicidio y el daño autoinducidono suicida son trastornos frecuentes entre población joven y se están incrementando. La relación entre esos procesos es incierta pero probablemente existe y refleja trastornos psiquiátricos importantes.Revisamos la casuística de los menores de 19 años que acudieron a nuestra urgencia por intento de suicidio, ideación suicida o daño autoinducido no suicida (DAINS) a lo largo del año 2018, analizar en ellos diferentes variables sicosociales que permitan analizar el perfil de estos jóvenes y establecer una mejor identificación de los mismos.36 pacientes cumplían el criterio. Fueron adolescentes, predominantemente mujeres, conalgún episodio previo similar. Frecuentemente existe algún tipo de trastorno de la esfera psico-psiquiátrica, recibían medicación antidepresiva previamente al episodio, sin ser infrecuente el consumo de sustancias. El mecanismo lesivo elegido habitual es la ingesta de sustancias (47%) si bien el uso de arma blanca como método para la autolesión ocurrió en 8 casos (22,2%). En un 60% existe algún tipo de antecedente de salud mental, existiendo conflictividad familiar en hasta el 43% (divorcio, y violencia de género). Del total de pacientes sólo uno precisó hospitalización, el caso de anorexia grave con ideación suicida (2,8%).El DAINS y la ideación suicida son comportamientos que deben ser tenidos muy en cuenta pues pueden estar ligados al suicidio y no son simplemente una llamada de atención. Son el reflejo de trastornos psicosociales que deben ser atendidos adecuadamente.Suicidal ideation, suicide, and non-suicidal self-harm are frequent disorders among the young population and are increasing. The relationship between these processes is uncertain but probably exists and reflects important psychiatric disorders.We review the records of those under 19 who have come to our emergency room for attempted suicide, suicidal ideation or nonsuicidal self-harm (NSSH) throughout 2018, analyzing different psychosocial variables in them that allow us to identify the profile of these young people and to establish a better identification of them.36 patients met the criteria. They were teenagers, predominantly women, with a previous similar episode, often with some kind of disorder of the psycho-psychiatric sphere, among which is not infrequent the consumption of legal and illegal substances. It is common that they are receiving antidepressant medication prior to the episode, especially women. The usual chosen harmful mechanism was substance intake (47%), although the use of a self-cutting as a method for self-harm occurred in 8 cases (22.2%). 60% recognize some type of mental health history and in which there is family conflict in up to 43% (divorce, and gender violence). Of the total of patients, only one required hospitalization, a case of severe anorexia with suicidal ideation (2.8%).NSSH and suicidal ideation are behaviors that must be taken into account because they can be linked to suicide and are not simply a wake-up call. They are the reflection of psychosocial disorders that must be adequately addresse

Evaluación prospectiva y controlada de las características técnicas de un nuevo ecoendoscopio de punción frontal

RESUMEN Introducción: la ultrasonografía endoscópica (USE) es una técnica de gran utilidad en el diagnóstico y tratamiento de distintas patologías del tracto digestivo. Objetivo: evaluar de forma prospectiva la utilidad clínica de un nuevo ecoendoscopio de visión frontal (FV-CLA). Métodos: estudio observacional transversal. Todos los pacientes sometidos a una USE durante un periodo de dos meses fueron evaluados para su inclusión en el estudio. Se analizaron de forma sistemática todas las estaciones mediastínicas, perigástricas y periduodenales (evaluando la facilidad de obtener los cortes ultrasonográficos y la calidad de los mismos) y se realizó punción de las lesiones indicadas clínicamente. Resultados: se incluyeron un total de 45 pacientes. La exploración ecoendoscópica pudo ser completada en el 100% de los pacientes, registrándose dos complicaciones menores. La manejabilidad del ecoendoscopio fue catalogada como sobresaliente; la visibilidad global del plano USE, como notable; y tan solo la visualización USE de las estaciones 4L y 5 fue puntuada como insuficiente. La visualización del páncreas y del resto de las estaciones USE fue puntuada como sobresaliente o notable. La facilidad de realizar punción, incluso desde la segunda porción duodenal, fue puntuada como notable o sobresaliente. Conclusión: el FV-CLA permite realizar una exploración completa y de calidad en el tracto digestivo superior, incluyendo punciones. Existen algunas estaciones mediastínicas que parecen poco accesibles para este nuevo aparato. Sería interesante validar la utilidad del FV-CLA en la terapéutica guiada por USE

Does the C34T mutation in AMPD1 alter exercise capacity in the elderly?

Ageing does affect functional capacity through several changes at the peripheral muscle level that impair the muscles capacity to produce energy and generate force. The skeletal muscle-specific isoform of AMP deaminase (AMPD) plays an important regulatory role in muscle metabolism and in determining energy charge. Since nearly 20 % of the general Caucasian population is heterozygous (CT) for the most common C34T mutation of the gene (AMPD1) encoding for this enzyme, it would be worthwhile to study if such a condition further increases the effects of ageing. Twenty-one women (61 - 80 yrs) served as subjects, and depending on the results of previous genotyping, were assigned to a group with the C34T mutation (heterozygous; n = 4; mean ± SEM age: 71 ± 1 yrs) or with no mutation (n = 17; 68 ± 1 yrs). Several indices of maximal (peak oxygen uptake [VO↓2peak], peak power output) and submaximal endurance performance (ventilatory threshold, mechanical efficiency) and functional tests (one-mile walk test and a specific test of lower-body functional performance [sit-stand test]) were compared between the two groups. No significant differences were found in exercise capacity between both groups, e. g. VO↓2peak of 19.1 ± 1.0 vs. 20.1 ± 1.9 ml · kg↑-1 · min↑-1, VO↓2 at the VT of 11.9 ± 0.6 vs. 12.9 ± 1.0 ml · kg↑-1 · min↑-1, or time to complete the one-mile walk test (951 ± 18 s vs. 962 ± 61 s) and sit-stand test (9.9 ± 0.2 vs. 9.2 ± 0.2) (no mutation vs. C34T mutation, respectively). Although more research is necessary, it seems that the C34T mutation of the AMPD1, at least in heterozygous individuals, does not affect functional capacity in the elderly.Sin financiación1.240 JCR (2006) Q2, 31/73 Sport sciencesUE